Leukemia, Myelodysplasia, Transplantation

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for midostaurin (PKC412) to treat acute myeloid leukemia (AML).

Midostaurin is a multi-targeted kinase inhibitor being developed for adults with newly diagnosed AML who are FLT3-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.

Breakthrough therapy designation is intended to expedite the development and review of new medicines intended to treat serious or life-threatening conditions. The therapy must demonstrate substantial improvement over an available therapy on at least one clinically significant endpoint.

The designation includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.

Phase 3 trial

The breakthrough designation for midostaurin is primarily based on the results of the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 717 patients with newly diagnosed, FLT3-positive AML who were younger than 60 at enrollment. All of the patients received standard induction and consolidation therapy. Roughly half also received midostaurin (n=360), while the other half received placebo (n=357).

Patients who received midostaurin experienced a significant improvement in overall survival (hazard ratio=0.77, P=0.0074). The median overall survival was 74.4 months in the midostaurin arm and 25.6 months in the placebo arm.

The median event-free survival was 8 months in the midostaurin arm and 3.6 months in the placebo arm (P=0.0032). The 5-year event-free survival was 27.5% for midostaurin and 19.3% for placebo.

There was no significant difference between the treatment arms with regard to most non-hematologic grade 3/4 adverse events. The exception was rash/desquamation, which occurred in 13% of patients in the midostaurin arm and 8% of patients in the placebo arm (P=0.02).

Other grade 3/4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation.

Midostaurin development

Novartis has opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable midostaurin access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.

To help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. which is leading regulatory submissions for a companion diagnostic.

Midostaurin is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for midostaurin (PKC412) to treat acute myeloid leukemia (AML).

Midostaurin is a multi-targeted kinase inhibitor being developed for adults with newly diagnosed AML who are FLT3-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.

Breakthrough therapy designation is intended to expedite the development and review of new medicines intended to treat serious or life-threatening conditions. The therapy must demonstrate substantial improvement over an available therapy on at least one clinically significant endpoint.

The designation includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.

Phase 3 trial

The breakthrough designation for midostaurin is primarily based on the results of the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 717 patients with newly diagnosed, FLT3-positive AML who were younger than 60 at enrollment. All of the patients received standard induction and consolidation therapy. Roughly half also received midostaurin (n=360), while the other half received placebo (n=357).

Patients who received midostaurin experienced a significant improvement in overall survival (hazard ratio=0.77, P=0.0074). The median overall survival was 74.4 months in the midostaurin arm and 25.6 months in the placebo arm.

The median event-free survival was 8 months in the midostaurin arm and 3.6 months in the placebo arm (P=0.0032). The 5-year event-free survival was 27.5% for midostaurin and 19.3% for placebo.

There was no significant difference between the treatment arms with regard to most non-hematologic grade 3/4 adverse events. The exception was rash/desquamation, which occurred in 13% of patients in the midostaurin arm and 8% of patients in the placebo arm (P=0.02).

Other grade 3/4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation.

Midostaurin development

Novartis has opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable midostaurin access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.

To help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. which is leading regulatory submissions for a companion diagnostic.

Midostaurin is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for midostaurin (PKC412) to treat acute myeloid leukemia (AML).

Midostaurin is a multi-targeted kinase inhibitor being developed for adults with newly diagnosed AML who are FLT3-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.

Breakthrough therapy designation is intended to expedite the development and review of new medicines intended to treat serious or life-threatening conditions. The therapy must demonstrate substantial improvement over an available therapy on at least one clinically significant endpoint.

The designation includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.

Phase 3 trial

The breakthrough designation for midostaurin is primarily based on the results of the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 717 patients with newly diagnosed, FLT3-positive AML who were younger than 60 at enrollment. All of the patients received standard induction and consolidation therapy. Roughly half also received midostaurin (n=360), while the other half received placebo (n=357).

Patients who received midostaurin experienced a significant improvement in overall survival (hazard ratio=0.77, P=0.0074). The median overall survival was 74.4 months in the midostaurin arm and 25.6 months in the placebo arm.

The median event-free survival was 8 months in the midostaurin arm and 3.6 months in the placebo arm (P=0.0032). The 5-year event-free survival was 27.5% for midostaurin and 19.3% for placebo.

There was no significant difference between the treatment arms with regard to most non-hematologic grade 3/4 adverse events. The exception was rash/desquamation, which occurred in 13% of patients in the midostaurin arm and 8% of patients in the placebo arm (P=0.02).

Other grade 3/4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation.

Midostaurin development

Novartis has opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable midostaurin access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.

