Leukemia, Myelodysplasia, Transplantation

Mantle cell lymphoma

PHILADELPHIA—The Bcl-2 inhibitor ABT-199 and the Bruton tyrosine kinase inhibitor ibrutinib can have a synergistic effect against mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), preclinical data suggest.

In one set of experiments with MCL and CLL samples, the drugs induced apoptosis at a much higher rate when used together than when used alone.

However, in other experiments with CLL samples, ABT-199 and ibrutinib did not consistently display synergistic cytoxicity.

The researchers said this indicates substantial patient heterogeneity in response to the combination that may be due to variations in the genetic landscape.

Michael J. Weber, PhD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues presented this research at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“We took an empirical but systematic approach to identify combinations of drugs that might improve the ability of ibrutinib to kill cancer cells,” Dr Weber said. “The combination of ibrutinib and ABT-199 was, by far, the most effective in our assays, and we are in the very earliest stages of planning a clinical trial to test this combination in the clinic.”

In previous studies, Dr Weber and his colleagues found that ibrutinib synergized with both ABT-199 and the proteasome inhibitor carfilzomib to kill MCL cell lines. In this study, the team assessed the effects of exposure to these 2 combinations on samples from patients with MCL or CLL.

The researchers found that apoptosis occurred in 23% of cells exposed to ABT-199 and ibrutinib in combination, compared to 3.8% of cells exposed to ibrutinib and 3% exposed to ABT-199.

The combination of ibrutinib and carfilzomib also increased apoptosis in MCL and CLL cells compared to either agent alone, though to a lesser degree than the ABT-199 combination. Apoptosis occurred in 5.5% of cells exposed to ibrutinib and carfilzomib, 3.8% exposed to ibrutinib, and 1.7% exposed to carfilzomib.

The researchers observed minimal apoptosis in normal T cells, both with the single agents and the combinations.

Further analysis showed that ibrutinib and ABT-199 worked synergistically to cause apoptosis in leukemic cells from 5 of 9 patients with CLL.

According to Dr Weber, the variable response to this combination points to the importance of understanding how these combinations work, so we can match the treatments with the most appropriate patients.

“Ibrutinib and ABT-199 target different pathways involved in promoting cancer cell survival and growth,” Dr Weber said.

“This is very intriguing because, in most instances where cancer cells are resistant to a particular molecularly targeted drug, we find that cancer cells adapt and find new ways to reactivate the pathway being targeted by the drug and that combinations of drugs targeting this pathway in different ways can improve outcomes. Here, we found that targeting a pathway outside the primary pathway was effective.”

This study was funded by the University of Virginia Cancer Center. Dr Weber declared no conflicts of interest.

Mantle cell lymphoma

PHILADELPHIA—The Bcl-2 inhibitor ABT-199 and the Bruton tyrosine kinase inhibitor ibrutinib can have a synergistic effect against mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), preclinical data suggest.

In one set of experiments with MCL and CLL samples, the drugs induced apoptosis at a much higher rate when used together than when used alone.

However, in other experiments with CLL samples, ABT-199 and ibrutinib did not consistently display synergistic cytoxicity.

The researchers said this indicates substantial patient heterogeneity in response to the combination that may be due to variations in the genetic landscape.

Michael J. Weber, PhD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues presented this research at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“We took an empirical but systematic approach to identify combinations of drugs that might improve the ability of ibrutinib to kill cancer cells,” Dr Weber said. “The combination of ibrutinib and ABT-199 was, by far, the most effective in our assays, and we are in the very earliest stages of planning a clinical trial to test this combination in the clinic.”

In previous studies, Dr Weber and his colleagues found that ibrutinib synergized with both ABT-199 and the proteasome inhibitor carfilzomib to kill MCL cell lines. In this study, the team assessed the effects of exposure to these 2 combinations on samples from patients with MCL or CLL.

The researchers found that apoptosis occurred in 23% of cells exposed to ABT-199 and ibrutinib in combination, compared to 3.8% of cells exposed to ibrutinib and 3% exposed to ABT-199.

The combination of ibrutinib and carfilzomib also increased apoptosis in MCL and CLL cells compared to either agent alone, though to a lesser degree than the ABT-199 combination. Apoptosis occurred in 5.5% of cells exposed to ibrutinib and carfilzomib, 3.8% exposed to ibrutinib, and 1.7% exposed to carfilzomib.

The researchers observed minimal apoptosis in normal T cells, both with the single agents and the combinations.

Further analysis showed that ibrutinib and ABT-199 worked synergistically to cause apoptosis in leukemic cells from 5 of 9 patients with CLL.

According to Dr Weber, the variable response to this combination points to the importance of understanding how these combinations work, so we can match the treatments with the most appropriate patients.

“Ibrutinib and ABT-199 target different pathways involved in promoting cancer cell survival and growth,” Dr Weber said.

“This is very intriguing because, in most instances where cancer cells are resistant to a particular molecularly targeted drug, we find that cancer cells adapt and find new ways to reactivate the pathway being targeted by the drug and that combinations of drugs targeting this pathway in different ways can improve outcomes. Here, we found that targeting a pathway outside the primary pathway was effective.”

This study was funded by the University of Virginia Cancer Center. Dr Weber declared no conflicts of interest.

Mantle cell lymphoma

PHILADELPHIA—The Bcl-2 inhibitor ABT-199 and the Bruton tyrosine kinase inhibitor ibrutinib can have a synergistic effect against mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), preclinical data suggest.

In one set of experiments with MCL and CLL samples, the drugs induced apoptosis at a much higher rate when used together than when used alone.

However, in other experiments with CLL samples, ABT-199 and ibrutinib did not consistently display synergistic cytoxicity.

The researchers said this indicates substantial patient heterogeneity in response to the combination that may be due to variations in the genetic landscape.

Michael J. Weber, PhD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues presented this research at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

“We took an empirical but systematic approach to identify combinations of drugs that might improve the ability of ibrutinib to kill cancer cells,” Dr Weber said. “The combination of ibrutinib and ABT-199 was, by far, the most effective in our assays, and we are in the very earliest stages of planning a clinical trial to test this combination in the clinic.”

