Hematology Times

Blood for transfusion

Photo by Elise Amendola

Certain methods of manufacturing red cell concentrates (RCCs) may be less damaging than others, according to research published in Vox Sanguinis.

The study showed that damage-associated molecular patterns (DAMPs) in stored blood differ according to the process and materials used to collect or prepare RCCs for transfusion.

Researchers believe this discovery could help reduce adverse reactions in transfusion recipients and potentially impact how blood is collected around the world.

To conduct this study, the researchers compared RCCs collected at blood donation centers in the US and Canada. The team examined the influence of manufacturing methods on the levels of mitochondrial (mt) DNA and extracellular vesicle (EV) DAMPs in RCCs.

“Working with the American team at Blood Systems Research Institute was key to this research because of the wide variations in blood manufacturing processes present in the US,” said Jason Acker, PhD, of Canadian Blood Services’ Centre for Innovation in Edmonton, Alberta.

“In countries like Canada, where there is a national blood service, manufacturing methods are largely standardized, so it is difficult to compare various methods. But blood collection in the US is characterized by dozens of independent blood centers that use a variety of available manufacturing processes. The Americans provided the variations we needed to measure red cell damage and to ascertain whether it can be attributed to different manufacturing methods.”

Manufacturing methods

The researchers evaluated 87 RCCs prepared using 9 different methods, outlined in the following table.

Results

For all RCCs, the researchers assessed the levels of mtDNA and the number and cell of origin of EVs on storage days 5 and 42.

They observed a 100-fold difference in mtDNA levels between the different methods.

The highest mtDNA levels were in the non-leukoreduced RCCs, followed by the MCS+ and Trima apheresis RCCs. The mean levels were 5.3 x 10⁵ copies/µL, 1.3 x 10⁵ copies/µL, and 1.2 x 10⁵ copies/µL, respectively.

The lowest mtDNA levels were seen with the semi-automated methods. The mean levels ranged from 3.8 x 10³ copies/µL to 5.9 x 10³ copies/µL.

The researchers also saw a 10-fold difference in EV levels between the different methods.

The team detected red blood cell-derived CD235a+ EVs in fresh RCCs, which increased in most RCCs over the storage period (but not for FenBC and MCS+).

Platelet-derived CD41a+ EVs were highest in non-leukoreduced and Trima RCCs and did not change significantly during storage.

White blood cell-derived CD11b+ and CD66b+ EVs were low in most RCCs (though not in Trima and FenMAN-non-LR RCCs), and their levels did not significantly change during storage.

White blood cell-derived CD14+ EVs were negligible in fresh RCCs but increased in several RCCs during storage (FenMAN, Alyx, MCS+, and Trima).

Next steps

“There must be more testing of the apheresis collections equipment, blood bags, leukoreduction filters, and other variations in manufacturing methods to determine what single element or combination of elements in the various red blood cell manufacturing processes result in high levels of DAMPs and why,” said Michael Busch, MD, PhD, of Blood Systems Research Institute in San Francisco, California.

“We also need to understand how mitochondrial DAMPs are involved in adverse reactions to red blood cell transfusions,” added Sonia Bakkour, PhD, also from Blood Systems Research Institute.

“Some recently published studies on platelet components link high levels of mitochondrial DAMPs to adverse transfusion reactions. We need to see if DAMPs have similar adverse effects on recipients of red blood cell transfusions.”

“We think that our research could lead to finding the best way to manufacture red blood cells,” Dr Acker noted.

“It’s clear now that manufacturing methods matter. We . . . are keen to explore what’s in the blood bag or in the filters or in the tubing, for example, that can be minimized or eliminated, improving the outcome in patients who receive blood transfusions.”

Blood for transfusion

Photo by Elise Amendola

Certain methods of manufacturing red cell concentrates (RCCs) may be less damaging than others, according to research published in Vox Sanguinis.

The study showed that damage-associated molecular patterns (DAMPs) in stored blood differ according to the process and materials used to collect or prepare RCCs for transfusion.

Researchers believe this discovery could help reduce adverse reactions in transfusion recipients and potentially impact how blood is collected around the world.

To conduct this study, the researchers compared RCCs collected at blood donation centers in the US and Canada. The team examined the influence of manufacturing methods on the levels of mitochondrial (mt) DNA and extracellular vesicle (EV) DAMPs in RCCs.

“Working with the American team at Blood Systems Research Institute was key to this research because of the wide variations in blood manufacturing processes present in the US,” said Jason Acker, PhD, of Canadian Blood Services’ Centre for Innovation in Edmonton, Alberta.

“In countries like Canada, where there is a national blood service, manufacturing methods are largely standardized, so it is difficult to compare various methods. But blood collection in the US is characterized by dozens of independent blood centers that use a variety of available manufacturing processes. The Americans provided the variations we needed to measure red cell damage and to ascertain whether it can be attributed to different manufacturing methods.”

Manufacturing methods

The researchers evaluated 87 RCCs prepared using 9 different methods, outlined in the following table.

Results

For all RCCs, the researchers assessed the levels of mtDNA and the number and cell of origin of EVs on storage days 5 and 42.

They observed a 100-fold difference in mtDNA levels between the different methods.

The highest mtDNA levels were in the non-leukoreduced RCCs, followed by the MCS+ and Trima apheresis RCCs. The mean levels were 5.3 x 10⁵ copies/µL, 1.3 x 10⁵ copies/µL, and 1.2 x 10⁵ copies/µL, respectively.

The lowest mtDNA levels were seen with the semi-automated methods. The mean levels ranged from 3.8 x 10³ copies/µL to 5.9 x 10³ copies/µL.

The researchers also saw a 10-fold difference in EV levels between the different methods.

The team detected red blood cell-derived CD235a+ EVs in fresh RCCs, which increased in most RCCs over the storage period (but not for FenBC and MCS+).

Platelet-derived CD41a+ EVs were highest in non-leukoreduced and Trima RCCs and did not change significantly during storage.

White blood cell-derived CD11b+ and CD66b+ EVs were low in most RCCs (though not in Trima and FenMAN-non-LR RCCs), and their levels did not significantly change during storage.

White blood cell-derived CD14+ EVs were negligible in fresh RCCs but increased in several RCCs during storage (FenMAN, Alyx, MCS+, and Trima).

Next steps

“There must be more testing of the apheresis collections equipment, blood bags, leukoreduction filters, and other variations in manufacturing methods to determine what single element or combination of elements in the various red blood cell manufacturing processes result in high levels of DAMPs and why,” said Michael Busch, MD, PhD, of Blood Systems Research Institute in San Francisco, California.

“We also need to understand how mitochondrial DAMPs are involved in adverse reactions to red blood cell transfusions,” added Sonia Bakkour, PhD, also from Blood Systems Research Institute.

“Some recently published studies on platelet components link high levels of mitochondrial DAMPs to adverse transfusion reactions. We need to see if DAMPs have similar adverse effects on recipients of red blood cell transfusions.”

“We think that our research could lead to finding the best way to manufacture red blood cells,” Dr Acker noted.

“It’s clear now that manufacturing methods matter. We . . . are keen to explore what’s in the blood bag or in the filters or in the tubing, for example, that can be minimized or eliminated, improving the outcome in patients who receive blood transfusions.”

Blood for transfusion

Photo by Elise Amendola

Certain methods of manufacturing red cell concentrates (RCCs) may be less damaging than others, according to research published in Vox Sanguinis.

The study showed that damage-associated molecular patterns (DAMPs) in stored blood differ according to the process and materials used to collect or prepare RCCs for transfusion.

Researchers believe this discovery could help reduce adverse reactions in transfusion recipients and potentially impact how blood is collected around the world.

To conduct this study, the researchers compared RCCs collected at blood donation centers in the US and Canada. The team examined the influence of manufacturing methods on the levels of mitochondrial (mt) DNA and extracellular vesicle (EV) DAMPs in RCCs.

“Working with the American team at Blood Systems Research Institute was key to this research because of the wide variations in blood manufacturing processes present in the US,” said Jason Acker, PhD, of Canadian Blood Services’ Centre for Innovation in Edmonton, Alberta.

“In countries like Canada, where there is a national blood service, manufacturing methods are largely standardized, so it is difficult to compare various methods. But blood collection in the US is characterized by dozens of independent blood centers that use a variety of available manufacturing processes. The Americans provided the variations we needed to measure red cell damage and to ascertain whether it can be attributed to different manufacturing methods.”

Manufacturing methods

The researchers evaluated 87 RCCs prepared using 9 different methods, outlined in the following table.

Results

For all RCCs, the researchers assessed the levels of mtDNA and the number and cell of origin of EVs on storage days 5 and 42.

They observed a 100-fold difference in mtDNA levels between the different methods.