To help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. which is leading regulatory submissions for a companion diagnostic.

Midostaurin is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

An experimental treatment targeting a form of acute myeloid leukemia has been designated a breakthrough therapy by the Food and Drug Administration, according to the drug’s manufacturer.

Midostaurin (Novartis) is an oral drug used alongside standard chemotherapy for adults with newly-diagnosed AML who are positive for the FMS-like tyrosine 3 (FLT-3) mutation and can undergo chemotherapy. AML has the lowest survival rate of all leukemias, and about one-third of AML patients have the FLT-3 mutation.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

The FDA’s breakthrough therapy designation, in place since 2012, is an intensive form of fast-tracking in which the agency offers the manufacturer more guidance on an efficient drug development program and a higher level of organizational support, though future approval is not guaranteed. To qualify, a therapy must come with preliminary clinical evidence demonstrating substantial improvement on at least one clinically significant endpoint over available therapy, according to the agency.

Results from a phase III clinical trial, presented in December 2015 at the 57th annual meeting of the American Society of Hematology, showed that among 717 patients randomized to receive midostaurin alongside standard induction and consolidation chemotherapy or the same chemotherapy protocol alone, the midostaurin group saw significant improvement in overall survival (hazard ratio, 0.77, P = .0074).

Mean OS for patients in the midostaurin arm was 74.7 months (95% CI: 31.7, not attained), compared with 25.6 months for the placebo arm (18.6, 42.9). Median follow-up in the study was 57 months for surviving patients.

In a news release Feb. 19, Novartis said that midostaurin would be submitted for FDA approval for FLT-3-positive AML and that the company had launched compassionate use and expanded access programs allowing newly diagnosed patients aged 18 and older to receive midostaurin alongside standard induction and consolidation therapy. No targeted AML treatments are currently approved by FDA.

FLT3 is a receptor tyrosine kinase that plays a role in the proliferation in the number of certain blood cells. Midostaurin is a multi-targeted kinase inhibitor that is also being investigated for the treatment of aggressive systemic mast cell leukemia, according to Novartis.

An experimental treatment targeting a form of acute myeloid leukemia has been designated a breakthrough therapy by the Food and Drug Administration, according to the drug’s manufacturer.

Midostaurin (Novartis) is an oral drug used alongside standard chemotherapy for adults with newly-diagnosed AML who are positive for the FMS-like tyrosine 3 (FLT-3) mutation and can undergo chemotherapy. AML has the lowest survival rate of all leukemias, and about one-third of AML patients have the FLT-3 mutation.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

The FDA’s breakthrough therapy designation, in place since 2012, is an intensive form of fast-tracking in which the agency offers the manufacturer more guidance on an efficient drug development program and a higher level of organizational support, though future approval is not guaranteed. To qualify, a therapy must come with preliminary clinical evidence demonstrating substantial improvement on at least one clinically significant endpoint over available therapy, according to the agency.

Results from a phase III clinical trial, presented in December 2015 at the 57th annual meeting of the American Society of Hematology, showed that among 717 patients randomized to receive midostaurin alongside standard induction and consolidation chemotherapy or the same chemotherapy protocol alone, the midostaurin group saw significant improvement in overall survival (hazard ratio, 0.77, P = .0074).

Mean OS for patients in the midostaurin arm was 74.7 months (95% CI: 31.7, not attained), compared with 25.6 months for the placebo arm (18.6, 42.9). Median follow-up in the study was 57 months for surviving patients.

In a news release Feb. 19, Novartis said that midostaurin would be submitted for FDA approval for FLT-3-positive AML and that the company had launched compassionate use and expanded access programs allowing newly diagnosed patients aged 18 and older to receive midostaurin alongside standard induction and consolidation therapy. No targeted AML treatments are currently approved by FDA.

FLT3 is a receptor tyrosine kinase that plays a role in the proliferation in the number of certain blood cells. Midostaurin is a multi-targeted kinase inhibitor that is also being investigated for the treatment of aggressive systemic mast cell leukemia, according to Novartis.

An experimental treatment targeting a form of acute myeloid leukemia has been designated a breakthrough therapy by the Food and Drug Administration, according to the drug’s manufacturer.

Midostaurin (Novartis) is an oral drug used alongside standard chemotherapy for adults with newly-diagnosed AML who are positive for the FMS-like tyrosine 3 (FLT-3) mutation and can undergo chemotherapy. AML has the lowest survival rate of all leukemias, and about one-third of AML patients have the FLT-3 mutation.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

The FDA’s breakthrough therapy designation, in place since 2012, is an intensive form of fast-tracking in which the agency offers the manufacturer more guidance on an efficient drug development program and a higher level of organizational support, though future approval is not guaranteed. To qualify, a therapy must come with preliminary clinical evidence demonstrating substantial improvement on at least one clinically significant endpoint over available therapy, according to the agency.