In previous studies, Dr Weber and his colleagues found that ibrutinib synergized with both ABT-199 and the proteasome inhibitor carfilzomib to kill MCL cell lines. In this study, the team assessed the effects of exposure to these 2 combinations on samples from patients with MCL or CLL.

The researchers found that apoptosis occurred in 23% of cells exposed to ABT-199 and ibrutinib in combination, compared to 3.8% of cells exposed to ibrutinib and 3% exposed to ABT-199.

The combination of ibrutinib and carfilzomib also increased apoptosis in MCL and CLL cells compared to either agent alone, though to a lesser degree than the ABT-199 combination. Apoptosis occurred in 5.5% of cells exposed to ibrutinib and carfilzomib, 3.8% exposed to ibrutinib, and 1.7% exposed to carfilzomib.

The researchers observed minimal apoptosis in normal T cells, both with the single agents and the combinations.

Further analysis showed that ibrutinib and ABT-199 worked synergistically to cause apoptosis in leukemic cells from 5 of 9 patients with CLL.

According to Dr Weber, the variable response to this combination points to the importance of understanding how these combinations work, so we can match the treatments with the most appropriate patients.

“Ibrutinib and ABT-199 target different pathways involved in promoting cancer cell survival and growth,” Dr Weber said.

“This is very intriguing because, in most instances where cancer cells are resistant to a particular molecularly targeted drug, we find that cancer cells adapt and find new ways to reactivate the pathway being targeted by the drug and that combinations of drugs targeting this pathway in different ways can improve outcomes. Here, we found that targeting a pathway outside the primary pathway was effective.”

This study was funded by the University of Virginia Cancer Center. Dr Weber declared no conflicts of interest.

Lab mice

Credit: Aaron Logan

Exercising during doxorubicin treatment can amplify the drug’s cancer-fighting ability, according to preclinical research.

Previous studies showed that adopting an exercise regimen before receiving doxorubicin could protect against the cardiac side effects associated with the drug.

Now, researchers have reported that exercising during doxorubicin treatment does not protect the heart, but it does help shrink tumors in mice.

Joseph Libonati, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology.

The researchers conducted experiments with 4 groups of mice, all of which received an injection of melanoma cells.

During the next 2 weeks, 2 of the groups received doxorubicin in 2 doses, while the other 2 groups received placebo injections.

A treated group and a placebo group were put on exercise regimens, walking for 45 minutes 5 days a week on mouse-sized treadmills, while the rest of the mice remained sedentary.

After the 2-week trial, the researchers examined the animals’ hearts using echocardiogram and tissue analysis.

As expected, doxorubicin reduced the heart’s function and size and increased fibrosis. Mice that exercised were not protected from this damage.

“We looked, and the exercise didn’t do anything to the heart; it didn’t worsen it, it didn’t help it,” Dr Libonati said. “But the tumor data—I find them actually amazing.”

The mice that received doxorubicin and exercised had significantly smaller tumors after 2 weeks than mice that only received doxorubicin (P<0.05).

Further studies will investigate exactly how exercise enhances the effect of doxorubicin, but the researchers believe it could be, in part, because exercise increases blood flow to the tumor, bringing with it more of the drug in the bloodstream.

“If exercise helps in this way, you could potentially use a smaller dose of the drug and get fewer side effects,” Dr Libonati said.

Gaining a clearer understanding of the many ways that exercise affects various systems of the body could also pave the way for developing drugs that mimic the effects of exercise.

“People don’t take a drug and then sit down all day,” Dr Libonati said. “Something as simple as moving affects how drugs are metabolized. We’re only just beginning to understand the complexities.”

Lab mice

Credit: Aaron Logan

Exercising during doxorubicin treatment can amplify the drug’s cancer-fighting ability, according to preclinical research.

Previous studies showed that adopting an exercise regimen before receiving doxorubicin could protect against the cardiac side effects associated with the drug.

Now, researchers have reported that exercising during doxorubicin treatment does not protect the heart, but it does help shrink tumors in mice.

Joseph Libonati, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology.

The researchers conducted experiments with 4 groups of mice, all of which received an injection of melanoma cells.

During the next 2 weeks, 2 of the groups received doxorubicin in 2 doses, while the other 2 groups received placebo injections.

A treated group and a placebo group were put on exercise regimens, walking for 45 minutes 5 days a week on mouse-sized treadmills, while the rest of the mice remained sedentary.

After the 2-week trial, the researchers examined the animals’ hearts using echocardiogram and tissue analysis.

As expected, doxorubicin reduced the heart’s function and size and increased fibrosis. Mice that exercised were not protected from this damage.

“We looked, and the exercise didn’t do anything to the heart; it didn’t worsen it, it didn’t help it,” Dr Libonati said. “But the tumor data—I find them actually amazing.”

The mice that received doxorubicin and exercised had significantly smaller tumors after 2 weeks than mice that only received doxorubicin (P<0.05).

Further studies will investigate exactly how exercise enhances the effect of doxorubicin, but the researchers believe it could be, in part, because exercise increases blood flow to the tumor, bringing with it more of the drug in the bloodstream.

“If exercise helps in this way, you could potentially use a smaller dose of the drug and get fewer side effects,” Dr Libonati said.

Gaining a clearer understanding of the many ways that exercise affects various systems of the body could also pave the way for developing drugs that mimic the effects of exercise.

“People don’t take a drug and then sit down all day,” Dr Libonati said. “Something as simple as moving affects how drugs are metabolized. We’re only just beginning to understand the complexities.”

Lab mice

Credit: Aaron Logan

Exercising during doxorubicin treatment can amplify the drug’s cancer-fighting ability, according to preclinical research.

Previous studies showed that adopting an exercise regimen before receiving doxorubicin could protect against the cardiac side effects associated with the drug.

Now, researchers have reported that exercising during doxorubicin treatment does not protect the heart, but it does help shrink tumors in mice.

Joseph Libonati, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology.

The researchers conducted experiments with 4 groups of mice, all of which received an injection of melanoma cells.