The highest mtDNA levels were in the non-leukoreduced RCCs, followed by the MCS+ and Trima apheresis RCCs. The mean levels were 5.3 x 10⁵ copies/µL, 1.3 x 10⁵ copies/µL, and 1.2 x 10⁵ copies/µL, respectively.

The lowest mtDNA levels were seen with the semi-automated methods. The mean levels ranged from 3.8 x 10³ copies/µL to 5.9 x 10³ copies/µL.

The researchers also saw a 10-fold difference in EV levels between the different methods.

The team detected red blood cell-derived CD235a+ EVs in fresh RCCs, which increased in most RCCs over the storage period (but not for FenBC and MCS+).

Platelet-derived CD41a+ EVs were highest in non-leukoreduced and Trima RCCs and did not change significantly during storage.

White blood cell-derived CD11b+ and CD66b+ EVs were low in most RCCs (though not in Trima and FenMAN-non-LR RCCs), and their levels did not significantly change during storage.

White blood cell-derived CD14+ EVs were negligible in fresh RCCs but increased in several RCCs during storage (FenMAN, Alyx, MCS+, and Trima).

Next steps

“There must be more testing of the apheresis collections equipment, blood bags, leukoreduction filters, and other variations in manufacturing methods to determine what single element or combination of elements in the various red blood cell manufacturing processes result in high levels of DAMPs and why,” said Michael Busch, MD, PhD, of Blood Systems Research Institute in San Francisco, California.

“We also need to understand how mitochondrial DAMPs are involved in adverse reactions to red blood cell transfusions,” added Sonia Bakkour, PhD, also from Blood Systems Research Institute.

“Some recently published studies on platelet components link high levels of mitochondrial DAMPs to adverse transfusion reactions. We need to see if DAMPs have similar adverse effects on recipients of red blood cell transfusions.”

“We think that our research could lead to finding the best way to manufacture red blood cells,” Dr Acker noted.

“It’s clear now that manufacturing methods matter. We . . . are keen to explore what’s in the blood bag or in the filters or in the tubing, for example, that can be minimized or eliminated, improving the outcome in patients who receive blood transfusions.”

Prescription medications

Photo courtesy of the CDC

The US Food and Drug Administration (FDA) has granted accelerated approval for venetoclax (Venclexta) to treat patients with chronic lymphocytic leukemia (CLL) who have 17p deletion and have received at least one prior therapy.

Venetoclax will be available in the US within about a week, according to the companies developing the drug, AbbVie and Genentech (a member of the

Roche Group).

The companies said they plan to offer patient assistance programs for qualifying patients who wish to receive venetoclax.

Venetoclax (formerly ABT-199) is the first FDA-approved treatment that targets the BCL-2 protein, which is overexpressed in many patients with CLL.

The drug is indicated for daily use after 17p deletion is confirmed via the FDA-approved companion diagnostic Vysis CLL FISH probe kit, which is manufactured by Abbott Molecular.

The FDA granted venetoclax accelerated approval rather than traditional approval because the drug has not yet shown a clinical benefit. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of venetoclax for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted venetoclax breakthrough therapy designation, priority review status, and orphan drug designation.

Phase 2 trial

Results from the pivotal phase 2 trial of venetoclax (M13-982, NCT01889186) were presented at the 2015 ASH Annual Meeting. According to those data, 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.

Eighty-five patients responded to treatment, for an overall response rate of 79.4%. Eight patients (7.5%) achieved a complete response or complete response with incomplete count recovery, 3 (2.8%) had a near partial response, and 74 (69.2%) had a partial response. Twenty-two patients (20.6%) did not respond.

As of the ASH presentation, 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 72.0%, and the overall survival estimate was 86.7%.

Treatment-emergent adverse events of any grade occurred in 96% of patients. The most frequent were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), fatigue (22%), pyrexia (20%), thrombocytopenia (19%), hyperphosphatemia (16%), vomiting (15%), and upper respiratory tract infection (15%). (About 22% of patients had neutropenia at baseline.)

The most frequent grade 3/4 adverse events were neutropenia (40%), anemia (18%), and thrombocytopenia (15%). Infections occurred in 72% of patients, with 20% of patients experiencing grade 3 or higher infections.

Serious adverse events occurred in 55% of patients, the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Laboratory tumor lysis syndrome (TLS) occurred in 5 patients during the ramp-up period only. Two patients required a dose interruption of 1 day each. There were no clinical TLS events.

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.

Venetoclax is currently being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Prescription medications

Photo courtesy of the CDC

The US Food and Drug Administration (FDA) has granted accelerated approval for venetoclax (Venclexta) to treat patients with chronic lymphocytic leukemia (CLL) who have 17p deletion and have received at least one prior therapy.

Venetoclax will be available in the US within about a week, according to the companies developing the drug, AbbVie and Genentech (a member of the

Roche Group).

The companies said they plan to offer patient assistance programs for qualifying patients who wish to receive venetoclax.

Venetoclax (formerly ABT-199) is the first FDA-approved treatment that targets the BCL-2 protein, which is overexpressed in many patients with CLL.

The drug is indicated for daily use after 17p deletion is confirmed via the FDA-approved companion diagnostic Vysis CLL FISH probe kit, which is manufactured by Abbott Molecular.

The FDA granted venetoclax accelerated approval rather than traditional approval because the drug has not yet shown a clinical benefit. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of venetoclax for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted venetoclax breakthrough therapy designation, priority review status, and orphan drug designation.

Phase 2 trial

Results from the pivotal phase 2 trial of venetoclax (M13-982, NCT01889186) were presented at the 2015 ASH Annual Meeting. According to those data, 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.

Eighty-five patients responded to treatment, for an overall response rate of 79.4%. Eight patients (7.5%) achieved a complete response or complete response with incomplete count recovery, 3 (2.8%) had a near partial response, and 74 (69.2%) had a partial response. Twenty-two patients (20.6%) did not respond.

As of the ASH presentation, 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 72.0%, and the overall survival estimate was 86.7%.

Treatment-emergent adverse events of any grade occurred in 96% of patients. The most frequent were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), fatigue (22%), pyrexia (20%), thrombocytopenia (19%), hyperphosphatemia (16%), vomiting (15%), and upper respiratory tract infection (15%). (About 22% of patients had neutropenia at baseline.)

The most frequent grade 3/4 adverse events were neutropenia (40%), anemia (18%), and thrombocytopenia (15%). Infections occurred in 72% of patients, with 20% of patients experiencing grade 3 or higher infections.

Serious adverse events occurred in 55% of patients, the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Laboratory tumor lysis syndrome (TLS) occurred in 5 patients during the ramp-up period only. Two patients required a dose interruption of 1 day each. There were no clinical TLS events.

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.

Venetoclax is currently being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Prescription medications

Photo courtesy of the CDC

The US Food and Drug Administration (FDA) has granted accelerated approval for venetoclax (Venclexta) to treat patients with chronic lymphocytic leukemia (CLL) who have 17p deletion and have received at least one prior therapy.

Venetoclax will be available in the US within about a week, according to the companies developing the drug, AbbVie and Genentech (a member of the

Roche Group).

The companies said they plan to offer patient assistance programs for qualifying patients who wish to receive venetoclax.

Venetoclax (formerly ABT-199) is the first FDA-approved treatment that targets the BCL-2 protein, which is overexpressed in many patients with CLL.

The drug is indicated for daily use after 17p deletion is confirmed via the FDA-approved companion diagnostic Vysis CLL FISH probe kit, which is manufactured by Abbott Molecular.

The FDA granted venetoclax accelerated approval rather than traditional approval because the drug has not yet shown a clinical benefit. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of venetoclax for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA previously granted venetoclax breakthrough therapy designation, priority review status, and orphan drug designation.

Phase 2 trial

Results from the pivotal phase 2 trial of venetoclax (M13-982, NCT01889186) were presented at the 2015 ASH Annual Meeting. According to those data, 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.

Eighty-five patients responded to treatment, for an overall response rate of 79.4%. Eight patients (7.5%) achieved a complete response or complete response with incomplete count recovery, 3 (2.8%) had a near partial response, and 74 (69.2%) had a partial response. Twenty-two patients (20.6%) did not respond.

As of the ASH presentation, 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 72.0%, and the overall survival estimate was 86.7%.

Treatment-emergent adverse events of any grade occurred in 96% of patients. The most frequent were neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%), fatigue (22%), pyrexia (20%), thrombocytopenia (19%), hyperphosphatemia (16%), vomiting (15%), and upper respiratory tract infection (15%). (About 22% of patients had neutropenia at baseline.)

The most frequent grade 3/4 adverse events were neutropenia (40%), anemia (18%), and thrombocytopenia (15%). Infections occurred in 72% of patients, with 20% of patients experiencing grade 3 or higher infections.

Serious adverse events occurred in 55% of patients, the most common being pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Laboratory tumor lysis syndrome (TLS) occurred in 5 patients during the ramp-up period only. Two patients required a dose interruption of 1 day each. There were no clinical TLS events.