Results from a phase III clinical trial, presented in December 2015 at the 57th annual meeting of the American Society of Hematology, showed that among 717 patients randomized to receive midostaurin alongside standard induction and consolidation chemotherapy or the same chemotherapy protocol alone, the midostaurin group saw significant improvement in overall survival (hazard ratio, 0.77, P = .0074).

Mean OS for patients in the midostaurin arm was 74.7 months (95% CI: 31.7, not attained), compared with 25.6 months for the placebo arm (18.6, 42.9). Median follow-up in the study was 57 months for surviving patients.

In a news release Feb. 19, Novartis said that midostaurin would be submitted for FDA approval for FLT-3-positive AML and that the company had launched compassionate use and expanded access programs allowing newly diagnosed patients aged 18 and older to receive midostaurin alongside standard induction and consolidation therapy. No targeted AML treatments are currently approved by FDA.

FLT3 is a receptor tyrosine kinase that plays a role in the proliferation in the number of certain blood cells. Midostaurin is a multi-targeted kinase inhibitor that is also being investigated for the treatment of aggressive systemic mast cell leukemia, according to Novartis.

Lab mouse

The gene EZH2 is a driver of, and potential therapeutic target for, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), according to a new study.

A previous study, published in Nature in 2012, suggested that nearly half of ETP-ALLs have inactivating alterations in EZH2.

Loss of EZH2 function can inactivate Polycomb repressive complex 2 (PRC2), but it was not clear how PRC2 loss-of-function mutations would aid leukemia growth.

The new study, published in Cell Reports, provides some insight.

Tobias Neff, MD, of the University of Colorado Denver in Aurora, and his colleagues developed a mouse model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL.

Experiments with this model revealed that inactivation of EZH2 helps accelerate leukemia development and enhances a stem-cell-related transcriptional program.

“We have 2 major features of [ETP-ALL]—stem-like cells and increased growth—and, now, we show an actor implicated in both—namely, EZH2/PRC2,” Dr Neff said.

“How exactly the stem-cell-like gene expression profile contributes to the aggressiveness of ETP-ALL is unknown, but we’ve known that these stem-like cells are associated with poor prognosis in acute leukemia.”

The researchers also found that EZH2 inactivation resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. This led them to wonder whether the JAK/STAT pathway might be important in their ETP-ALL model.

The team tested the JAK1/2 inhibitor ruxolitinib in NRASQ61K cells with EZH2 deletion and observed inhibition of cell growth.

“Ruxolitinib is unlikely to treat the disease by itself, but this model will help us test possible drug combinations that could eventually benefit ETP-ALL patients,” Dr Neff said.

He and his colleagues also plan to test the activity of different drugs against other cell types with inactivated EZH2.

“In addition to our specific finding in this disease, we are excited to now have a model that allows us to explore consequences of EZH2 inactivation that may enrich our understanding of a number of other conditions with a similar set of genetic changes,” Dr Neff said.

He and his colleagues noted that EZH2 is known to be inactivated in myelodysplastic syndromes, myeloproliferative neoplasms, and other hematologic malignancies.

Lab mouse

The gene EZH2 is a driver of, and potential therapeutic target for, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), according to a new study.

A previous study, published in Nature in 2012, suggested that nearly half of ETP-ALLs have inactivating alterations in EZH2.

Loss of EZH2 function can inactivate Polycomb repressive complex 2 (PRC2), but it was not clear how PRC2 loss-of-function mutations would aid leukemia growth.

The new study, published in Cell Reports, provides some insight.

Tobias Neff, MD, of the University of Colorado Denver in Aurora, and his colleagues developed a mouse model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL.

Experiments with this model revealed that inactivation of EZH2 helps accelerate leukemia development and enhances a stem-cell-related transcriptional program.

“We have 2 major features of [ETP-ALL]—stem-like cells and increased growth—and, now, we show an actor implicated in both—namely, EZH2/PRC2,” Dr Neff said.

“How exactly the stem-cell-like gene expression profile contributes to the aggressiveness of ETP-ALL is unknown, but we’ve known that these stem-like cells are associated with poor prognosis in acute leukemia.”

The researchers also found that EZH2 inactivation resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. This led them to wonder whether the JAK/STAT pathway might be important in their ETP-ALL model.

The team tested the JAK1/2 inhibitor ruxolitinib in NRASQ61K cells with EZH2 deletion and observed inhibition of cell growth.

