Leukemia, Myelodysplasia, Transplantation

Blood collection

Credit: Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, to treat patients with  relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

Breakthrough designation is designed to help accelerate the development and review of new drugs for serious or life-threatening conditions.

The designation comes with potential benefits, including intensive FDA guidance and eligibility for priority review. It is granted to applicants when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinical endpoints.

The FDA recently granted JCAR015 orphan designation to treat ALL as well.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial. Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following persistent seizure activity.

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases. The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures. The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation at Memorial Sloan-Kettering Cancer Center in a phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

Two other CAR T-cell product candidates under development by the same company, Juno Therapeutics, Inc., are being tested in clinical trials as well. JCAR017 is under investigation at Seattle Children’s Hospital for relapsed/refractory CD19-positive pediatric leukemia.

JCAR014 is being tested for refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and ALL at the Fred Hutchinson Cancer Research Center. Data on these programs are set to be presented at the 56th ASH Annual Meeting next week in San Francisco.

Blood collection

Credit: Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, to treat patients with  relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

Breakthrough designation is designed to help accelerate the development and review of new drugs for serious or life-threatening conditions.

The designation comes with potential benefits, including intensive FDA guidance and eligibility for priority review. It is granted to applicants when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinical endpoints.

The FDA recently granted JCAR015 orphan designation to treat ALL as well.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial. Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following persistent seizure activity.

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases. The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures. The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation at Memorial Sloan-Kettering Cancer Center in a phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

Two other CAR T-cell product candidates under development by the same company, Juno Therapeutics, Inc., are being tested in clinical trials as well. JCAR017 is under investigation at Seattle Children’s Hospital for relapsed/refractory CD19-positive pediatric leukemia.

JCAR014 is being tested for refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and ALL at the Fred Hutchinson Cancer Research Center. Data on these programs are set to be presented at the 56th ASH Annual Meeting next week in San Francisco.

Blood collection

Credit: Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, to treat patients with  relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

Breakthrough designation is designed to help accelerate the development and review of new drugs for serious or life-threatening conditions.

The designation comes with potential benefits, including intensive FDA guidance and eligibility for priority review. It is granted to applicants when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinical endpoints.

The FDA recently granted JCAR015 orphan designation to treat ALL as well.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial. Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following persistent seizure activity.

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases. The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures. The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation at Memorial Sloan-Kettering Cancer Center in a phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

Two other CAR T-cell product candidates under development by the same company, Juno Therapeutics, Inc., are being tested in clinical trials as well. JCAR017 is under investigation at Seattle Children’s Hospital for relapsed/refractory CD19-positive pediatric leukemia.

JCAR014 is being tested for refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and ALL at the Fred Hutchinson Cancer Research Center. Data on these programs are set to be presented at the 56th ASH Annual Meeting next week in San Francisco.

Doctor and patient

Credit: NIH

In a phase 2 study, the anticancer quinolone derivative vosaroxin produced responses in poor-risk, elderly patients with previously untreated acute myeloid leukemia (AML), but most patients ultimately died.

Twenty-nine percent of patients achieved a complete response (CR) following treatment with vosaroxin.

However, 84% of patients discontinued treatment, most due to treatment failure. And 91% of patients died, most from disease progression.

Still, study investigators said single-agent vosaroxin shows promise as a treatment option for this group of patients, who are unlikely to benefit from standard induction chemotherapy.

“There remains an acute unmet medical need for new treatment options in AML, including patients 60 years of age and older who are unlikely to benefit from standard induction chemotherapy,” said Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center.

“Vosaroxin is active and well-tolerated in this population, both as a single agent, as seen in [this] study, and in combination with decitabine, as seen in an ongoing MD Anderson Cancer Center-sponsored study.”

Dr Ravandi and his colleagues reported results of the phase 2 trial, called REVEAL-1, in the British Journal of Haematology. The study was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.

The investigators evaluated vosaroxin in 113 patients aged 60 and older who had previously untreated AML with an unfavorable prognosis.

The patients’ median age was 75 years, and most (82%) had 2 or more risk factors, which included being 70 or older, having antecedent hematologic disease, having an ECOG performance status of 2, and having intermediate/unfavorable cytogenetics.