During the next 2 weeks, 2 of the groups received doxorubicin in 2 doses, while the other 2 groups received placebo injections.

A treated group and a placebo group were put on exercise regimens, walking for 45 minutes 5 days a week on mouse-sized treadmills, while the rest of the mice remained sedentary.

After the 2-week trial, the researchers examined the animals’ hearts using echocardiogram and tissue analysis.

As expected, doxorubicin reduced the heart’s function and size and increased fibrosis. Mice that exercised were not protected from this damage.

“We looked, and the exercise didn’t do anything to the heart; it didn’t worsen it, it didn’t help it,” Dr Libonati said. “But the tumor data—I find them actually amazing.”

The mice that received doxorubicin and exercised had significantly smaller tumors after 2 weeks than mice that only received doxorubicin (P<0.05).

Further studies will investigate exactly how exercise enhances the effect of doxorubicin, but the researchers believe it could be, in part, because exercise increases blood flow to the tumor, bringing with it more of the drug in the bloodstream.

“If exercise helps in this way, you could potentially use a smaller dose of the drug and get fewer side effects,” Dr Libonati said.

Gaining a clearer understanding of the many ways that exercise affects various systems of the body could also pave the way for developing drugs that mimic the effects of exercise.

“People don’t take a drug and then sit down all day,” Dr Libonati said. “Something as simple as moving affects how drugs are metabolized. We’re only just beginning to understand the complexities.”

 

 

Micrograph showing FL

 

The European Commission has granted marketing authorization for the PI3K delta inhibitor idelalisib (Zydelig) to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in the European Union.

The drug is now approved for use in combination with rituximab for CLL patients who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and are not eligible for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for FL patients who were refractory to 2 prior lines of treatment.

These approvals are based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the rituximab-idelalisib arm had a much higher overall response rate than patients in the rituximab-placebo arm—81% and 13%, respectively (P<0.001). There were no complete responses.

At 24 weeks, the rate of progression-free survival was 93% in the rituximab-idelalisib arm and 46% in the rituximab-placebo arm (P<0.001). The median progression-free survival was 5.5 months in the rituximab-placebo arm and not reached in the rituximab-idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the rituximab-idelalisib arm and 80% in the rituximab-placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the rituximab-idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the rituximab-placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the rituximab-idelalisib arm than in the rituximab-placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

This phase 2 trial enrolled 125 patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent. Patients received idelalisib monotherapy.

Of the 72 subjects with FL, 54% achieved a response, and 8% had a complete response. The median duration of response was not reached (range, 0-14.8 months).

Improvements in survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

Idelalisib is under development by Gilead Sciences. The drug is already approved in the US for the aforementioned indications, as well as to treat small lymphocytic lymphoma.

 

 

Micrograph showing FL

 

The European Commission has granted marketing authorization for the PI3K delta inhibitor idelalisib (Zydelig) to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in the European Union.

The drug is now approved for use in combination with rituximab for CLL patients who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and are not eligible for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for FL patients who were refractory to 2 prior lines of treatment.

These approvals are based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the rituximab-idelalisib arm had a much higher overall response rate than patients in the rituximab-placebo arm—81% and 13%, respectively (P<0.001). There were no complete responses.

At 24 weeks, the rate of progression-free survival was 93% in the rituximab-idelalisib arm and 46% in the rituximab-placebo arm (P<0.001). The median progression-free survival was 5.5 months in the rituximab-placebo arm and not reached in the rituximab-idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the rituximab-idelalisib arm and 80% in the rituximab-placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the rituximab-idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the rituximab-placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the rituximab-idelalisib arm than in the rituximab-placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

This phase 2 trial enrolled 125 patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent. Patients received idelalisib monotherapy.

Of the 72 subjects with FL, 54% achieved a response, and 8% had a complete response. The median duration of response was not reached (range, 0-14.8 months).

Improvements in survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

Idelalisib is under development by Gilead Sciences. The drug is already approved in the US for the aforementioned indications, as well as to treat small lymphocytic lymphoma.

 

 

Micrograph showing FL

 

The European Commission has granted marketing authorization for the PI3K delta inhibitor idelalisib (Zydelig) to treat chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) in the European Union.

The drug is now approved for use in combination with rituximab for CLL patients who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and are not eligible for chemo-immunotherapy.

Idelalisib is also approved as monotherapy for FL patients who were refractory to 2 prior lines of treatment.

These approvals are based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the rituximab-idelalisib arm had a much higher overall response rate than patients in the rituximab-placebo arm—81% and 13%, respectively (P<0.001). There were no complete responses.

At 24 weeks, the rate of progression-free survival was 93% in the rituximab-idelalisib arm and 46% in the rituximab-placebo arm (P<0.001). The median progression-free survival was 5.5 months in the rituximab-placebo arm and not reached in the rituximab-idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the rituximab-idelalisib arm and 80% in the rituximab-placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the rituximab-idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the rituximab-placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the rituximab-idelalisib arm than in the rituximab-placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

This phase 2 trial enrolled 125 patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent. Patients received idelalisib monotherapy.

Of the 72 subjects with FL, 54% achieved a response, and 8% had a complete response. The median duration of response was not reached (range, 0-14.8 months).

Improvements in survival or disease-related symptoms have not been established.

In all patients, the most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

Idelalisib is under development by Gilead Sciences. The drug is already approved in the US for the aforementioned indications, as well as to treat small lymphocytic lymphoma.

Cancer patient receives therapy

Credit: Rhoda Baer

A mathematical formula may help physicians predict which cancer survivors are likely to have normal sperm production following chemotherapy with alkylating agents.

Researchers developed the formula to calculate survivors’ cumulative treatment exposure to alkylating agents as a cyclophosphamide-equivalent dose (CED).

The team used this formula to evaluate a cohort of cancer survivors and found that CEDs of 4 g/m² or less were associated with normal sperm concentrations.

An account of this research was published in The Lancet Oncology.