“Ruxolitinib is unlikely to treat the disease by itself, but this model will help us test possible drug combinations that could eventually benefit ETP-ALL patients,” Dr Neff said.

He and his colleagues also plan to test the activity of different drugs against other cell types with inactivated EZH2.

“In addition to our specific finding in this disease, we are excited to now have a model that allows us to explore consequences of EZH2 inactivation that may enrich our understanding of a number of other conditions with a similar set of genetic changes,” Dr Neff said.

He and his colleagues noted that EZH2 is known to be inactivated in myelodysplastic syndromes, myeloproliferative neoplasms, and other hematologic malignancies.

Lab mouse

The gene EZH2 is a driver of, and potential therapeutic target for, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), according to a new study.

A previous study, published in Nature in 2012, suggested that nearly half of ETP-ALLs have inactivating alterations in EZH2.

Loss of EZH2 function can inactivate Polycomb repressive complex 2 (PRC2), but it was not clear how PRC2 loss-of-function mutations would aid leukemia growth.

The new study, published in Cell Reports, provides some insight.

Tobias Neff, MD, of the University of Colorado Denver in Aurora, and his colleagues developed a mouse model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL.

Experiments with this model revealed that inactivation of EZH2 helps accelerate leukemia development and enhances a stem-cell-related transcriptional program.

“We have 2 major features of [ETP-ALL]—stem-like cells and increased growth—and, now, we show an actor implicated in both—namely, EZH2/PRC2,” Dr Neff said.

“How exactly the stem-cell-like gene expression profile contributes to the aggressiveness of ETP-ALL is unknown, but we’ve known that these stem-like cells are associated with poor prognosis in acute leukemia.”

The researchers also found that EZH2 inactivation resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. This led them to wonder whether the JAK/STAT pathway might be important in their ETP-ALL model.

The team tested the JAK1/2 inhibitor ruxolitinib in NRASQ61K cells with EZH2 deletion and observed inhibition of cell growth.

“Ruxolitinib is unlikely to treat the disease by itself, but this model will help us test possible drug combinations that could eventually benefit ETP-ALL patients,” Dr Neff said.

He and his colleagues also plan to test the activity of different drugs against other cell types with inactivated EZH2.

“In addition to our specific finding in this disease, we are excited to now have a model that allows us to explore consequences of EZH2 inactivation that may enrich our understanding of a number of other conditions with a similar set of genetic changes,” Dr Neff said.

He and his colleagues noted that EZH2 is known to be inactivated in myelodysplastic syndromes, myeloproliferative neoplasms, and other hematologic malignancies.

Father and son

A study of Norwegian men has revealed several factors that may help predict reproductive problems among males diagnosed with cancer before age 25.

Cancer type, age at diagnosis, and time period of diagnosis were all associated with the likelihood of paternity.

And although cancer survivors were less likely to reproduce and more likely to use assisted reproductive technology, their first offspring were no less healthy than the offspring of control subjects.

This research was published in the British Journal of Cancer.

The study began with all Norwegian men born between 1965 and 1985 (n=626,495). The researchers excluded men who emigrated or died before reaching fertile age, which left 2687 men who were diagnosed with cancer before age 25 and 607,668 cancer-free controls.

The most common cancers were testicular cancer (27%), CNS tumors (18%), lymphoma (15%), and leukemia (13%). Thirty percent of the cancer cases were diagnosed in childhood (0–14 years of age), 26% in adolescence (15–19 years), and 43% in young adulthood (20–24 years).

Nine percent (n=247) of cancer cases were diagnosed from 1965 through 1979, 50% (n=1346) from 1980 through 1994, and 41% (n=1094) from 1995 through 2007.

The cancer survivors were less likely to have children than controls, with a hazard ratio (HR) of 0.72.

The reduction in paternity was significant for survivors of leukemia (HR=0.78), lymphoma (HR=0.78), testicular cancer (HR=0.77), CNS tumors (HR=0.45), bone tumors (HR=0.69), sympathetic nervous system tumors (HR=0.50), and retinoblastoma (HR=0.52).

The reduction in paternity was also more pronounced for cancer patients diagnosed before 1995. The HR was 0.61 for those diagnosed from 1965 through 1979 and 0.66 for those diagnosed from 1980 through 1994.

Patients who were diagnosed before age 15 were less likely to reproduce as well, with an HR of 0.59.

“These finds are important for male cancer survivors, seeing as we can identify groups at risk of having reproduction problems,” said study author Maria Winther Gunnes, a PhD candidate at the University of Bergen in Norway.