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.

Venetoclax is currently being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Daughter T cells

(with c-Myc in green)

Image courtesy of

Katherine Verbist and St. Jude

New research published in Nature helps explain how 2 types of cells arise from activated T cells.

Investigators found that distribution of the regulatory protein c-Myc during asymmetric cell division impacts an activated T cell’s fate, determining whether it will become an effector T cell or a memory T cell.

The team therefore believes that manipulating c-Myc levels could make vaccines more effective or advance immunotherapies for cancer treatment.

“Our work suggests that it may be possible to manipulate the immune response by nudging production of c-Myc in one direction or the other,” said study author Douglas Green, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Potentially, that could mean more effective vaccines or help to advance T-cell immune therapy for cancer treatment.”

Through a series of experiments, Dr Green and his colleagues found that, during asymmetric cell division of activated T cells, high levels of c-Myc accumulated in one daughter cell.

There, c-Myc launched and sustained the rapid proliferation of effector T cells, including those in mice infected with the influenza virus.

In contrast, daughter cells with low levels of c-Myc functioned like memory T cells, proliferating to mount an immune response a month later when mice were again exposed to the virus.

The investigators also identified the metabolic and signaling pathways that serve as a positive feedback loop to sustain the high levels of c-Myc that effector T cells require to maintain their identities and function.

The team showed that disrupting certain components of the system disturbed c-Myc production, which altered the fate of T cells and caused effector T cells to operate like memory T cells.

“While daughter cells of activated T cells seem to have very different fates, we showed their behavior could be altered by manipulating these metabolic and regulatory pathways to increase or decrease c-Myc levels,” Dr Green said.

Daughter T cells

(with c-Myc in green)

Image courtesy of

Katherine Verbist and St. Jude

New research published in Nature helps explain how 2 types of cells arise from activated T cells.

Investigators found that distribution of the regulatory protein c-Myc during asymmetric cell division impacts an activated T cell’s fate, determining whether it will become an effector T cell or a memory T cell.

The team therefore believes that manipulating c-Myc levels could make vaccines more effective or advance immunotherapies for cancer treatment.

“Our work suggests that it may be possible to manipulate the immune response by nudging production of c-Myc in one direction or the other,” said study author Douglas Green, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Potentially, that could mean more effective vaccines or help to advance T-cell immune therapy for cancer treatment.”

Through a series of experiments, Dr Green and his colleagues found that, during asymmetric cell division of activated T cells, high levels of c-Myc accumulated in one daughter cell.

There, c-Myc launched and sustained the rapid proliferation of effector T cells, including those in mice infected with the influenza virus.

In contrast, daughter cells with low levels of c-Myc functioned like memory T cells, proliferating to mount an immune response a month later when mice were again exposed to the virus.

The investigators also identified the metabolic and signaling pathways that serve as a positive feedback loop to sustain the high levels of c-Myc that effector T cells require to maintain their identities and function.

The team showed that disrupting certain components of the system disturbed c-Myc production, which altered the fate of T cells and caused effector T cells to operate like memory T cells.

“While daughter cells of activated T cells seem to have very different fates, we showed their behavior could be altered by manipulating these metabolic and regulatory pathways to increase or decrease c-Myc levels,” Dr Green said.

Daughter T cells

(with c-Myc in green)

Image courtesy of

Katherine Verbist and St. Jude

New research published in Nature helps explain how 2 types of cells arise from activated T cells.

Investigators found that distribution of the regulatory protein c-Myc during asymmetric cell division impacts an activated T cell’s fate, determining whether it will become an effector T cell or a memory T cell.

The team therefore believes that manipulating c-Myc levels could make vaccines more effective or advance immunotherapies for cancer treatment.

“Our work suggests that it may be possible to manipulate the immune response by nudging production of c-Myc in one direction or the other,” said study author Douglas Green, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Potentially, that could mean more effective vaccines or help to advance T-cell immune therapy for cancer treatment.”

Through a series of experiments, Dr Green and his colleagues found that, during asymmetric cell division of activated T cells, high levels of c-Myc accumulated in one daughter cell.

There, c-Myc launched and sustained the rapid proliferation of effector T cells, including those in mice infected with the influenza virus.

In contrast, daughter cells with low levels of c-Myc functioned like memory T cells, proliferating to mount an immune response a month later when mice were again exposed to the virus.

The investigators also identified the metabolic and signaling pathways that serve as a positive feedback loop to sustain the high levels of c-Myc that effector T cells require to maintain their identities and function.

The team showed that disrupting certain components of the system disturbed c-Myc production, which altered the fate of T cells and caused effector T cells to operate like memory T cells.

“While daughter cells of activated T cells seem to have very different fates, we showed their behavior could be altered by manipulating these metabolic and regulatory pathways to increase or decrease c-Myc levels,” Dr Green said.

Researchers in the lab

Photo by Rhoda Baer

Researchers have established a public repository of leukemia and lymphoma xenografts, according to a report in Cancer Cell.

The repository, known as the Public Repository of Xenografts (PRoXe), contains material from bone marrow, peripheral blood, and lymph nodes of mice.

It also contains information on the patients from whom the cancer tissues were derived and details on the characteristics of the tumors themselves.

PRoXe is based at Dana-Farber Cancer Institute in Boston, Massachusetts, but it has a web portal that can be accessed by researchers around the world.

Those who register with PRoxE can access the repository and search for cells from patients with specific hematologic malignancies.

Researchers can then have frozen cells shipped to them and transplant the cells into mice to create patient-derived xenograft (PDX) models for testing drugs.

“About 90% of compounds that show anticancer activity in preclinical tests don’t work when given to patients,” said David Weinstock, MD, of the Dana-Farber Cancer Institute.

“By trying drugs in PDX models, we can ‘mimic’ large and expensive human clinical trials and get answers about efficacy more quickly, less expensively, and without the need for patients to get investigational drugs that won’t work.”

To demonstrate how PRoXe can be used, Dr Weinstock and his colleagues tested the MDM2 inhibitor CGM097 against B-cell acute lymphoblastic leukemia (B-ALL) in 2 groups of mice. One group had a mutation in the TP53 tumor suppressor gene, and the other did not.

The researchers observed superior survival in the mice with wild-type TP53. This result corresponds with the results of previous research, which showed that inhibitors that disrupt the MDM2-p53 interaction can be effective in tumor models and patient tumors with wild-type TP53.

Dr Weinstock and his colleagues said their results provide strong preclinical evidence for testing CGM097 in patients who have been extensively treated for B-ALL and have wild-type TP53.

Dr Weinstock also noted that the leaders of ProXe are negotiating with a number of academic centers in an attempt to incorporate their PDX models into the repository.

The Cancer Cell manuscript had 95 authors from 14 different centers that contributed samples, models, and/or effort to the project.

Researchers in the lab

Photo by Rhoda Baer

Researchers have established a public repository of leukemia and lymphoma xenografts, according to a report in Cancer Cell.

The repository, known as the Public Repository of Xenografts (PRoXe), contains material from bone marrow, peripheral blood, and lymph nodes of mice.

It also contains information on the patients from whom the cancer tissues were derived and details on the characteristics of the tumors themselves.

PRoXe is based at Dana-Farber Cancer Institute in Boston, Massachusetts, but it has a web portal that can be accessed by researchers around the world.

Those who register with PRoxE can access the repository and search for cells from patients with specific hematologic malignancies.

Researchers can then have frozen cells shipped to them and transplant the cells into mice to create patient-derived xenograft (PDX) models for testing drugs.

“About 90% of compounds that show anticancer activity in preclinical tests don’t work when given to patients,” said David Weinstock, MD, of the Dana-Farber Cancer Institute.

“By trying drugs in PDX models, we can ‘mimic’ large and expensive human clinical trials and get answers about efficacy more quickly, less expensively, and without the need for patients to get investigational drugs that won’t work.”

To demonstrate how PRoXe can be used, Dr Weinstock and his colleagues tested the MDM2 inhibitor CGM097 against B-cell acute lymphoblastic leukemia (B-ALL) in 2 groups of mice. One group had a mutation in the TP53 tumor suppressor gene, and the other did not.

The researchers observed superior survival in the mice with wild-type TP53. This result corresponds with the results of previous research, which showed that inhibitors that disrupt the MDM2-p53 interaction can be effective in tumor models and patient tumors with wild-type TP53.

Dr Weinstock and his colleagues said their results provide strong preclinical evidence for testing CGM097 in patients who have been extensively treated for B-ALL and have wild-type TP53.

Dr Weinstock also noted that the leaders of ProXe are negotiating with a number of academic centers in an attempt to incorporate their PDX models into the repository.

The Cancer Cell manuscript had 95 authors from 14 different centers that contributed samples, models, and/or effort to the project.