Patients received vosaroxin in sequential cohorts. In group A, they received 72 mg/m² on days 1, 8, and 15. In group B, they received 72 mg/m² on days 1 and 8. And in group C, they received 72 mg/m² or 90 mg/m² on days 1 and 4.

The primary efficacy endpoint was the combined CR rate and the rate of CR with incomplete platelet recovery (CRp). CR and CR/CRp rates were 29% and 32%, respectively. Responses occurred in all categories of risk factors, including in patients with 2 or more risk factors.

Ninety-five patients (84%) discontinued treatment due to treatment failure (n=50), death (n=21), unacceptable adverse events (n=6), relapse (n=5), their physician’s decision (n=5) or other reasons (n=8).

The all-cause mortality rate was 12% at 30 days and 31% at 60 days. The median overall survival (OS) was 7.0 months, and the 1-year OS rate was 34%.

Common grade 3/4 hematologic adverse events (occurring in 20% of patients or more) included thrombocytopenia (59%), febrile neutropenia (50%), anemia (49%), and neutropenia (29%).

Common grade 3/4 nonhematologic adverse events included sepsis (39%), pneumonia (30%), hypokalemia (25%), and oral mucositis/stomatitis (22%).

Ninety-one patients (81%) had one or more serious adverse event. The most common were pneumonia (24%), febrile neutropenia (21%), and oral mucositis/stomatitis (10%).

Of the 113 patients treated, 103 died. Most deaths (78%) were due to progressive disease.

Patients in group C (72 mg/m²) had the most favorable balance of safety and efficacy. They had faster hematologic recovery (a median of 27 days) than the other groups and the lowest incidence of aggregate sepsis (24%) and 30-day (7%) and 60-day (17%) all-cause mortality.

At this dose and schedule, CR and CR/CRp rates were 31% and 35%, respectively. The median OS was 7.7 months, and the 1-year OS rate was 38%.

“Publication of these data in the British Journal of Haematology further support our goal of establishing vosaroxin as a new standard of care in AML,” said Adam Craig, chief medical officer of Sunesis.

“Given ongoing demographic shifts in the US and other major territories, the challenge of treating AML in older adults will continue to grow, underscoring a need for new treatment options. We look forward to building on these data through further investigator-sponsored studies and, with the outcome of VALOR in relapsed or refractory AML, progressing towards initial regulatory approval.”

Based on results of the phase 3 VALOR trial, which were recently announced, Sunesis has filed a marketing authorization application with the European Medicines Agency and plans to meet with the US Food and Drug Administration to determine the appropriate regulatory path forward for vosaroxin in the treatment of relapsed or refractory AML.

Doctor and patient

Credit: NIH

In a phase 2 study, the anticancer quinolone derivative vosaroxin produced responses in poor-risk, elderly patients with previously untreated acute myeloid leukemia (AML), but most patients ultimately died.

Twenty-nine percent of patients achieved a complete response (CR) following treatment with vosaroxin.

However, 84% of patients discontinued treatment, most due to treatment failure. And 91% of patients died, most from disease progression.

Still, study investigators said single-agent vosaroxin shows promise as a treatment option for this group of patients, who are unlikely to benefit from standard induction chemotherapy.

“There remains an acute unmet medical need for new treatment options in AML, including patients 60 years of age and older who are unlikely to benefit from standard induction chemotherapy,” said Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center.

“Vosaroxin is active and well-tolerated in this population, both as a single agent, as seen in [this] study, and in combination with decitabine, as seen in an ongoing MD Anderson Cancer Center-sponsored study.”

Dr Ravandi and his colleagues reported results of the phase 2 trial, called REVEAL-1, in the British Journal of Haematology. The study was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.

The investigators evaluated vosaroxin in 113 patients aged 60 and older who had previously untreated AML with an unfavorable prognosis.

The patients’ median age was 75 years, and most (82%) had 2 or more risk factors, which included being 70 or older, having antecedent hematologic disease, having an ECOG performance status of 2, and having intermediate/unfavorable cytogenetics.

Patients received vosaroxin in sequential cohorts. In group A, they received 72 mg/m² on days 1, 8, and 15. In group B, they received 72 mg/m² on days 1 and 8. And in group C, they received 72 mg/m² or 90 mg/m² on days 1 and 4.