Another finding was that male cancer survivors were more likely than controls to have pregnancies resulting from assisted reproductive technology. The relative risk was 3.32.

When assessed by cancer type, the relative risk was 2.29 for leukemia, 3.79 for lymphoma, 2.41 for CNS tumors, 5.71 for sympathetic nervous system tumors, 2.20 for renal tumors, 4.77 for bone tumors, 1.32 for soft tissue sarcomas, 3.70 for testicular cancer, 4.36 for thyroid carcinoma, and 0.45 for malignant melanoma.

There was no increased risk among the first offspring of cancer survivors for perinatal death, congenital malformations, being small for gestational age, low birth weight, or preterm birth.

“It is important to be able to assure young male cancer survivors that their illness and treatment will not have a negative impact on their own children,” Gunnes said.

Father and son

A study of Norwegian men has revealed several factors that may help predict reproductive problems among males diagnosed with cancer before age 25.

Cancer type, age at diagnosis, and time period of diagnosis were all associated with the likelihood of paternity.

And although cancer survivors were less likely to reproduce and more likely to use assisted reproductive technology, their first offspring were no less healthy than the offspring of control subjects.

This research was published in the British Journal of Cancer.

The study began with all Norwegian men born between 1965 and 1985 (n=626,495). The researchers excluded men who emigrated or died before reaching fertile age, which left 2687 men who were diagnosed with cancer before age 25 and 607,668 cancer-free controls.

The most common cancers were testicular cancer (27%), CNS tumors (18%), lymphoma (15%), and leukemia (13%). Thirty percent of the cancer cases were diagnosed in childhood (0–14 years of age), 26% in adolescence (15–19 years), and 43% in young adulthood (20–24 years).

Nine percent (n=247) of cancer cases were diagnosed from 1965 through 1979, 50% (n=1346) from 1980 through 1994, and 41% (n=1094) from 1995 through 2007.

The cancer survivors were less likely to have children than controls, with a hazard ratio (HR) of 0.72.

The reduction in paternity was significant for survivors of leukemia (HR=0.78), lymphoma (HR=0.78), testicular cancer (HR=0.77), CNS tumors (HR=0.45), bone tumors (HR=0.69), sympathetic nervous system tumors (HR=0.50), and retinoblastoma (HR=0.52).

The reduction in paternity was also more pronounced for cancer patients diagnosed before 1995. The HR was 0.61 for those diagnosed from 1965 through 1979 and 0.66 for those diagnosed from 1980 through 1994.

Patients who were diagnosed before age 15 were less likely to reproduce as well, with an HR of 0.59.

“These finds are important for male cancer survivors, seeing as we can identify groups at risk of having reproduction problems,” said study author Maria Winther Gunnes, a PhD candidate at the University of Bergen in Norway.

Another finding was that male cancer survivors were more likely than controls to have pregnancies resulting from assisted reproductive technology. The relative risk was 3.32.

When assessed by cancer type, the relative risk was 2.29 for leukemia, 3.79 for lymphoma, 2.41 for CNS tumors, 5.71 for sympathetic nervous system tumors, 2.20 for renal tumors, 4.77 for bone tumors, 1.32 for soft tissue sarcomas, 3.70 for testicular cancer, 4.36 for thyroid carcinoma, and 0.45 for malignant melanoma.

There was no increased risk among the first offspring of cancer survivors for perinatal death, congenital malformations, being small for gestational age, low birth weight, or preterm birth.

“It is important to be able to assure young male cancer survivors that their illness and treatment will not have a negative impact on their own children,” Gunnes said.

Father and son

A study of Norwegian men has revealed several factors that may help predict reproductive problems among males diagnosed with cancer before age 25.

Cancer type, age at diagnosis, and time period of diagnosis were all associated with the likelihood of paternity.

And although cancer survivors were less likely to reproduce and more likely to use assisted reproductive technology, their first offspring were no less healthy than the offspring of control subjects.

This research was published in the British Journal of Cancer.

The study began with all Norwegian men born between 1965 and 1985 (n=626,495). The researchers excluded men who emigrated or died before reaching fertile age, which left 2687 men who were diagnosed with cancer before age 25 and 607,668 cancer-free controls.

The most common cancers were testicular cancer (27%), CNS tumors (18%), lymphoma (15%), and leukemia (13%). Thirty percent of the cancer cases were diagnosed in childhood (0–14 years of age), 26% in adolescence (15–19 years), and 43% in young adulthood (20–24 years).

Nine percent (n=247) of cancer cases were diagnosed from 1965 through 1979, 50% (n=1346) from 1980 through 1994, and 41% (n=1094) from 1995 through 2007.