Researchers in the lab

Photo by Rhoda Baer

Researchers have established a public repository of leukemia and lymphoma xenografts, according to a report in Cancer Cell.

The repository, known as the Public Repository of Xenografts (PRoXe), contains material from bone marrow, peripheral blood, and lymph nodes of mice.

It also contains information on the patients from whom the cancer tissues were derived and details on the characteristics of the tumors themselves.

PRoXe is based at Dana-Farber Cancer Institute in Boston, Massachusetts, but it has a web portal that can be accessed by researchers around the world.

Those who register with PRoxE can access the repository and search for cells from patients with specific hematologic malignancies.

Researchers can then have frozen cells shipped to them and transplant the cells into mice to create patient-derived xenograft (PDX) models for testing drugs.

“About 90% of compounds that show anticancer activity in preclinical tests don’t work when given to patients,” said David Weinstock, MD, of the Dana-Farber Cancer Institute.

“By trying drugs in PDX models, we can ‘mimic’ large and expensive human clinical trials and get answers about efficacy more quickly, less expensively, and without the need for patients to get investigational drugs that won’t work.”

To demonstrate how PRoXe can be used, Dr Weinstock and his colleagues tested the MDM2 inhibitor CGM097 against B-cell acute lymphoblastic leukemia (B-ALL) in 2 groups of mice. One group had a mutation in the TP53 tumor suppressor gene, and the other did not.

The researchers observed superior survival in the mice with wild-type TP53. This result corresponds with the results of previous research, which showed that inhibitors that disrupt the MDM2-p53 interaction can be effective in tumor models and patient tumors with wild-type TP53.

Dr Weinstock and his colleagues said their results provide strong preclinical evidence for testing CGM097 in patients who have been extensively treated for B-ALL and have wild-type TP53.

Dr Weinstock also noted that the leaders of ProXe are negotiating with a number of academic centers in an attempt to incorporate their PDX models into the repository.

The Cancer Cell manuscript had 95 authors from 14 different centers that contributed samples, models, and/or effort to the project.

PET scan

Image by Jens Langner

Using PET imaging to guide chemotherapy can improve outcomes for patients with advanced Hodgkin lymphoma (HL), according to research published in the Journal of Clinical Oncology.

The study indicated that PET-guided treatment can improve progression-free survival (PFS) among patients who do not achieve remission with 2 cycles of ABVD.

The results also suggested the approach can spare some patients unnecessary toxicity.

“The goal of cancer treatment is to cure as many people as possible with as little toxicity as possible,” said study author Oliver Press, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“We found a promising way to do that by tailoring treatment to Hodgkin patients, an approach which could lead to a new standard of care.”

Dr Press and his colleagues began this study with 358 HIV-negative patients with advanced HL, but only 336 of them were eligible and evaluable at baseline.

The patients’ median age was 32 (range, 18 to 60). Fifty-two percent had stage III disease, 48% had stage IV, 49% had an International Prognostic Score of 0 to 2, and 51% had a score of 3 to 7.

All of the patients received ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and underwent a PET scan to gauge their response after 2 cycles (PET2).

If the scan was negative, patients received a final 4 cycles of ABVD. If the scan was positive, patients received 6 cycles of eBEACOPP (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone).

Central review of the PET2 scan was performed in 331 patients. Most (82%, n=271) had a negative scan.

Forty-nine of the 60 PET2-positive patients went on to receive eBEACOPP as planned, but 11 patients declined.

The median follow-up was 39.7 months. For the entire study cohort, the estimated 2-year overall survival was 98%, and the estimated 2-year PFS was 79%.

The 2-year estimated PFS was 82% for PET2-negative patients and 64% for PET2-positive patients. The researchers noted that, typically, if HL patients have a positive PET scan after 2 rounds of ABVD, their expected 2-year PFS ranges from about 15% to 30%.

The researchers also pointed out that eBEACOPP was significantly more toxic than ABVD. The incidence of grade 4/5 toxicities was 85.7% and 36.7%, respectively (P<0.001).

There were 3 treatment-related deaths—1 in the ABVD group and 2 in the eBEACOPP group. And 6 patients developed secondary malignancies—3 in each group—including 2 non-Hodgkin lymphomas, 2 kidney cancers, 1 melanoma, and 1 skin cancer.

“[O]nly 20% of the patients in our trial were exposed to eBEACOPP, which means [most patients] weren’t exposed to its bad effects,” said Jonathan Friedberg, MD, of the University of Rochester Medical Center in Rochester, New York.

“That’s important because many people diagnosed with Hodgkin lymphoma are in their 20s and 30s and want to have children. This response-adapted therapy would ensure that the people who need the more toxic drugs receive them and would spare others from infertility and serious toxicities.”

PET scan

Image by Jens Langner

Using PET imaging to guide chemotherapy can improve outcomes for patients with advanced Hodgkin lymphoma (HL), according to research published in the Journal of Clinical Oncology.

The study indicated that PET-guided treatment can improve progression-free survival (PFS) among patients who do not achieve remission with 2 cycles of ABVD.

The results also suggested the approach can spare some patients unnecessary toxicity.

“The goal of cancer treatment is to cure as many people as possible with as little toxicity as possible,” said study author Oliver Press, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“We found a promising way to do that by tailoring treatment to Hodgkin patients, an approach which could lead to a new standard of care.”

Dr Press and his colleagues began this study with 358 HIV-negative patients with advanced HL, but only 336 of them were eligible and evaluable at baseline.

The patients’ median age was 32 (range, 18 to 60). Fifty-two percent had stage III disease, 48% had stage IV, 49% had an International Prognostic Score of 0 to 2, and 51% had a score of 3 to 7.

All of the patients received ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and underwent a PET scan to gauge their response after 2 cycles (PET2).

If the scan was negative, patients received a final 4 cycles of ABVD. If the scan was positive, patients received 6 cycles of eBEACOPP (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone).

Central review of the PET2 scan was performed in 331 patients. Most (82%, n=271) had a negative scan.

Forty-nine of the 60 PET2-positive patients went on to receive eBEACOPP as planned, but 11 patients declined.

The median follow-up was 39.7 months. For the entire study cohort, the estimated 2-year overall survival was 98%, and the estimated 2-year PFS was 79%.

The 2-year estimated PFS was 82% for PET2-negative patients and 64% for PET2-positive patients. The researchers noted that, typically, if HL patients have a positive PET scan after 2 rounds of ABVD, their expected 2-year PFS ranges from about 15% to 30%.

The researchers also pointed out that eBEACOPP was significantly more toxic than ABVD. The incidence of grade 4/5 toxicities was 85.7% and 36.7%, respectively (P<0.001).

There were 3 treatment-related deaths—1 in the ABVD group and 2 in the eBEACOPP group. And 6 patients developed secondary malignancies—3 in each group—including 2 non-Hodgkin lymphomas, 2 kidney cancers, 1 melanoma, and 1 skin cancer.

“[O]nly 20% of the patients in our trial were exposed to eBEACOPP, which means [most patients] weren’t exposed to its bad effects,” said Jonathan Friedberg, MD, of the University of Rochester Medical Center in Rochester, New York.

“That’s important because many people diagnosed with Hodgkin lymphoma are in their 20s and 30s and want to have children. This response-adapted therapy would ensure that the people who need the more toxic drugs receive them and would spare others from infertility and serious toxicities.”

PET scan

Image by Jens Langner

Using PET imaging to guide chemotherapy can improve outcomes for patients with advanced Hodgkin lymphoma (HL), according to research published in the Journal of Clinical Oncology.

The study indicated that PET-guided treatment can improve progression-free survival (PFS) among patients who do not achieve remission with 2 cycles of ABVD.

The results also suggested the approach can spare some patients unnecessary toxicity.

“The goal of cancer treatment is to cure as many people as possible with as little toxicity as possible,” said study author Oliver Press, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“We found a promising way to do that by tailoring treatment to Hodgkin patients, an approach which could lead to a new standard of care.”

Dr Press and his colleagues began this study with 358 HIV-negative patients with advanced HL, but only 336 of them were eligible and evaluable at baseline.

The patients’ median age was 32 (range, 18 to 60). Fifty-two percent had stage III disease, 48% had stage IV, 49% had an International Prognostic Score of 0 to 2, and 51% had a score of 3 to 7.

All of the patients received ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and underwent a PET scan to gauge their response after 2 cycles (PET2).

If the scan was negative, patients received a final 4 cycles of ABVD. If the scan was positive, patients received 6 cycles of eBEACOPP (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone).

Central review of the PET2 scan was performed in 331 patients. Most (82%, n=271) had a negative scan.

Forty-nine of the 60 PET2-positive patients went on to receive eBEACOPP as planned, but 11 patients declined.

The median follow-up was 39.7 months. For the entire study cohort, the estimated 2-year overall survival was 98%, and the estimated 2-year PFS was 79%.