The primary efficacy endpoint was the combined CR rate and the rate of CR with incomplete platelet recovery (CRp). CR and CR/CRp rates were 29% and 32%, respectively. Responses occurred in all categories of risk factors, including in patients with 2 or more risk factors.

Ninety-five patients (84%) discontinued treatment due to treatment failure (n=50), death (n=21), unacceptable adverse events (n=6), relapse (n=5), their physician’s decision (n=5) or other reasons (n=8).

The all-cause mortality rate was 12% at 30 days and 31% at 60 days. The median overall survival (OS) was 7.0 months, and the 1-year OS rate was 34%.

Common grade 3/4 hematologic adverse events (occurring in 20% of patients or more) included thrombocytopenia (59%), febrile neutropenia (50%), anemia (49%), and neutropenia (29%).

Common grade 3/4 nonhematologic adverse events included sepsis (39%), pneumonia (30%), hypokalemia (25%), and oral mucositis/stomatitis (22%).

Ninety-one patients (81%) had one or more serious adverse event. The most common were pneumonia (24%), febrile neutropenia (21%), and oral mucositis/stomatitis (10%).

Of the 113 patients treated, 103 died. Most deaths (78%) were due to progressive disease.

Patients in group C (72 mg/m²) had the most favorable balance of safety and efficacy. They had faster hematologic recovery (a median of 27 days) than the other groups and the lowest incidence of aggregate sepsis (24%) and 30-day (7%) and 60-day (17%) all-cause mortality.

At this dose and schedule, CR and CR/CRp rates were 31% and 35%, respectively. The median OS was 7.7 months, and the 1-year OS rate was 38%.

“Publication of these data in the British Journal of Haematology further support our goal of establishing vosaroxin as a new standard of care in AML,” said Adam Craig, chief medical officer of Sunesis.

“Given ongoing demographic shifts in the US and other major territories, the challenge of treating AML in older adults will continue to grow, underscoring a need for new treatment options. We look forward to building on these data through further investigator-sponsored studies and, with the outcome of VALOR in relapsed or refractory AML, progressing towards initial regulatory approval.”

Based on results of the phase 3 VALOR trial, which were recently announced, Sunesis has filed a marketing authorization application with the European Medicines Agency and plans to meet with the US Food and Drug Administration to determine the appropriate regulatory path forward for vosaroxin in the treatment of relapsed or refractory AML.

Doctor and patient

Credit: NIH

In a phase 2 study, the anticancer quinolone derivative vosaroxin produced responses in poor-risk, elderly patients with previously untreated acute myeloid leukemia (AML), but most patients ultimately died.

Twenty-nine percent of patients achieved a complete response (CR) following treatment with vosaroxin.

However, 84% of patients discontinued treatment, most due to treatment failure. And 91% of patients died, most from disease progression.

Still, study investigators said single-agent vosaroxin shows promise as a treatment option for this group of patients, who are unlikely to benefit from standard induction chemotherapy.

“There remains an acute unmet medical need for new treatment options in AML, including patients 60 years of age and older who are unlikely to benefit from standard induction chemotherapy,” said Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center.

“Vosaroxin is active and well-tolerated in this population, both as a single agent, as seen in [this] study, and in combination with decitabine, as seen in an ongoing MD Anderson Cancer Center-sponsored study.”

Dr Ravandi and his colleagues reported results of the phase 2 trial, called REVEAL-1, in the British Journal of Haematology. The study was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.

The investigators evaluated vosaroxin in 113 patients aged 60 and older who had previously untreated AML with an unfavorable prognosis.

The patients’ median age was 75 years, and most (82%) had 2 or more risk factors, which included being 70 or older, having antecedent hematologic disease, having an ECOG performance status of 2, and having intermediate/unfavorable cytogenetics.

Patients received vosaroxin in sequential cohorts. In group A, they received 72 mg/m² on days 1, 8, and 15. In group B, they received 72 mg/m² on days 1 and 8. And in group C, they received 72 mg/m² or 90 mg/m² on days 1 and 4.

The primary efficacy endpoint was the combined CR rate and the rate of CR with incomplete platelet recovery (CRp). CR and CR/CRp rates were 29% and 32%, respectively. Responses occurred in all categories of risk factors, including in patients with 2 or more risk factors.