The cancer survivors were less likely to have children than controls, with a hazard ratio (HR) of 0.72.

The reduction in paternity was significant for survivors of leukemia (HR=0.78), lymphoma (HR=0.78), testicular cancer (HR=0.77), CNS tumors (HR=0.45), bone tumors (HR=0.69), sympathetic nervous system tumors (HR=0.50), and retinoblastoma (HR=0.52).

The reduction in paternity was also more pronounced for cancer patients diagnosed before 1995. The HR was 0.61 for those diagnosed from 1965 through 1979 and 0.66 for those diagnosed from 1980 through 1994.

Patients who were diagnosed before age 15 were less likely to reproduce as well, with an HR of 0.59.

“These finds are important for male cancer survivors, seeing as we can identify groups at risk of having reproduction problems,” said study author Maria Winther Gunnes, a PhD candidate at the University of Bergen in Norway.

Another finding was that male cancer survivors were more likely than controls to have pregnancies resulting from assisted reproductive technology. The relative risk was 3.32.

When assessed by cancer type, the relative risk was 2.29 for leukemia, 3.79 for lymphoma, 2.41 for CNS tumors, 5.71 for sympathetic nervous system tumors, 2.20 for renal tumors, 4.77 for bone tumors, 1.32 for soft tissue sarcomas, 3.70 for testicular cancer, 4.36 for thyroid carcinoma, and 0.45 for malignant melanoma.

There was no increased risk among the first offspring of cancer survivors for perinatal death, congenital malformations, being small for gestational age, low birth weight, or preterm birth.

“It is important to be able to assure young male cancer survivors that their illness and treatment will not have a negative impact on their own children,” Gunnes said.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Children reading

Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.

Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.

“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”

The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).

The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.

Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).

The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.

Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).

Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).

“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.

“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”

Children reading

Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.

Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.

“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”

The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).

The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.

Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).

The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.

Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).

Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).

“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.

“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”

Children reading

Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.

Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.

“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”

The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).

The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.

Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).

The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.

Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).

Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).

“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.

“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”

Researchers from University Hospital Tübingen, Germany, say that although the data for treating acute leukemia with dronabinol (THC), a cannabinoid derivative, are “controversial,” it has been shown to have antitumor potential for several cancers. When the researchers tested THC in several leukemia cell lines and native leukemia blasts cultured ex vivo, they found “meaningful” antiproliferative and proapoptotic effects.

Related: Lawmakers Urge VA to Reform Medical Marijuana Rules

From the data, they also found cannabinoid receptor agonists may be useful as low-toxic agents, especially for patients who are “heavily pretreated,” elderly, or have refractory disease. Evidence was cited that THC retained antileukemic activity in a sample from a patient with otherwise chemotherapy- and steroid-refractory acute lymphocytic leukemia (ALL).

Related: Veterans’ Use of Designer Cathinones and Cannabinoids

Due to the excellent safety profile of THC, the researchers say, effective doses are achievable in vivo, although tolerable doses may vary widely. They suggest starting with a subeffective dose and increasing gradually, which will help the patient build tolerance to the well-known psychoactive effects, which have been a drawback to widespread use of THC for patients with cancer.

They add that, due to sparse densities of cannabinoid receptors in lower brain stem areas, severe intoxications with THC rarely have been reported.

Related: Surgeon General Murthy Discusses Marijuana Efficacy

In addition to the direct antileukemic effects, the researchers suggest that therapeutic use of THC has many desirable adverse effects, such as general physical well-being, cachexia control, and relief of pain, anxiety and stress—which, they note, should “facilitate the decision process.”

Source:
Kampa-Schittenhelm KM, Salitzky O, Akmut F, et al. BMC Cancer. 2016;16(25)1-12.
doi: 10.1186/s12885-015-2029.

Researchers from University Hospital Tübingen, Germany, say that although the data for treating acute leukemia with dronabinol (THC), a cannabinoid derivative, are “controversial,” it has been shown to have antitumor potential for several cancers. When the researchers tested THC in several leukemia cell lines and native leukemia blasts cultured ex vivo, they found “meaningful” antiproliferative and proapoptotic effects.

Related: Lawmakers Urge VA to Reform Medical Marijuana Rules

From the data, they also found cannabinoid receptor agonists may be useful as low-toxic agents, especially for patients who are “heavily pretreated,” elderly, or have refractory disease. Evidence was cited that THC retained antileukemic activity in a sample from a patient with otherwise chemotherapy- and steroid-refractory acute lymphocytic leukemia (ALL).