“Based on these results, we would recommend pretreatment fertility preservation be offered, whenever clinically possible, to any male whose projected treatment is expected to include a cyclophosphamide-equivalent dose greater than 4 g/m²,” said study author Daniel Green, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Green and his colleagues had studied 214 male survivors of childhood cancer who had a median age of 29. Subjects had received cyclophosphamide and other alkylating agents, but their treatment did not include radiation.

The researchers performed semen analysis in the survivors a median of 21 years from their diagnosis. The analysis showed that 47.6% of survivors had normal sperm concentrations (at least 15 million per milliliter), 27.6% had low sperm counts, and 24.8% produced no sperm.

To determine the impact of alkylating agents on the survivors’ sperm production, the researchers calculated each survivor’s cumulative treatment exposure as a CED.

They did this using the following formula: CED (mg/m²)= 1.0 (cumulative cyclophosphamide dose [mg/m²]) + 0.244 (cumulative ifosfamide dose [mg/m²]) + 0.857 (cumulative procarbazine dose [mg/m²]) + 14.286 (cumulative chlorambucil dose [mg/m²]) + 15.0 (cumulative carmustine dose [mg/m²]) + 16.0 (cumulative lomustine dose [mg/m²]) + 40 (cumulative melphalan dose [mg/m²]) + 50 (cumulative thiotepa dose [mg/m²]) + 100 cumulative chlormethine dose [mg/m²]) + 8.823 (cumulative busulfan dose [mg/m²]).

The researchers could not identify a uniformly safe or toxic dose of these drugs, but they found that survivor sperm concentrations generally decreased as cumulative exposure to alkylating agents increased.

And CEDs of 4 g/m² or less were associated with normal sperm concentrations. Almost 89% of survivors whose CED was 4 g/m² or less had a normal sperm count. Their sperm were also more likely than sperm from other survivors to look and behave normally.

Dr Green did note that, although a lower cumulative dose of alkylating agents was associated with normal sperm production, outcomes for individual patients were unpredictable and varied.

Cancer patient receives therapy

Credit: Rhoda Baer

A mathematical formula may help physicians predict which cancer survivors are likely to have normal sperm production following chemotherapy with alkylating agents.

Researchers developed the formula to calculate survivors’ cumulative treatment exposure to alkylating agents as a cyclophosphamide-equivalent dose (CED).

The team used this formula to evaluate a cohort of cancer survivors and found that CEDs of 4 g/m² or less were associated with normal sperm concentrations.

An account of this research was published in The Lancet Oncology.

“Based on these results, we would recommend pretreatment fertility preservation be offered, whenever clinically possible, to any male whose projected treatment is expected to include a cyclophosphamide-equivalent dose greater than 4 g/m²,” said study author Daniel Green, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Green and his colleagues had studied 214 male survivors of childhood cancer who had a median age of 29. Subjects had received cyclophosphamide and other alkylating agents, but their treatment did not include radiation.

The researchers performed semen analysis in the survivors a median of 21 years from their diagnosis. The analysis showed that 47.6% of survivors had normal sperm concentrations (at least 15 million per milliliter), 27.6% had low sperm counts, and 24.8% produced no sperm.

To determine the impact of alkylating agents on the survivors’ sperm production, the researchers calculated each survivor’s cumulative treatment exposure as a CED.

They did this using the following formula: CED (mg/m²)= 1.0 (cumulative cyclophosphamide dose [mg/m²]) + 0.244 (cumulative ifosfamide dose [mg/m²]) + 0.857 (cumulative procarbazine dose [mg/m²]) + 14.286 (cumulative chlorambucil dose [mg/m²]) + 15.0 (cumulative carmustine dose [mg/m²]) + 16.0 (cumulative lomustine dose [mg/m²]) + 40 (cumulative melphalan dose [mg/m²]) + 50 (cumulative thiotepa dose [mg/m²]) + 100 cumulative chlormethine dose [mg/m²]) + 8.823 (cumulative busulfan dose [mg/m²]).

The researchers could not identify a uniformly safe or toxic dose of these drugs, but they found that survivor sperm concentrations generally decreased as cumulative exposure to alkylating agents increased.

And CEDs of 4 g/m² or less were associated with normal sperm concentrations. Almost 89% of survivors whose CED was 4 g/m² or less had a normal sperm count. Their sperm were also more likely than sperm from other survivors to look and behave normally.

Dr Green did note that, although a lower cumulative dose of alkylating agents was associated with normal sperm production, outcomes for individual patients were unpredictable and varied.

Cancer patient receives therapy

Credit: Rhoda Baer

A mathematical formula may help physicians predict which cancer survivors are likely to have normal sperm production following chemotherapy with alkylating agents.

Researchers developed the formula to calculate survivors’ cumulative treatment exposure to alkylating agents as a cyclophosphamide-equivalent dose (CED).

The team used this formula to evaluate a cohort of cancer survivors and found that CEDs of 4 g/m² or less were associated with normal sperm concentrations.

An account of this research was published in The Lancet Oncology.

“Based on these results, we would recommend pretreatment fertility preservation be offered, whenever clinically possible, to any male whose projected treatment is expected to include a cyclophosphamide-equivalent dose greater than 4 g/m²,” said study author Daniel Green, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Green and his colleagues had studied 214 male survivors of childhood cancer who had a median age of 29. Subjects had received cyclophosphamide and other alkylating agents, but their treatment did not include radiation.

The researchers performed semen analysis in the survivors a median of 21 years from their diagnosis. The analysis showed that 47.6% of survivors had normal sperm concentrations (at least 15 million per milliliter), 27.6% had low sperm counts, and 24.8% produced no sperm.

To determine the impact of alkylating agents on the survivors’ sperm production, the researchers calculated each survivor’s cumulative treatment exposure as a CED.

They did this using the following formula: CED (mg/m²)= 1.0 (cumulative cyclophosphamide dose [mg/m²]) + 0.244 (cumulative ifosfamide dose [mg/m²]) + 0.857 (cumulative procarbazine dose [mg/m²]) + 14.286 (cumulative chlorambucil dose [mg/m²]) + 15.0 (cumulative carmustine dose [mg/m²]) + 16.0 (cumulative lomustine dose [mg/m²]) + 40 (cumulative melphalan dose [mg/m²]) + 50 (cumulative thiotepa dose [mg/m²]) + 100 cumulative chlormethine dose [mg/m²]) + 8.823 (cumulative busulfan dose [mg/m²]).