Ninety-five patients (84%) discontinued treatment due to treatment failure (n=50), death (n=21), unacceptable adverse events (n=6), relapse (n=5), their physician’s decision (n=5) or other reasons (n=8).

The all-cause mortality rate was 12% at 30 days and 31% at 60 days. The median overall survival (OS) was 7.0 months, and the 1-year OS rate was 34%.

Common grade 3/4 hematologic adverse events (occurring in 20% of patients or more) included thrombocytopenia (59%), febrile neutropenia (50%), anemia (49%), and neutropenia (29%).

Common grade 3/4 nonhematologic adverse events included sepsis (39%), pneumonia (30%), hypokalemia (25%), and oral mucositis/stomatitis (22%).

Ninety-one patients (81%) had one or more serious adverse event. The most common were pneumonia (24%), febrile neutropenia (21%), and oral mucositis/stomatitis (10%).

Of the 113 patients treated, 103 died. Most deaths (78%) were due to progressive disease.

Patients in group C (72 mg/m²) had the most favorable balance of safety and efficacy. They had faster hematologic recovery (a median of 27 days) than the other groups and the lowest incidence of aggregate sepsis (24%) and 30-day (7%) and 60-day (17%) all-cause mortality.

At this dose and schedule, CR and CR/CRp rates were 31% and 35%, respectively. The median OS was 7.7 months, and the 1-year OS rate was 38%.

“Publication of these data in the British Journal of Haematology further support our goal of establishing vosaroxin as a new standard of care in AML,” said Adam Craig, chief medical officer of Sunesis.

“Given ongoing demographic shifts in the US and other major territories, the challenge of treating AML in older adults will continue to grow, underscoring a need for new treatment options. We look forward to building on these data through further investigator-sponsored studies and, with the outcome of VALOR in relapsed or refractory AML, progressing towards initial regulatory approval.”

Based on results of the phase 3 VALOR trial, which were recently announced, Sunesis has filed a marketing authorization application with the European Medicines Agency and plans to meet with the US Food and Drug Administration to determine the appropriate regulatory path forward for vosaroxin in the treatment of relapsed or refractory AML.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

Researcher in the lab

Credit: NIH

A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.

The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.

NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.

“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.

“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”

Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).

Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.

To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.

The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.

The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.

Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.

One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.

AML cells

Credit: Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for the Axl inhibitor BGB324 to treat acute myeloid leukemia (AML).

BGB324 is a highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition, a key driver in drug resistance and metastasis.

BerGenBio, the company developing BGB324, has estimated that more than 50% of AML patients have elevated levels of Axl.

And a study published in Blood last year showed that Axl inhibition by BGB324 prompts antileukemic activity in FLT3-mutated and FLT3-wild-type AML.

Earlier this month, BerGenBio said the first patient had been dosed in its multicenter phase 1b trial of BGB324 in patients with AML.

The primary goal of this 2-part trial is to investigate the safety and tolerability of BGB324 as a single agent and in combination with cytarabine. Secondary endpoints include clinical response and assessment of novel biomarkers.

The study will be conducted at 6 sites in Norway, Germany, and the US. BerGenBio expects data from this trial to be available in 2015.

The FDA’s orphan designation will provide BerGenBio with access to various development incentives for BGB324.

This includes tax credits for qualified clinical testing, exemption from prescription drug user fees for BGB324 in AML, and 7 years of market exclusivity in the US upon FDA approval.

AML cells

Credit: Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for the Axl inhibitor BGB324 to treat acute myeloid leukemia (AML).

BGB324 is a highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition, a key driver in drug resistance and metastasis.

BerGenBio, the company developing BGB324, has estimated that more than 50% of AML patients have elevated levels of Axl.

And a study published in Blood last year showed that Axl inhibition by BGB324 prompts antileukemic activity in FLT3-mutated and FLT3-wild-type AML.

Earlier this month, BerGenBio said the first patient had been dosed in its multicenter phase 1b trial of BGB324 in patients with AML.

The primary goal of this 2-part trial is to investigate the safety and tolerability of BGB324 as a single agent and in combination with cytarabine. Secondary endpoints include clinical response and assessment of novel biomarkers.