Related: Veterans’ Use of Designer Cathinones and Cannabinoids

Due to the excellent safety profile of THC, the researchers say, effective doses are achievable in vivo, although tolerable doses may vary widely. They suggest starting with a subeffective dose and increasing gradually, which will help the patient build tolerance to the well-known psychoactive effects, which have been a drawback to widespread use of THC for patients with cancer.

They add that, due to sparse densities of cannabinoid receptors in lower brain stem areas, severe intoxications with THC rarely have been reported.

Related: Surgeon General Murthy Discusses Marijuana Efficacy

In addition to the direct antileukemic effects, the researchers suggest that therapeutic use of THC has many desirable adverse effects, such as general physical well-being, cachexia control, and relief of pain, anxiety and stress—which, they note, should “facilitate the decision process.”

Source:
Kampa-Schittenhelm KM, Salitzky O, Akmut F, et al. BMC Cancer. 2016;16(25)1-12.
doi: 10.1186/s12885-015-2029.

Researchers from University Hospital Tübingen, Germany, say that although the data for treating acute leukemia with dronabinol (THC), a cannabinoid derivative, are “controversial,” it has been shown to have antitumor potential for several cancers. When the researchers tested THC in several leukemia cell lines and native leukemia blasts cultured ex vivo, they found “meaningful” antiproliferative and proapoptotic effects.

Related: Lawmakers Urge VA to Reform Medical Marijuana Rules

From the data, they also found cannabinoid receptor agonists may be useful as low-toxic agents, especially for patients who are “heavily pretreated,” elderly, or have refractory disease. Evidence was cited that THC retained antileukemic activity in a sample from a patient with otherwise chemotherapy- and steroid-refractory acute lymphocytic leukemia (ALL).

Related: Veterans’ Use of Designer Cathinones and Cannabinoids

Due to the excellent safety profile of THC, the researchers say, effective doses are achievable in vivo, although tolerable doses may vary widely. They suggest starting with a subeffective dose and increasing gradually, which will help the patient build tolerance to the well-known psychoactive effects, which have been a drawback to widespread use of THC for patients with cancer.

They add that, due to sparse densities of cannabinoid receptors in lower brain stem areas, severe intoxications with THC rarely have been reported.

Related: Surgeon General Murthy Discusses Marijuana Efficacy

In addition to the direct antileukemic effects, the researchers suggest that therapeutic use of THC has many desirable adverse effects, such as general physical well-being, cachexia control, and relief of pain, anxiety and stress—which, they note, should “facilitate the decision process.”

Source:
Kampa-Schittenhelm KM, Salitzky O, Akmut F, et al. BMC Cancer. 2016;16(25)1-12.
doi: 10.1186/s12885-015-2029.

Dendritic cells in the skin

Dendritic cells may play a key role in T-cell acute lymphoblastic leukemia (T-ALL), according to research published in PNAS.

Investigators identified tumor-associated dendritic cells that appeared to promote T-ALL growth and survival at primary and metastatic tumor sites in mice.

Analyses of samples from patients with T-ALL suggested dendritic cells are positioned to support T-ALL growth in humans as well.

“It’s only more recently that people have really appreciated that tumors are complex organs in and of themselves, with all of the heterogenous cell types that can talk to each other and promote each other’s survival and proliferation,” said study author Lauren Ehrlich, PhD, of the University of Texas at Austin.

Dr Ehrlich and her colleagues first found that primary T-ALL cells required tumor stroma for survival ex vivo. When T-ALL cells were cultured alone or in wild-type thymic stroma, the cells died off. Only T-ALL cells cultured with tumor-associated stroma survived.

Subsequent experiments suggested it was tumor-associated dendritic cells that spurred T-ALL growth, both for newly developing T-ALL cells and tumors that had spread to distant organs in mouse models. Tissue samples from pediatric T-ALL patients had similar growth environments with abundant dendritic cells.

To determine the mechanism by which dendritic cells support T-ALL, the investigators performed gene expression profiling. They found upregulation of PDGFRB and IGF1R on T-ALL cells, with concomitant expression of their ligands by tumor-associated dendritic cells.

The team said PDGFRB and IGF1R were activated in T-ALL cells ex vivo. And when they cocultured T-ALL cells with tumor-associated dendritic cells, they observed sustained IGF1R activation. However, they did not see this activation when they cocultured T-ALL cells with normal thymic dendritic cells.

Finally, the investigators found that IGF1R signaling was necessary for dendritic cell-mediated T-ALL survival.

The team said this is the first evidence that endogenous tumor-associated dendritic cells supply signals driving T-ALL growth.

“We hope this study will be a catalyst to spur other research groups to further elucidate the roles of dendritic cells in supporting T-ALL,” said study author Todd Triplett, PhD, also of the University of Texas at Austin.