The researchers could not identify a uniformly safe or toxic dose of these drugs, but they found that survivor sperm concentrations generally decreased as cumulative exposure to alkylating agents increased.

And CEDs of 4 g/m² or less were associated with normal sperm concentrations. Almost 89% of survivors whose CED was 4 g/m² or less had a normal sperm count. Their sperm were also more likely than sperm from other survivors to look and behave normally.

Dr Green did note that, although a lower cumulative dose of alkylating agents was associated with normal sperm production, outcomes for individual patients were unpredictable and varied.

Micrograph showing AML

Credit: Lance Liotta

Understanding the relationship between mutated and wild-type genes could lead to new therapies for acute myeloid leukemia (AML), according to researchers.

The group discovered that RUNX1/ETO, generated by the chromosomal translocation t(8;21), regulates a leukemia-propagating transcriptional network via a dynamic equilibrium with RUNX1.

But depleting RUNX1/ETO prompts the formation of a transcriptional network that promotes myeloid differentiation.

Constanze Bonifer, PhD, of the University of Birmingham in the UK, and her colleagues detailed this work in Cell Reports.

The researchers likened normal hematopoiesis to a production line, with genes acting as regulators to control each step of blood formation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted, with drastic consequences.

Using digital footprinting and chromatin immunoprecipitation sequencing, the team showed that RUNX1/ETO switches off hundreds of other genes, many of them regulators themselves. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells form.

“Understanding how these rogue regulators operate is essential,” Dr Bonifer said. “[T]hese leukemic cells have one mutated gene and one unchanged one that would make the normal regulator. What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time.”

“This is compounded by the normal regulator, which tries to compensate for defeat, and, in doing so, changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”

More specifically, the researchers found that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes.

Disrupting this equilibrium in t(8;21) cells by depleting RUNX1/ETO led to a global redistribution of transcription factor complexes within pre-existing open chromatin. And this prompted the formation of a transcriptional network that drives myeloid differentiation.

“If targeting [RUNX1/ETO] can reverse the changes it is making to the cellular production line, then it would ultimately point towards new avenues for a more precise treatment of leukemia,” said study author Olaf Heidenreich, PhD, of Newcastle University in the UK.

“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab than it is in the human body. But now we know how this works, we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”

Micrograph showing AML

Credit: Lance Liotta

Understanding the relationship between mutated and wild-type genes could lead to new therapies for acute myeloid leukemia (AML), according to researchers.

The group discovered that RUNX1/ETO, generated by the chromosomal translocation t(8;21), regulates a leukemia-propagating transcriptional network via a dynamic equilibrium with RUNX1.

But depleting RUNX1/ETO prompts the formation of a transcriptional network that promotes myeloid differentiation.

Constanze Bonifer, PhD, of the University of Birmingham in the UK, and her colleagues detailed this work in Cell Reports.

The researchers likened normal hematopoiesis to a production line, with genes acting as regulators to control each step of blood formation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted, with drastic consequences.

Using digital footprinting and chromatin immunoprecipitation sequencing, the team showed that RUNX1/ETO switches off hundreds of other genes, many of them regulators themselves. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells form.

“Understanding how these rogue regulators operate is essential,” Dr Bonifer said. “[T]hese leukemic cells have one mutated gene and one unchanged one that would make the normal regulator. What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time.”

“This is compounded by the normal regulator, which tries to compensate for defeat, and, in doing so, changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”

More specifically, the researchers found that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes.

Disrupting this equilibrium in t(8;21) cells by depleting RUNX1/ETO led to a global redistribution of transcription factor complexes within pre-existing open chromatin. And this prompted the formation of a transcriptional network that drives myeloid differentiation.

“If targeting [RUNX1/ETO] can reverse the changes it is making to the cellular production line, then it would ultimately point towards new avenues for a more precise treatment of leukemia,” said study author Olaf Heidenreich, PhD, of Newcastle University in the UK.

“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab than it is in the human body. But now we know how this works, we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”

Micrograph showing AML

Credit: Lance Liotta

Understanding the relationship between mutated and wild-type genes could lead to new therapies for acute myeloid leukemia (AML), according to researchers.

The group discovered that RUNX1/ETO, generated by the chromosomal translocation t(8;21), regulates a leukemia-propagating transcriptional network via a dynamic equilibrium with RUNX1.

But depleting RUNX1/ETO prompts the formation of a transcriptional network that promotes myeloid differentiation.

Constanze Bonifer, PhD, of the University of Birmingham in the UK, and her colleagues detailed this work in Cell Reports.

The researchers likened normal hematopoiesis to a production line, with genes acting as regulators to control each step of blood formation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted, with drastic consequences.

Using digital footprinting and chromatin immunoprecipitation sequencing, the team showed that RUNX1/ETO switches off hundreds of other genes, many of them regulators themselves. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells form.

“Understanding how these rogue regulators operate is essential,” Dr Bonifer said. “[T]hese leukemic cells have one mutated gene and one unchanged one that would make the normal regulator. What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time.”

“This is compounded by the normal regulator, which tries to compensate for defeat, and, in doing so, changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”

More specifically, the researchers found that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes.

Disrupting this equilibrium in t(8;21) cells by depleting RUNX1/ETO led to a global redistribution of transcription factor complexes within pre-existing open chromatin. And this prompted the formation of a transcriptional network that drives myeloid differentiation.

“If targeting [RUNX1/ETO] can reverse the changes it is making to the cellular production line, then it would ultimately point towards new avenues for a more precise treatment of leukemia,” said study author Olaf Heidenreich, PhD, of Newcastle University in the UK.

“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab than it is in the human body. But now we know how this works, we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”

Lab mice

Credit: Aaron Logan

A compound that has demonstrated efficacy in older adults with acute myeloid leukemia (AML) may be a viable option for childhood acute lymphoblastic

leukemia (ALL) as well.