The 2-year estimated PFS was 82% for PET2-negative patients and 64% for PET2-positive patients. The researchers noted that, typically, if HL patients have a positive PET scan after 2 rounds of ABVD, their expected 2-year PFS ranges from about 15% to 30%.

The researchers also pointed out that eBEACOPP was significantly more toxic than ABVD. The incidence of grade 4/5 toxicities was 85.7% and 36.7%, respectively (P<0.001).

There were 3 treatment-related deaths—1 in the ABVD group and 2 in the eBEACOPP group. And 6 patients developed secondary malignancies—3 in each group—including 2 non-Hodgkin lymphomas, 2 kidney cancers, 1 melanoma, and 1 skin cancer.

“[O]nly 20% of the patients in our trial were exposed to eBEACOPP, which means [most patients] weren’t exposed to its bad effects,” said Jonathan Friedberg, MD, of the University of Rochester Medical Center in Rochester, New York.

“That’s important because many people diagnosed with Hodgkin lymphoma are in their 20s and 30s and want to have children. This response-adapted therapy would ensure that the people who need the more toxic drugs receive them and would spare others from infertility and serious toxicities.”

Micrograph showing B-ALL

Combining a MEK inhibitor and a BCL-2/BCL-XL inhibitor may be a feasible treatment option for B-cell acute lymphoblastic leukemia (B-ALL), according to preclinical research published in Cell Death and Disease.

Researchers found that, when given alone, the MEK inhibitor trametinib did not block B-ALL cell growth.

And the BCL-2/BCL-XL inhibitors navitoclax (ABT-263) and venetoclax (ABT-199) did not prove particularly effective either.

However, combining trametinib with navitoclax or venetoclax successfully induced apoptosis in B-ALL cells.

“Cancer cells often outwit us by rewiring themselves, but this early research offers a promising idea to get ahead of them,” said study author Richard Marais, PhD, of the Cancer Research UK Manchester Institute.

“We’ll still need to do further research to prove that this is the case beyond cancer cells in the laboratory, and it may take many years before we see it in the clinic, but it’s the first step to finding a new, effective drug combination for B-cell acute lymphoblastic leukemia.”

Dr Marais and his colleagues found that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition alone did not suppress B-ALL cell growth.

And although B-ALL cells were sensitive to treatment with navitoclax or venetoclax alone, the researchers did not see complete loss of cell viability at clinically achievable doses.

However, trametinib did synergize with either navitoclax or venetoclax to suppress proliferation and induce apoptosis in B-ALL cells.

Further investigation revealed that the resistance of B-ALL cells to BCL-2/BCL-XL inhibition is mediated by MCL-1. And the synergism between trametinib and navitoclax/venetoclax is mediated by the pro-apoptotic factor BIM.

BIM is dephosphorylated as a result of MEK inhibition, which allows it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death.

The researchers said they observed this effect in B-ALL cells driven by a range of genetic abnormalities, so the combination of a MEK inhibitor and a BCL-2/BCL-XL inhibitor could have therapeutic potential in a range of B-ALL subtypes.

Micrograph showing B-ALL

Combining a MEK inhibitor and a BCL-2/BCL-XL inhibitor may be a feasible treatment option for B-cell acute lymphoblastic leukemia (B-ALL), according to preclinical research published in Cell Death and Disease.

Researchers found that, when given alone, the MEK inhibitor trametinib did not block B-ALL cell growth.

And the BCL-2/BCL-XL inhibitors navitoclax (ABT-263) and venetoclax (ABT-199) did not prove particularly effective either.

However, combining trametinib with navitoclax or venetoclax successfully induced apoptosis in B-ALL cells.

“Cancer cells often outwit us by rewiring themselves, but this early research offers a promising idea to get ahead of them,” said study author Richard Marais, PhD, of the Cancer Research UK Manchester Institute.

“We’ll still need to do further research to prove that this is the case beyond cancer cells in the laboratory, and it may take many years before we see it in the clinic, but it’s the first step to finding a new, effective drug combination for B-cell acute lymphoblastic leukemia.”

Dr Marais and his colleagues found that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition alone did not suppress B-ALL cell growth.

And although B-ALL cells were sensitive to treatment with navitoclax or venetoclax alone, the researchers did not see complete loss of cell viability at clinically achievable doses.

However, trametinib did synergize with either navitoclax or venetoclax to suppress proliferation and induce apoptosis in B-ALL cells.

Further investigation revealed that the resistance of B-ALL cells to BCL-2/BCL-XL inhibition is mediated by MCL-1. And the synergism between trametinib and navitoclax/venetoclax is mediated by the pro-apoptotic factor BIM.

BIM is dephosphorylated as a result of MEK inhibition, which allows it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death.

The researchers said they observed this effect in B-ALL cells driven by a range of genetic abnormalities, so the combination of a MEK inhibitor and a BCL-2/BCL-XL inhibitor could have therapeutic potential in a range of B-ALL subtypes.

Micrograph showing B-ALL

Combining a MEK inhibitor and a BCL-2/BCL-XL inhibitor may be a feasible treatment option for B-cell acute lymphoblastic leukemia (B-ALL), according to preclinical research published in Cell Death and Disease.

Researchers found that, when given alone, the MEK inhibitor trametinib did not block B-ALL cell growth.

And the BCL-2/BCL-XL inhibitors navitoclax (ABT-263) and venetoclax (ABT-199) did not prove particularly effective either.

However, combining trametinib with navitoclax or venetoclax successfully induced apoptosis in B-ALL cells.

“Cancer cells often outwit us by rewiring themselves, but this early research offers a promising idea to get ahead of them,” said study author Richard Marais, PhD, of the Cancer Research UK Manchester Institute.

“We’ll still need to do further research to prove that this is the case beyond cancer cells in the laboratory, and it may take many years before we see it in the clinic, but it’s the first step to finding a new, effective drug combination for B-cell acute lymphoblastic leukemia.”

Dr Marais and his colleagues found that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition alone did not suppress B-ALL cell growth.

And although B-ALL cells were sensitive to treatment with navitoclax or venetoclax alone, the researchers did not see complete loss of cell viability at clinically achievable doses.

However, trametinib did synergize with either navitoclax or venetoclax to suppress proliferation and induce apoptosis in B-ALL cells.

Further investigation revealed that the resistance of B-ALL cells to BCL-2/BCL-XL inhibition is mediated by MCL-1. And the synergism between trametinib and navitoclax/venetoclax is mediated by the pro-apoptotic factor BIM.

BIM is dephosphorylated as a result of MEK inhibition, which allows it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death.

The researchers said they observed this effect in B-ALL cells driven by a range of genetic abnormalities, so the combination of a MEK inhibitor and a BCL-2/BCL-XL inhibitor could have therapeutic potential in a range of B-ALL subtypes.

Bride and groom

Photo by Alena Kratochvilova

Results from two new studies provide a possible explanation for the link between marital status and survival in cancer patients.

Previous studies have shown that married cancer patients are more likely to survive and tend to have longer survival times than unmarried cancer patients.

Now, a pair of studies published in Cancer suggest it is the social support a patient receives from a spouse that may improve the patient’s outcome.

In the first study, Scarlett Lin Gomez, PhD, of the Cancer Prevention Institute of California, and her colleagues assessed the impact of socioeconomic factors and marital status on survival in cancer patients.

The team found evidence to suggest that economic resources play a minimal role in explaining the inferior survival observed in unmarried cancer patients.

In the second study, María Elena Martínez, PhD, of UC San Diego Moores Cancer Center, and her colleagues assessed the roles that race/ethnicity, sex, and nativity play in the survival of married and unmarried cancer patients.

The group found that not being married was associated with higher mortality, but the association varied by race/ethnicity and sex. The researchers believe these differences can be explained by the differences in social support networks between racial/ethnic groups and between men and women.

Patient cohort

Both studies were conducted on the same cohort of patients from the California Cancer Registry.

The researchers studied 783,167 cancer patients—393,470 males and 389,697 females. They were diagnosed from 2000 through 2009 with a first primary, invasive cancer of the 10 most common sites of cancer-related death for each sex, which included leukemias and lymphomas.

The patients were followed through December 31, 2012. A total of 386,607 patients died from any cause—204,007 males and 182,600 females.

Economic factors

Dr Gomez and her colleagues evaluated health insurance status and neighborhood socioeconomic status for the nearly 800,000 patients.

The researchers found that unmarried cancer patients had a greater risk of death than married patients, and this risk was higher among males than females. The hazard ratio (HR) for males was 1.27 (95% CI, 1.26-1.29), and the HR for females was 1.19 (95% CI, 1.18-1.20, P-interaction <0.001).

When the researchers adjusted for insurance status and neighborhood socioeconomic status, the marital status HRs decreased to 1.22 (95% CI, 1.21–1.24) for males and 1.15 (95% CI, 1.14–1.16) for females.