The study will be conducted at 6 sites in Norway, Germany, and the US. BerGenBio expects data from this trial to be available in 2015.

The FDA’s orphan designation will provide BerGenBio with access to various development incentives for BGB324.

This includes tax credits for qualified clinical testing, exemption from prescription drug user fees for BGB324 in AML, and 7 years of market exclusivity in the US upon FDA approval.

AML cells

Credit: Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for the Axl inhibitor BGB324 to treat acute myeloid leukemia (AML).

BGB324 is a highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition, a key driver in drug resistance and metastasis.

BerGenBio, the company developing BGB324, has estimated that more than 50% of AML patients have elevated levels of Axl.

And a study published in Blood last year showed that Axl inhibition by BGB324 prompts antileukemic activity in FLT3-mutated and FLT3-wild-type AML.

Earlier this month, BerGenBio said the first patient had been dosed in its multicenter phase 1b trial of BGB324 in patients with AML.

The primary goal of this 2-part trial is to investigate the safety and tolerability of BGB324 as a single agent and in combination with cytarabine. Secondary endpoints include clinical response and assessment of novel biomarkers.

The study will be conducted at 6 sites in Norway, Germany, and the US. BerGenBio expects data from this trial to be available in 2015.

The FDA’s orphan designation will provide BerGenBio with access to various development incentives for BGB324.

This includes tax credits for qualified clinical testing, exemption from prescription drug user fees for BGB324 in AML, and 7 years of market exclusivity in the US upon FDA approval.

Daniel Pollyea, MD

Credit: University of Colorado

BARCELONA—An agent that inhibits isocitrate dehydrogenase (IDH) 1 shows the potential to transform therapy for certain patients with acute myeloid leukemia (AML), according to a speaker at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

The drug, known as AG-120, demonstrated clinical activity and was considered to be well-tolerated in a phase 1 study of patients with advanced, IDH1 mutant-positive AML.

Daniel Pollyea, MD, of the University of Colorado School of Medicine in Aurora, presented data on AG-120 at the symposium as abstract LBA1. The research was sponsored by Agios Pharmaceuticals, makers of AG-120.

“This is the first study in humans of an inhibitor of mutant IDH1 and the first demonstration of clinical activity of AG-120 in AML patients whose cancers have the IDH1 mutation,” Dr Pollyea said. “Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of phase 1 studies are to determine safety and tolerability.”

Dr Pollyea noted that mutations in IDH1 lead to a cascade of metabolic events that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which prevents cells from maturing into normal, functioning cells, and this leads to malignancy.

In this study, the researchers found that AG-120 reduced 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells.

The trial included 17 patients with relapsed and/or refractory AML, who had received a median of 2 prior treatments. Patients were scheduled to

receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous 28-day cycles.

Fourteen patients were evaluable for response, and 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. In the 4 patients who achieved a complete response, there was early evidence of durability, ranging from 15 days to 5 months. All responding patients remain on AG-120, and 1 patient with stable disease remains on the drug.

“AML is a devastating disease that has historically been very difficult to treat, and these findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” Dr Pollyea said.

He and his colleagues also found that AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction. This patient is in complete remission and remains on AG-120.

The maximum-tolerated dose of AG-120 has not been reached.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

Dr Pollyea and his colleagues are continuing this study with the aim of fully understanding the safety of the drug, determining the maximum-tolerated dose, and assessing its efficacy in treating AML and myelodysplastic syndromes.

Daniel Pollyea, MD

Credit: University of Colorado

BARCELONA—An agent that inhibits isocitrate dehydrogenase (IDH) 1 shows the potential to transform therapy for certain patients with acute myeloid leukemia (AML), according to a speaker at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

The drug, known as AG-120, demonstrated clinical activity and was considered to be well-tolerated in a phase 1 study of patients with advanced, IDH1 mutant-positive AML.

Daniel Pollyea, MD, of the University of Colorado School of Medicine in Aurora, presented data on AG-120 at the symposium as abstract LBA1. The research was sponsored by Agios Pharmaceuticals, makers of AG-120.

“This is the first study in humans of an inhibitor of mutant IDH1 and the first demonstration of clinical activity of AG-120 in AML patients whose cancers have the IDH1 mutation,” Dr Pollyea said. “Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of phase 1 studies are to determine safety and tolerability.”