The drug, CPX-351, is a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

It previously showed promise in a phase 2 trial of AML patients ages 60 to 75 years. Now, preclinical results suggest CPX-351 can work against aggressive

pediatric ALL too.

The research appears in Pediatric Blood & Cancer. It was supported by the National Cancer Institute.

“Cytarabine and anthracyclines such as daunorubicin are commonly used to treat ALL in pediatric patients, and while these drug are very effective in front-line, multidrug, combination chemotherapy regimens, there remains room for improvement, especially in pediatric patients who relapse within 36 months of diagnosis,” said study author Richard Lock, PhD, of Children’s Cancer Institute in Sydney, Australia.

“We are very encouraged by these preclinical results, indicating that the proprietary CPX-351 formulation of cytarabine and daunorubicin may be an important tool to maximize efficacy outcomes in relapsed ALL, and we believe these data substantiate the need for additional, clinical study in pediatric patients.”

Dr Lock and his colleagues studied CPX-351 in mice inoculated with leukemia cells from 5 children who had died from ALL. Three of the children, 2 with B-precursor ALL and 1 with T-cell ALL, had relapsed disease at the time of biopsy.

The researchers inoculated up to 18 mice for each of the 5 leukemia types and then randomized the mice to treatment or control.

The maximum-tolerated dose of CPX-351 was 5 units/kg (corresponding to 5 mg/kg cytarabine and 2.2 mg/kg daunorubicin). This dose provided clinically relevant plasma drug exposure and correlated to the pharmacokinetic properties observed in patients with AML.

The researchers found that all 5 models of ALL were “highly responsive” to CPX-351. In the 4 models of B-precursor ALL, the median group response was a complete response. In the mice inoculated with T-cell ALL, the median group response was a partial response.

Among treated mice, event-free survival ranged from 32.8 days to 41.9 days. And among controls, event-free survival ranged from 2.4 days to 10.8 days.

Dr Lock and his colleagues believe these results suggest CPX-351 may be a promising treatment for ALL and support its testing in pediatric leukemia patients.

CPX-351 is currently under investigation in a phase 3 trial in older patients with high-risk (secondary) AML.

Lab mice

Credit: Aaron Logan

A compound that has demonstrated efficacy in older adults with acute myeloid leukemia (AML) may be a viable option for childhood acute lymphoblastic

leukemia (ALL) as well.

The drug, CPX-351, is a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

It previously showed promise in a phase 2 trial of AML patients ages 60 to 75 years. Now, preclinical results suggest CPX-351 can work against aggressive

pediatric ALL too.

The research appears in Pediatric Blood & Cancer. It was supported by the National Cancer Institute.

“Cytarabine and anthracyclines such as daunorubicin are commonly used to treat ALL in pediatric patients, and while these drug are very effective in front-line, multidrug, combination chemotherapy regimens, there remains room for improvement, especially in pediatric patients who relapse within 36 months of diagnosis,” said study author Richard Lock, PhD, of Children’s Cancer Institute in Sydney, Australia.

“We are very encouraged by these preclinical results, indicating that the proprietary CPX-351 formulation of cytarabine and daunorubicin may be an important tool to maximize efficacy outcomes in relapsed ALL, and we believe these data substantiate the need for additional, clinical study in pediatric patients.”

Dr Lock and his colleagues studied CPX-351 in mice inoculated with leukemia cells from 5 children who had died from ALL. Three of the children, 2 with B-precursor ALL and 1 with T-cell ALL, had relapsed disease at the time of biopsy.

The researchers inoculated up to 18 mice for each of the 5 leukemia types and then randomized the mice to treatment or control.

The maximum-tolerated dose of CPX-351 was 5 units/kg (corresponding to 5 mg/kg cytarabine and 2.2 mg/kg daunorubicin). This dose provided clinically relevant plasma drug exposure and correlated to the pharmacokinetic properties observed in patients with AML.

The researchers found that all 5 models of ALL were “highly responsive” to CPX-351. In the 4 models of B-precursor ALL, the median group response was a complete response. In the mice inoculated with T-cell ALL, the median group response was a partial response.

Among treated mice, event-free survival ranged from 32.8 days to 41.9 days. And among controls, event-free survival ranged from 2.4 days to 10.8 days.

Dr Lock and his colleagues believe these results suggest CPX-351 may be a promising treatment for ALL and support its testing in pediatric leukemia patients.

CPX-351 is currently under investigation in a phase 3 trial in older patients with high-risk (secondary) AML.

Lab mice

Credit: Aaron Logan

A compound that has demonstrated efficacy in older adults with acute myeloid leukemia (AML) may be a viable option for childhood acute lymphoblastic

leukemia (ALL) as well.

The drug, CPX-351, is a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle.

It previously showed promise in a phase 2 trial of AML patients ages 60 to 75 years. Now, preclinical results suggest CPX-351 can work against aggressive

pediatric ALL too.

The research appears in Pediatric Blood & Cancer. It was supported by the National Cancer Institute.

“Cytarabine and anthracyclines such as daunorubicin are commonly used to treat ALL in pediatric patients, and while these drug are very effective in front-line, multidrug, combination chemotherapy regimens, there remains room for improvement, especially in pediatric patients who relapse within 36 months of diagnosis,” said study author Richard Lock, PhD, of Children’s Cancer Institute in Sydney, Australia.

“We are very encouraged by these preclinical results, indicating that the proprietary CPX-351 formulation of cytarabine and daunorubicin may be an important tool to maximize efficacy outcomes in relapsed ALL, and we believe these data substantiate the need for additional, clinical study in pediatric patients.”

Dr Lock and his colleagues studied CPX-351 in mice inoculated with leukemia cells from 5 children who had died from ALL. Three of the children, 2 with B-precursor ALL and 1 with T-cell ALL, had relapsed disease at the time of biopsy.

The researchers inoculated up to 18 mice for each of the 5 leukemia types and then randomized the mice to treatment or control.

The maximum-tolerated dose of CPX-351 was 5 units/kg (corresponding to 5 mg/kg cytarabine and 2.2 mg/kg daunorubicin). This dose provided clinically relevant plasma drug exposure and correlated to the pharmacokinetic properties observed in patients with AML.