“[T]hat could ultimately lead to the discovery of novel therapeutic targets that are more effective and less toxic than current treatment regimens.”

Dendritic cells in the skin

Dendritic cells may play a key role in T-cell acute lymphoblastic leukemia (T-ALL), according to research published in PNAS.

Investigators identified tumor-associated dendritic cells that appeared to promote T-ALL growth and survival at primary and metastatic tumor sites in mice.

Analyses of samples from patients with T-ALL suggested dendritic cells are positioned to support T-ALL growth in humans as well.

“It’s only more recently that people have really appreciated that tumors are complex organs in and of themselves, with all of the heterogenous cell types that can talk to each other and promote each other’s survival and proliferation,” said study author Lauren Ehrlich, PhD, of the University of Texas at Austin.

Dr Ehrlich and her colleagues first found that primary T-ALL cells required tumor stroma for survival ex vivo. When T-ALL cells were cultured alone or in wild-type thymic stroma, the cells died off. Only T-ALL cells cultured with tumor-associated stroma survived.

Subsequent experiments suggested it was tumor-associated dendritic cells that spurred T-ALL growth, both for newly developing T-ALL cells and tumors that had spread to distant organs in mouse models. Tissue samples from pediatric T-ALL patients had similar growth environments with abundant dendritic cells.

To determine the mechanism by which dendritic cells support T-ALL, the investigators performed gene expression profiling. They found upregulation of PDGFRB and IGF1R on T-ALL cells, with concomitant expression of their ligands by tumor-associated dendritic cells.

The team said PDGFRB and IGF1R were activated in T-ALL cells ex vivo. And when they cocultured T-ALL cells with tumor-associated dendritic cells, they observed sustained IGF1R activation. However, they did not see this activation when they cocultured T-ALL cells with normal thymic dendritic cells.

Finally, the investigators found that IGF1R signaling was necessary for dendritic cell-mediated T-ALL survival.

The team said this is the first evidence that endogenous tumor-associated dendritic cells supply signals driving T-ALL growth.

“We hope this study will be a catalyst to spur other research groups to further elucidate the roles of dendritic cells in supporting T-ALL,” said study author Todd Triplett, PhD, also of the University of Texas at Austin.

“[T]hat could ultimately lead to the discovery of novel therapeutic targets that are more effective and less toxic than current treatment regimens.”

Dendritic cells in the skin

Dendritic cells may play a key role in T-cell acute lymphoblastic leukemia (T-ALL), according to research published in PNAS.

Investigators identified tumor-associated dendritic cells that appeared to promote T-ALL growth and survival at primary and metastatic tumor sites in mice.

Analyses of samples from patients with T-ALL suggested dendritic cells are positioned to support T-ALL growth in humans as well.

“It’s only more recently that people have really appreciated that tumors are complex organs in and of themselves, with all of the heterogenous cell types that can talk to each other and promote each other’s survival and proliferation,” said study author Lauren Ehrlich, PhD, of the University of Texas at Austin.

Dr Ehrlich and her colleagues first found that primary T-ALL cells required tumor stroma for survival ex vivo. When T-ALL cells were cultured alone or in wild-type thymic stroma, the cells died off. Only T-ALL cells cultured with tumor-associated stroma survived.

Subsequent experiments suggested it was tumor-associated dendritic cells that spurred T-ALL growth, both for newly developing T-ALL cells and tumors that had spread to distant organs in mouse models. Tissue samples from pediatric T-ALL patients had similar growth environments with abundant dendritic cells.

To determine the mechanism by which dendritic cells support T-ALL, the investigators performed gene expression profiling. They found upregulation of PDGFRB and IGF1R on T-ALL cells, with concomitant expression of their ligands by tumor-associated dendritic cells.

The team said PDGFRB and IGF1R were activated in T-ALL cells ex vivo. And when they cocultured T-ALL cells with tumor-associated dendritic cells, they observed sustained IGF1R activation. However, they did not see this activation when they cocultured T-ALL cells with normal thymic dendritic cells.

Finally, the investigators found that IGF1R signaling was necessary for dendritic cell-mediated T-ALL survival.

The team said this is the first evidence that endogenous tumor-associated dendritic cells supply signals driving T-ALL growth.

“We hope this study will be a catalyst to spur other research groups to further elucidate the roles of dendritic cells in supporting T-ALL,” said study author Todd Triplett, PhD, also of the University of Texas at Austin.

“[T]hat could ultimately lead to the discovery of novel therapeutic targets that are more effective and less toxic than current treatment regimens.”