Based on these results, the researchers concluded that the survival benefit of marriage operates independently of the economic resources evaluated in this study.

“While other studies have found similar protective effects associated with being married, ours is the first in a large, population-based setting to assess the extent to which economic resources explain these protective effects,” Dr Gomez said. “Our study provides evidence for social support as a key driver.”

Race/ethnicity, nativity, and sex

Dr Martínez and her colleagues found that all-cause mortality was higher in the unmarried patients than in the married patients, but this varied significantly according to race/ethnicity and sex.

Marriage conferred less of a survival benefit for women than for men. However, for both sexes, non-Hispanic whites benefitted the most from being married, and Hispanics and Asian Pacific Islanders benefitted less.

Among males, the adjusted HRs were 1.24 (95% CI, 1.23-1.26) in non-Hispanic whites, 1.20 (95% CI, 1.16-1.24) in blacks, 1.20 (95% CI, 1.17-1.23) in Hispanics, and 1.11 (95% CI, 1.07-1.15) in Asian Pacific Islanders.

In females, the adjusted HRs were 1.17 (95% CI, 1.15-1.18) in non-Hispanic whites, 1.09 (95% CI, 1.05-1.13) in blacks, 1.11 (95% CI, 1.08-1.14) in Hispanics, and 1.07 (95% CI, 1.04-1.11) in Asian Pacific Islanders.

The researchers also found that all-cause mortality associated with unmarried status was higher in US-born Asian Pacific Islander and Hispanic men and women relative to their foreign-born counterparts.

“The results suggest that the more acculturated you become to US culture, the more it impacts cancer survivorship,” Dr Martínez said. “Our hypothesis is that non-Hispanic whites don’t have the same social network as other cultures that have stronger bonds with family and friends outside of marriage.”

“As individuals acculturate, they tend to lose those bonds. It’s also been shown that women seek out help for health concerns more frequently than men, and women tend to remind spouses to see their physicians and live a healthy lifestyle.”

Bride and groom

Photo by Alena Kratochvilova

Results from two new studies provide a possible explanation for the link between marital status and survival in cancer patients.

Previous studies have shown that married cancer patients are more likely to survive and tend to have longer survival times than unmarried cancer patients.

Now, a pair of studies published in Cancer suggest it is the social support a patient receives from a spouse that may improve the patient’s outcome.

In the first study, Scarlett Lin Gomez, PhD, of the Cancer Prevention Institute of California, and her colleagues assessed the impact of socioeconomic factors and marital status on survival in cancer patients.

The team found evidence to suggest that economic resources play a minimal role in explaining the inferior survival observed in unmarried cancer patients.

In the second study, María Elena Martínez, PhD, of UC San Diego Moores Cancer Center, and her colleagues assessed the roles that race/ethnicity, sex, and nativity play in the survival of married and unmarried cancer patients.

The group found that not being married was associated with higher mortality, but the association varied by race/ethnicity and sex. The researchers believe these differences can be explained by the differences in social support networks between racial/ethnic groups and between men and women.

Patient cohort

Both studies were conducted on the same cohort of patients from the California Cancer Registry.

The researchers studied 783,167 cancer patients—393,470 males and 389,697 females. They were diagnosed from 2000 through 2009 with a first primary, invasive cancer of the 10 most common sites of cancer-related death for each sex, which included leukemias and lymphomas.

The patients were followed through December 31, 2012. A total of 386,607 patients died from any cause—204,007 males and 182,600 females.

Economic factors

Dr Gomez and her colleagues evaluated health insurance status and neighborhood socioeconomic status for the nearly 800,000 patients.

The researchers found that unmarried cancer patients had a greater risk of death than married patients, and this risk was higher among males than females. The hazard ratio (HR) for males was 1.27 (95% CI, 1.26-1.29), and the HR for females was 1.19 (95% CI, 1.18-1.20, P-interaction <0.001).

When the researchers adjusted for insurance status and neighborhood socioeconomic status, the marital status HRs decreased to 1.22 (95% CI, 1.21–1.24) for males and 1.15 (95% CI, 1.14–1.16) for females.

Based on these results, the researchers concluded that the survival benefit of marriage operates independently of the economic resources evaluated in this study.

“While other studies have found similar protective effects associated with being married, ours is the first in a large, population-based setting to assess the extent to which economic resources explain these protective effects,” Dr Gomez said. “Our study provides evidence for social support as a key driver.”

Race/ethnicity, nativity, and sex

Dr Martínez and her colleagues found that all-cause mortality was higher in the unmarried patients than in the married patients, but this varied significantly according to race/ethnicity and sex.

Marriage conferred less of a survival benefit for women than for men. However, for both sexes, non-Hispanic whites benefitted the most from being married, and Hispanics and Asian Pacific Islanders benefitted less.

Among males, the adjusted HRs were 1.24 (95% CI, 1.23-1.26) in non-Hispanic whites, 1.20 (95% CI, 1.16-1.24) in blacks, 1.20 (95% CI, 1.17-1.23) in Hispanics, and 1.11 (95% CI, 1.07-1.15) in Asian Pacific Islanders.

In females, the adjusted HRs were 1.17 (95% CI, 1.15-1.18) in non-Hispanic whites, 1.09 (95% CI, 1.05-1.13) in blacks, 1.11 (95% CI, 1.08-1.14) in Hispanics, and 1.07 (95% CI, 1.04-1.11) in Asian Pacific Islanders.

The researchers also found that all-cause mortality associated with unmarried status was higher in US-born Asian Pacific Islander and Hispanic men and women relative to their foreign-born counterparts.

“The results suggest that the more acculturated you become to US culture, the more it impacts cancer survivorship,” Dr Martínez said. “Our hypothesis is that non-Hispanic whites don’t have the same social network as other cultures that have stronger bonds with family and friends outside of marriage.”

“As individuals acculturate, they tend to lose those bonds. It’s also been shown that women seek out help for health concerns more frequently than men, and women tend to remind spouses to see their physicians and live a healthy lifestyle.”

Bride and groom

Photo by Alena Kratochvilova

Results from two new studies provide a possible explanation for the link between marital status and survival in cancer patients.

Previous studies have shown that married cancer patients are more likely to survive and tend to have longer survival times than unmarried cancer patients.

Now, a pair of studies published in Cancer suggest it is the social support a patient receives from a spouse that may improve the patient’s outcome.

In the first study, Scarlett Lin Gomez, PhD, of the Cancer Prevention Institute of California, and her colleagues assessed the impact of socioeconomic factors and marital status on survival in cancer patients.

The team found evidence to suggest that economic resources play a minimal role in explaining the inferior survival observed in unmarried cancer patients.

In the second study, María Elena Martínez, PhD, of UC San Diego Moores Cancer Center, and her colleagues assessed the roles that race/ethnicity, sex, and nativity play in the survival of married and unmarried cancer patients.

The group found that not being married was associated with higher mortality, but the association varied by race/ethnicity and sex. The researchers believe these differences can be explained by the differences in social support networks between racial/ethnic groups and between men and women.

Patient cohort

Both studies were conducted on the same cohort of patients from the California Cancer Registry.

The researchers studied 783,167 cancer patients—393,470 males and 389,697 females. They were diagnosed from 2000 through 2009 with a first primary, invasive cancer of the 10 most common sites of cancer-related death for each sex, which included leukemias and lymphomas.

The patients were followed through December 31, 2012. A total of 386,607 patients died from any cause—204,007 males and 182,600 females.

Economic factors

Dr Gomez and her colleagues evaluated health insurance status and neighborhood socioeconomic status for the nearly 800,000 patients.

The researchers found that unmarried cancer patients had a greater risk of death than married patients, and this risk was higher among males than females. The hazard ratio (HR) for males was 1.27 (95% CI, 1.26-1.29), and the HR for females was 1.19 (95% CI, 1.18-1.20, P-interaction <0.001).

When the researchers adjusted for insurance status and neighborhood socioeconomic status, the marital status HRs decreased to 1.22 (95% CI, 1.21–1.24) for males and 1.15 (95% CI, 1.14–1.16) for females.

Based on these results, the researchers concluded that the survival benefit of marriage operates independently of the economic resources evaluated in this study.

“While other studies have found similar protective effects associated with being married, ours is the first in a large, population-based setting to assess the extent to which economic resources explain these protective effects,” Dr Gomez said. “Our study provides evidence for social support as a key driver.”

Race/ethnicity, nativity, and sex

Dr Martínez and her colleagues found that all-cause mortality was higher in the unmarried patients than in the married patients, but this varied significantly according to race/ethnicity and sex.

Marriage conferred less of a survival benefit for women than for men. However, for both sexes, non-Hispanic whites benefitted the most from being married, and Hispanics and Asian Pacific Islanders benefitted less.