Dr Pollyea noted that mutations in IDH1 lead to a cascade of metabolic events that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which prevents cells from maturing into normal, functioning cells, and this leads to malignancy.

In this study, the researchers found that AG-120 reduced 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells.

The trial included 17 patients with relapsed and/or refractory AML, who had received a median of 2 prior treatments. Patients were scheduled to

receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous 28-day cycles.

Fourteen patients were evaluable for response, and 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. In the 4 patients who achieved a complete response, there was early evidence of durability, ranging from 15 days to 5 months. All responding patients remain on AG-120, and 1 patient with stable disease remains on the drug.

“AML is a devastating disease that has historically been very difficult to treat, and these findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” Dr Pollyea said.

He and his colleagues also found that AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction. This patient is in complete remission and remains on AG-120.

The maximum-tolerated dose of AG-120 has not been reached.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

Dr Pollyea and his colleagues are continuing this study with the aim of fully understanding the safety of the drug, determining the maximum-tolerated dose, and assessing its efficacy in treating AML and myelodysplastic syndromes.

Daniel Pollyea, MD

Credit: University of Colorado

BARCELONA—An agent that inhibits isocitrate dehydrogenase (IDH) 1 shows the potential to transform therapy for certain patients with acute myeloid leukemia (AML), according to a speaker at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

The drug, known as AG-120, demonstrated clinical activity and was considered to be well-tolerated in a phase 1 study of patients with advanced, IDH1 mutant-positive AML.

Daniel Pollyea, MD, of the University of Colorado School of Medicine in Aurora, presented data on AG-120 at the symposium as abstract LBA1. The research was sponsored by Agios Pharmaceuticals, makers of AG-120.

“This is the first study in humans of an inhibitor of mutant IDH1 and the first demonstration of clinical activity of AG-120 in AML patients whose cancers have the IDH1 mutation,” Dr Pollyea said. “Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of phase 1 studies are to determine safety and tolerability.”

Dr Pollyea noted that mutations in IDH1 lead to a cascade of metabolic events that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which prevents cells from maturing into normal, functioning cells, and this leads to malignancy.

In this study, the researchers found that AG-120 reduced 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells.

The trial included 17 patients with relapsed and/or refractory AML, who had received a median of 2 prior treatments. Patients were scheduled to

receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous 28-day cycles.

Fourteen patients were evaluable for response, and 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. In the 4 patients who achieved a complete response, there was early evidence of durability, ranging from 15 days to 5 months. All responding patients remain on AG-120, and 1 patient with stable disease remains on the drug.

“AML is a devastating disease that has historically been very difficult to treat, and these findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” Dr Pollyea said.

He and his colleagues also found that AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction. This patient is in complete remission and remains on AG-120.

The maximum-tolerated dose of AG-120 has not been reached.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

Dr Pollyea and his colleagues are continuing this study with the aim of fully understanding the safety of the drug, determining the maximum-tolerated dose, and assessing its efficacy in treating AML and myelodysplastic syndromes.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

B-cell ALL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy JCAR015 to treat acute lymphoblastic leukemia (ALL).

The designation will provide the product’s developer, Juno Therapeutics, with multiple benefits, including the availability of grant money, certain tax credits, and 7 years of market exclusivity, as well as the possibility of an expedited regulatory process.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial.

Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following “persistent seizure activity.”

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases.

The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures.

The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation in another phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

B-cell ALL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy JCAR015 to treat acute lymphoblastic leukemia (ALL).

The designation will provide the product’s developer, Juno Therapeutics, with multiple benefits, including the availability of grant money, certain tax credits, and 7 years of market exclusivity, as well as the possibility of an expedited regulatory process.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial.

Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following “persistent seizure activity.”

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases.

The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures.

The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation in another phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

B-cell ALL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the chimeric antigen receptor (CAR) T-cell therapy JCAR015 to treat acute lymphoblastic leukemia (ALL).

The designation will provide the product’s developer, Juno Therapeutics, with multiple benefits, including the availability of grant money, certain tax credits, and 7 years of market exclusivity, as well as the possibility of an expedited regulatory process.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial.

Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following “persistent seizure activity.”

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases.

The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures.

The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation in another phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.