The researchers found that all 5 models of ALL were “highly responsive” to CPX-351. In the 4 models of B-precursor ALL, the median group response was a complete response. In the mice inoculated with T-cell ALL, the median group response was a partial response.

Among treated mice, event-free survival ranged from 32.8 days to 41.9 days. And among controls, event-free survival ranged from 2.4 days to 10.8 days.

Dr Lock and his colleagues believe these results suggest CPX-351 may be a promising treatment for ALL and support its testing in pediatric leukemia patients.

CPX-351 is currently under investigation in a phase 3 trial in older patients with high-risk (secondary) AML.

HyQvia

Credit: Baxter

The US Food and Drug Administration (FDA) has approved a subcutaneous immune globulin product for use in adults with primary immunodeficiency (PI).

The product, HyQvia, is an immune globulin with a recombinant human hyaluronidase. It requires a single infusion every 3 to 4 weeks and 1 injection site per infusion to deliver a full therapeutic dose of immune globulin.

Current therapies require weekly or bi-weekly treatment with multiple infusion sites per treatment.

Baxter International Inc. expects to launch HyQvia in the US in the coming weeks. The product has been FDA-approved with a black-box warning detailing the risk of thrombosis associated with immune globulin products.

The immune globulin component of HyQvia is a 10% solution prepared from large pools of human plasma consisting of at least 98% IgG. The recombinant human hyaluronidase increases the dispersion and absorption of the immune globulin.

In a phase 3 trial, HyQvia compared well with intravenous human immune globulin 10% (IVIG).

Researchers compared the treatments at different time periods in a cohort of PI patients with a median age of 35 (range, 4-78 years). All 87 patients studied received IVIG, and 83 of the patients received at least 1 dose of HyQvia.

Patients received HyQvia for a median of 366 days and IVIG for a median of 91 days. The median ratio (HyQvia:IVIG) for the IgG dosage administered was 1.088 (range, 0.986–1.382).

Trough IgG concentrations, the incidence of infection, and rates of adverse events were generally similar during the HyQvia treatment period and the IVIG treatment period.

For patients aged 12 years and older, the median IgG C_trough values with HyQvia were approximately the same as with IVIG. The median trough ratio (HyQvia:IVIG) was 0.985.

For patients younger than 12 (n=11), the median IgG C_trough values were 10.0 and 9.6 g/L after HyQvia and IVIG, respectively, with a median trough ratio of 1.038.

The overall infection rates were 2.97 per patient-year with HyQvia and 4.51 per patient-year with IVIG.

During the HyQvia treatment period, the rate of acute serious bacterial infection (SBI) was 0.025 per patient-year. The rate of acute SBIs occurring during IVIG treatment was not reported.

In patients age 18 and older (n=59), the rate of acute SBIs was 0.00 per patient-year, and the overall infection rate was 3.20 per patient-year.

For this same patient group, the local adverse reaction rate was 0.286 per infusion.

The rate of systemic adverse events temporally related to an infusion was 0.20 per infusion with HyQvia and 0.33 per infusion with IVIG. There were no serious adverse events reported in these patients with either treatment.

HyQvia was approved in Europe in 2013 for adults with PI syndromes and myeloma or chronic lymphocytic leukemia with severe secondary hypogammaglobulinemia and recurrent infections.

For more details on HyQvia, see the prescribing information.

HyQvia

Credit: Baxter

The US Food and Drug Administration (FDA) has approved a subcutaneous immune globulin product for use in adults with primary immunodeficiency (PI).

The product, HyQvia, is an immune globulin with a recombinant human hyaluronidase. It requires a single infusion every 3 to 4 weeks and 1 injection site per infusion to deliver a full therapeutic dose of immune globulin.

Current therapies require weekly or bi-weekly treatment with multiple infusion sites per treatment.

Baxter International Inc. expects to launch HyQvia in the US in the coming weeks. The product has been FDA-approved with a black-box warning detailing the risk of thrombosis associated with immune globulin products.

The immune globulin component of HyQvia is a 10% solution prepared from large pools of human plasma consisting of at least 98% IgG. The recombinant human hyaluronidase increases the dispersion and absorption of the immune globulin.

In a phase 3 trial, HyQvia compared well with intravenous human immune globulin 10% (IVIG).

Researchers compared the treatments at different time periods in a cohort of PI patients with a median age of 35 (range, 4-78 years). All 87 patients studied received IVIG, and 83 of the patients received at least 1 dose of HyQvia.

Patients received HyQvia for a median of 366 days and IVIG for a median of 91 days. The median ratio (HyQvia:IVIG) for the IgG dosage administered was 1.088 (range, 0.986–1.382).

Trough IgG concentrations, the incidence of infection, and rates of adverse events were generally similar during the HyQvia treatment period and the IVIG treatment period.

For patients aged 12 years and older, the median IgG C_trough values with HyQvia were approximately the same as with IVIG. The median trough ratio (HyQvia:IVIG) was 0.985.

For patients younger than 12 (n=11), the median IgG C_trough values were 10.0 and 9.6 g/L after HyQvia and IVIG, respectively, with a median trough ratio of 1.038.

The overall infection rates were 2.97 per patient-year with HyQvia and 4.51 per patient-year with IVIG.

During the HyQvia treatment period, the rate of acute serious bacterial infection (SBI) was 0.025 per patient-year. The rate of acute SBIs occurring during IVIG treatment was not reported.

In patients age 18 and older (n=59), the rate of acute SBIs was 0.00 per patient-year, and the overall infection rate was 3.20 per patient-year.

For this same patient group, the local adverse reaction rate was 0.286 per infusion.

The rate of systemic adverse events temporally related to an infusion was 0.20 per infusion with HyQvia and 0.33 per infusion with IVIG. There were no serious adverse events reported in these patients with either treatment.

HyQvia was approved in Europe in 2013 for adults with PI syndromes and myeloma or chronic lymphocytic leukemia with severe secondary hypogammaglobulinemia and recurrent infections.

For more details on HyQvia, see the prescribing information.