Among males, the adjusted HRs were 1.24 (95% CI, 1.23-1.26) in non-Hispanic whites, 1.20 (95% CI, 1.16-1.24) in blacks, 1.20 (95% CI, 1.17-1.23) in Hispanics, and 1.11 (95% CI, 1.07-1.15) in Asian Pacific Islanders.

In females, the adjusted HRs were 1.17 (95% CI, 1.15-1.18) in non-Hispanic whites, 1.09 (95% CI, 1.05-1.13) in blacks, 1.11 (95% CI, 1.08-1.14) in Hispanics, and 1.07 (95% CI, 1.04-1.11) in Asian Pacific Islanders.

The researchers also found that all-cause mortality associated with unmarried status was higher in US-born Asian Pacific Islander and Hispanic men and women relative to their foreign-born counterparts.

“The results suggest that the more acculturated you become to US culture, the more it impacts cancer survivorship,” Dr Martínez said. “Our hypothesis is that non-Hispanic whites don’t have the same social network as other cultures that have stronger bonds with family and friends outside of marriage.”

“As individuals acculturate, they tend to lose those bonds. It’s also been shown that women seek out help for health concerns more frequently than men, and women tend to remind spouses to see their physicians and live a healthy lifestyle.”

Megakaryocytes

in the bone marrow

Researchers in the UK have developed a new method of producing megakaryocytes from human pluripotent stem cells (hPSCs).

The team said their method generated large quantities of functional megakaryocytes that produced functional platelets.

They believe this work brings us one step closer to manufacturing platelets for transfusion.

The research was published in Nature Communications.

“Making megakaryocytes and platelets from stem cells for transfusion has been a long-standing challenge because of the sheer numbers we need to produce to make a single unit for transfusion,” said study author Cedric Ghevaert, MD, PhD, of the University of Cambridge and NHS Blood and Transplant in Cambridge, UK.

“We have found a way to ‘rewire’ the stem cells to make them become megakaryocytes a lot faster and more efficiently. It is a major step forward towards our goal to one day make blood cells in the laboratory to transfuse to patients.”

Dr Ghevaert and his colleagues employed a “forward programming” strategy in which 3 transcription factors—GATA1, FLI1, and TAL1—were used drive the differentiation of hPSCs into megakaryocytes.

The team said the forward-programmed megakaryocytes matured into platelet-producing cells that could be cryopreserved, maintained, and amplified in vitro for more than 90 days. The average yield was 200,000 megakaryocytes per hPSC.

The researchers generated platelets from the forward-programmed megakaryocytes via culture. And tests suggested these platelets were functionally similar to donor-derived platelets.

“The success of this research team in producing megakaryocytes in the laboratory has paved the way for the ultimate goal—manufacturing platelets for transfusion,” said Edwin Massey, MBChB, associate medical director for diagnostic and therapeutic services at NHS Blood and Transplant, who was not involved in this research.

“It will, however, be many years before a process for the large-scale production of platelets is developed. Donated platelets will still be needed by patients for the foreseeable future, either as part of a blood donation or by dedicated platelet donation using a machine collection process.”

Megakaryocytes

in the bone marrow

Researchers in the UK have developed a new method of producing megakaryocytes from human pluripotent stem cells (hPSCs).

The team said their method generated large quantities of functional megakaryocytes that produced functional platelets.

They believe this work brings us one step closer to manufacturing platelets for transfusion.

The research was published in Nature Communications.

“Making megakaryocytes and platelets from stem cells for transfusion has been a long-standing challenge because of the sheer numbers we need to produce to make a single unit for transfusion,” said study author Cedric Ghevaert, MD, PhD, of the University of Cambridge and NHS Blood and Transplant in Cambridge, UK.

“We have found a way to ‘rewire’ the stem cells to make them become megakaryocytes a lot faster and more efficiently. It is a major step forward towards our goal to one day make blood cells in the laboratory to transfuse to patients.”

Dr Ghevaert and his colleagues employed a “forward programming” strategy in which 3 transcription factors—GATA1, FLI1, and TAL1—were used drive the differentiation of hPSCs into megakaryocytes.

The team said the forward-programmed megakaryocytes matured into platelet-producing cells that could be cryopreserved, maintained, and amplified in vitro for more than 90 days. The average yield was 200,000 megakaryocytes per hPSC.

The researchers generated platelets from the forward-programmed megakaryocytes via culture. And tests suggested these platelets were functionally similar to donor-derived platelets.

“The success of this research team in producing megakaryocytes in the laboratory has paved the way for the ultimate goal—manufacturing platelets for transfusion,” said Edwin Massey, MBChB, associate medical director for diagnostic and therapeutic services at NHS Blood and Transplant, who was not involved in this research.

“It will, however, be many years before a process for the large-scale production of platelets is developed. Donated platelets will still be needed by patients for the foreseeable future, either as part of a blood donation or by dedicated platelet donation using a machine collection process.”

Megakaryocytes

in the bone marrow

Researchers in the UK have developed a new method of producing megakaryocytes from human pluripotent stem cells (hPSCs).

The team said their method generated large quantities of functional megakaryocytes that produced functional platelets.

They believe this work brings us one step closer to manufacturing platelets for transfusion.

The research was published in Nature Communications.

“Making megakaryocytes and platelets from stem cells for transfusion has been a long-standing challenge because of the sheer numbers we need to produce to make a single unit for transfusion,” said study author Cedric Ghevaert, MD, PhD, of the University of Cambridge and NHS Blood and Transplant in Cambridge, UK.

“We have found a way to ‘rewire’ the stem cells to make them become megakaryocytes a lot faster and more efficiently. It is a major step forward towards our goal to one day make blood cells in the laboratory to transfuse to patients.”

Dr Ghevaert and his colleagues employed a “forward programming” strategy in which 3 transcription factors—GATA1, FLI1, and TAL1—were used drive the differentiation of hPSCs into megakaryocytes.

The team said the forward-programmed megakaryocytes matured into platelet-producing cells that could be cryopreserved, maintained, and amplified in vitro for more than 90 days. The average yield was 200,000 megakaryocytes per hPSC.

The researchers generated platelets from the forward-programmed megakaryocytes via culture. And tests suggested these platelets were functionally similar to donor-derived platelets.

“The success of this research team in producing megakaryocytes in the laboratory has paved the way for the ultimate goal—manufacturing platelets for transfusion,” said Edwin Massey, MBChB, associate medical director for diagnostic and therapeutic services at NHS Blood and Transplant, who was not involved in this research.

“It will, however, be many years before a process for the large-scale production of platelets is developed. Donated platelets will still be needed by patients for the foreseeable future, either as part of a blood donation or by dedicated platelet donation using a machine collection process.”

Monocytes immunostained with

antibodies toward SHARPIN

(red) and caspase 1 (green).

Cell on right showing increase

in caspase 1 upon stimulation

with LPS and ATP and co-

localization with SHARPIN as

visualized by the merged

fluorescence (yellow). Nuclei

are stained blue with DAPI.

Image courtesy of The

American Journal of Pathology

A new study suggests that SHARPIN, a protein involved in regulating inflammation, has anti-septic effects.

Researchers believe this discovery, reported in The American Journal of Pathology, could spur the development of novel treatments for sepsis.

“Sepsis has been linked to enhanced activity of the enzyme caspase 1 and aberrant expression of pro-inflammatory interleukins 1β and 18,” said Liliana Schaefer, MD, of Goethe-Universität in Frankfurt, Germany.

“SHARPIN binds to caspase 1 and inhibits its activation. Our study proposes that the caspase 1/SHARPIN interaction may be a key pharmacological target in sepsis and perhaps in other inflammatory conditions where SHARPIN is involved.”

The researchers found that sepsis in mice bred to be deficient in SHARPIN resulted in enhanced levels of interleukins 1β and 18 and active caspase 1, as well as shortened survival.

Treatment with a caspase 1 inhibitor reversed these effects—reducing levels of interleukins 1β and 18, decreasing cell death in the spleen, and prolonging survival.

The researchers also found evidence to suggest this mechanism may be relevant to human sepsis.

“We found a decline in SHARPIN levels in septic patients correlating with enhanced activation of caspase 1 in circulating mononuclear cells and an increase of interleukin 1β/18 in the plasma,” Dr Schaefer said.

“Our findings suggest that using pharmacological caspase 1 inhibitors could be beneficial in septic patients with low SHARPIN levels, and these therapies may be more efficient than other anti-inflammatory therapies.”

Monocytes immunostained with

antibodies toward SHARPIN

(red) and caspase 1 (green).

Cell on right showing increase

in caspase 1 upon stimulation

with LPS and ATP and co-

localization with SHARPIN as

visualized by the merged

fluorescence (yellow). Nuclei

are stained blue with DAPI.

Image courtesy of The

American Journal of Pathology

A new study suggests that SHARPIN, a protein involved in regulating inflammation, has anti-septic effects.

Researchers believe this discovery, reported in The American Journal of Pathology, could spur the development of novel treatments for sepsis.

“Sepsis has been linked to enhanced activity of the enzyme caspase 1 and aberrant expression of pro-inflammatory interleukins 1β and 18,” said Liliana Schaefer, MD, of Goethe-Universität in Frankfurt, Germany.

“SHARPIN binds to caspase 1 and inhibits its activation. Our study proposes that the caspase 1/SHARPIN interaction may be a key pharmacological target in sepsis and perhaps in other inflammatory conditions where SHARPIN is involved.”

The researchers found that sepsis in mice bred to be deficient in SHARPIN resulted in enhanced levels of interleukins 1β and 18 and active caspase 1, as well as shortened survival.

Treatment with a caspase 1 inhibitor reversed these effects—reducing levels of interleukins 1β and 18, decreasing cell death in the spleen, and prolonging survival.

The researchers also found evidence to suggest this mechanism may be relevant to human sepsis.

“We found a decline in SHARPIN levels in septic patients correlating with enhanced activation of caspase 1 in circulating mononuclear cells and an increase of interleukin 1β/18 in the plasma,” Dr Schaefer said.

“Our findings suggest that using pharmacological caspase 1 inhibitors could be beneficial in septic patients with low SHARPIN levels, and these therapies may be more efficient than other anti-inflammatory therapies.”

Monocytes immunostained with

antibodies toward SHARPIN

(red) and caspase 1 (green).

Cell on right showing increase

in caspase 1 upon stimulation

with LPS and ATP and co-

localization with SHARPIN as

visualized by the merged

fluorescence (yellow). Nuclei

are stained blue with DAPI.

Image courtesy of The

American Journal of Pathology

A new study suggests that SHARPIN, a protein involved in regulating inflammation, has anti-septic effects.

Researchers believe this discovery, reported in The American Journal of Pathology, could spur the development of novel treatments for sepsis.

“Sepsis has been linked to enhanced activity of the enzyme caspase 1 and aberrant expression of pro-inflammatory interleukins 1β and 18,” said Liliana Schaefer, MD, of Goethe-Universität in Frankfurt, Germany.

“SHARPIN binds to caspase 1 and inhibits its activation. Our study proposes that the caspase 1/SHARPIN interaction may be a key pharmacological target in sepsis and perhaps in other inflammatory conditions where SHARPIN is involved.”

The researchers found that sepsis in mice bred to be deficient in SHARPIN resulted in enhanced levels of interleukins 1β and 18 and active caspase 1, as well as shortened survival.

Treatment with a caspase 1 inhibitor reversed these effects—reducing levels of interleukins 1β and 18, decreasing cell death in the spleen, and prolonging survival.

The researchers also found evidence to suggest this mechanism may be relevant to human sepsis.

“We found a decline in SHARPIN levels in septic patients correlating with enhanced activation of caspase 1 in circulating mononuclear cells and an increase of interleukin 1β/18 in the plasma,” Dr Schaefer said.

“Our findings suggest that using pharmacological caspase 1 inhibitors could be beneficial in septic patients with low SHARPIN levels, and these therapies may be more efficient than other anti-inflammatory therapies.”

Lab mouse

Results of preclinical research indicate that combining 2 kinase inhibitors may be a promising treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL).

Researchers found that combining a tyrosine kinase inhibitor (TKI) and an inhibitor of focal adhesion kinase (FAK) was “remarkably effective” against Ph+ B-ALL in vitro and in vivo.

The TKI dasatinib and the FAK inhibitor VS-4718 decreased leukemic cell survival and adhesion, inhibited tumor growth, and prolonged survival in mouse models of Ph+ B-ALL.

Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their results in JCI Insight.

The researchers noted that patients with Ph+ ALL have shown resistance to TKI therapy, and this resistance has been tied to alterations in IKZF1.

As FAK expression is elevated in IKZF1-mutated leukemias, the team speculated that adding a FAK inhibitor to TKI therapy might lead to better results.

First, the researchers set out to confirm that FAK is overexpressed in Ph+ B-ALL. Their experiments revealed upregulation of the FAK pathway in Ph+ B-ALL cells, with further overexpression of FAK in IKZF1-mutated Ph+ B-ALL cells.

When they inhibited FAK with VS-4718, the team observed decreases in the survival, clonogenicity, and adhesion of IKZF1-mutated Ph+ B-ALL cells from both mice and humans.

Next, the researchers found that VS-4718 synergizes with the TKI dasatinib in vitro and in vivo.

In in vitro experiments with both mouse and human Ph+ B-ALL cells, the combination decreased cell survival and adhesion and inhibited downstream targets of FAK.

In mouse models of Ph+ B-ALL, VS-4718 proved ineffective when given alone.

However, the researchers said the combination of VS-4718 and dasatinib “dramatically” decreased leukemic burden and extended the lives of mice.

In fact, 1 long-term survivor achieved a complete remission that endured after treatment was stopped.

The researchers said these results suggest that targeting FAK with VS-4718 can overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, potentiating responsiveness to TKIs.

Lab mouse

Results of preclinical research indicate that combining 2 kinase inhibitors may be a promising treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL).

Researchers found that combining a tyrosine kinase inhibitor (TKI) and an inhibitor of focal adhesion kinase (FAK) was “remarkably effective” against Ph+ B-ALL in vitro and in vivo.

The TKI dasatinib and the FAK inhibitor VS-4718 decreased leukemic cell survival and adhesion, inhibited tumor growth, and prolonged survival in mouse models of Ph+ B-ALL.

Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their results in JCI Insight.

The researchers noted that patients with Ph+ ALL have shown resistance to TKI therapy, and this resistance has been tied to alterations in IKZF1.

As FAK expression is elevated in IKZF1-mutated leukemias, the team speculated that adding a FAK inhibitor to TKI therapy might lead to better results.

First, the researchers set out to confirm that FAK is overexpressed in Ph+ B-ALL. Their experiments revealed upregulation of the FAK pathway in Ph+ B-ALL cells, with further overexpression of FAK in IKZF1-mutated Ph+ B-ALL cells.

When they inhibited FAK with VS-4718, the team observed decreases in the survival, clonogenicity, and adhesion of IKZF1-mutated Ph+ B-ALL cells from both mice and humans.

Next, the researchers found that VS-4718 synergizes with the TKI dasatinib in vitro and in vivo.

In in vitro experiments with both mouse and human Ph+ B-ALL cells, the combination decreased cell survival and adhesion and inhibited downstream targets of FAK.

In mouse models of Ph+ B-ALL, VS-4718 proved ineffective when given alone.

However, the researchers said the combination of VS-4718 and dasatinib “dramatically” decreased leukemic burden and extended the lives of mice.

In fact, 1 long-term survivor achieved a complete remission that endured after treatment was stopped.

The researchers said these results suggest that targeting FAK with VS-4718 can overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, potentiating responsiveness to TKIs.

Lab mouse

Results of preclinical research indicate that combining 2 kinase inhibitors may be a promising treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL).

Researchers found that combining a tyrosine kinase inhibitor (TKI) and an inhibitor of focal adhesion kinase (FAK) was “remarkably effective” against Ph+ B-ALL in vitro and in vivo.

The TKI dasatinib and the FAK inhibitor VS-4718 decreased leukemic cell survival and adhesion, inhibited tumor growth, and prolonged survival in mouse models of Ph+ B-ALL.

Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their results in JCI Insight.

The researchers noted that patients with Ph+ ALL have shown resistance to TKI therapy, and this resistance has been tied to alterations in IKZF1.

As FAK expression is elevated in IKZF1-mutated leukemias, the team speculated that adding a FAK inhibitor to TKI therapy might lead to better results.

First, the researchers set out to confirm that FAK is overexpressed in Ph+ B-ALL. Their experiments revealed upregulation of the FAK pathway in Ph+ B-ALL cells, with further overexpression of FAK in IKZF1-mutated Ph+ B-ALL cells.

When they inhibited FAK with VS-4718, the team observed decreases in the survival, clonogenicity, and adhesion of IKZF1-mutated Ph+ B-ALL cells from both mice and humans.

Next, the researchers found that VS-4718 synergizes with the TKI dasatinib in vitro and in vivo.

In in vitro experiments with both mouse and human Ph+ B-ALL cells, the combination decreased cell survival and adhesion and inhibited downstream targets of FAK.

In mouse models of Ph+ B-ALL, VS-4718 proved ineffective when given alone.

However, the researchers said the combination of VS-4718 and dasatinib “dramatically” decreased leukemic burden and extended the lives of mice.

In fact, 1 long-term survivor achieved a complete remission that endured after treatment was stopped.

The researchers said these results suggest that targeting FAK with VS-4718 can overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, potentiating responsiveness to TKIs.