HyQvia

Credit: Baxter

The US Food and Drug Administration (FDA) has approved a subcutaneous immune globulin product for use in adults with primary immunodeficiency (PI).

The product, HyQvia, is an immune globulin with a recombinant human hyaluronidase. It requires a single infusion every 3 to 4 weeks and 1 injection site per infusion to deliver a full therapeutic dose of immune globulin.

Current therapies require weekly or bi-weekly treatment with multiple infusion sites per treatment.

Baxter International Inc. expects to launch HyQvia in the US in the coming weeks. The product has been FDA-approved with a black-box warning detailing the risk of thrombosis associated with immune globulin products.

The immune globulin component of HyQvia is a 10% solution prepared from large pools of human plasma consisting of at least 98% IgG. The recombinant human hyaluronidase increases the dispersion and absorption of the immune globulin.

In a phase 3 trial, HyQvia compared well with intravenous human immune globulin 10% (IVIG).

Researchers compared the treatments at different time periods in a cohort of PI patients with a median age of 35 (range, 4-78 years). All 87 patients studied received IVIG, and 83 of the patients received at least 1 dose of HyQvia.

Patients received HyQvia for a median of 366 days and IVIG for a median of 91 days. The median ratio (HyQvia:IVIG) for the IgG dosage administered was 1.088 (range, 0.986–1.382).

Trough IgG concentrations, the incidence of infection, and rates of adverse events were generally similar during the HyQvia treatment period and the IVIG treatment period.

For patients aged 12 years and older, the median IgG C_trough values with HyQvia were approximately the same as with IVIG. The median trough ratio (HyQvia:IVIG) was 0.985.

For patients younger than 12 (n=11), the median IgG C_trough values were 10.0 and 9.6 g/L after HyQvia and IVIG, respectively, with a median trough ratio of 1.038.

The overall infection rates were 2.97 per patient-year with HyQvia and 4.51 per patient-year with IVIG.

During the HyQvia treatment period, the rate of acute serious bacterial infection (SBI) was 0.025 per patient-year. The rate of acute SBIs occurring during IVIG treatment was not reported.

In patients age 18 and older (n=59), the rate of acute SBIs was 0.00 per patient-year, and the overall infection rate was 3.20 per patient-year.

For this same patient group, the local adverse reaction rate was 0.286 per infusion.

The rate of systemic adverse events temporally related to an infusion was 0.20 per infusion with HyQvia and 0.33 per infusion with IVIG. There were no serious adverse events reported in these patients with either treatment.

HyQvia was approved in Europe in 2013 for adults with PI syndromes and myeloma or chronic lymphocytic leukemia with severe secondary hypogammaglobulinemia and recurrent infections.

For more details on HyQvia, see the prescribing information.

Charles Mullighan, MD, MBBS

Credit: St Jude Children’s

Research Hospital

New research indicates that Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) becomes more common with age and is associated with poor prognosis.

The study also showed that Ph-like ALL is characterized by genomic alterations that might make patients receptive to treatment with tyrosine kinase inhibitors (TKIs).

Initial tests in a small number of patients seem to support this theory, but trials are needed to verify and expand upon these results, according to researchers.

Charles Mullighan, MD, MBBS, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported the results in The New England Journal of Medicine.

Age and prognosis

The researchers performed genomic profiling of 1725 patients with precursor B-cell ALL, detailed genomic analyses of 154 patients with Ph-like ALL, and transcriptome sequencing for 160 patients with non-Ph-like ALL.

The team found the prevalence of Ph-like ALL increased significantly with age, from 10% among children with standard-risk B-ALL (ages 1 to 9) and 13% among those with high-risk ALL (ages 10 to 15) to 21% among adolescents (ages 16 to 20) and 27% among young adults with ALL (ages 21 to 39).

Regardless of their age, patients with Ph-like ALL were less likely than other B-ALL patients to be alive and leukemia-free 5 years after diagnosis.

Overall survival for children, adolescents, and young adults with Ph-like ALL was 62%, compared to 91% for other B-ALL patients of the same age. Leukemia-free survival was about 47% for patients with Ph-like ALL and about 83% for other patients.

Genomic alterations and TKI treatment

The researchers found that 91% of patients with Ph-like ALL had chromosomal rearrangements or other genetic alterations that activate cytokine receptor or kinase signaling.

“We identified several new subgroups of Ph-like ALL that were distinguished by the type of cytokine receptor or kinase gene alteration,” said Kathryn Roberts, PhD, also of St Jude Children’s Research Hospital.

Evidence suggests that several of these subtypes would be vulnerable to TKIs and other targeted therapies. For example, about 12% of patients had rearrangements involving the genes ABL1, ABL2, CSF1R, and PDGFRB, which are known to respond to dasatinib and related TKIs.

Other Ph-like ALL patients had gene rearrangements involving JAK2, EPOR, and other genes that can be targeted by the drug ruxolitinib.

To determine if TKIs are effective in these patients, the researchers administered TKIs to 12 patients with Ph-ALL. Follow-up is not sufficient for all of the patients, but 5 achieved remission following TKI treatment (alone, with chemotherapy, or followed by transplant), and 1 patient has been in remission for more than a year.

“We showed that Ph-like ALL is a common disease that spans the age spectrum, and we identified new genomic alterations that converge on a handful of signaling pathways that are vulnerable to treatment with tyrosine kinase inhibitors,” Dr Mullighan said. “The findings lead the way for clinical trials that could help to transform the outlook for patients, regardless of age.”

A study testing TKI therapy in children with Ph-like ALL is scheduled to begin later this year or early in 2015.

Charles Mullighan, MD, MBBS

Credit: St Jude Children’s

Research Hospital

New research indicates that Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) becomes more common with age and is associated with poor prognosis.

The study also showed that Ph-like ALL is characterized by genomic alterations that might make patients receptive to treatment with tyrosine kinase inhibitors (TKIs).

Initial tests in a small number of patients seem to support this theory, but trials are needed to verify and expand upon these results, according to researchers.

Charles Mullighan, MD, MBBS, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported the results in The New England Journal of Medicine.

Age and prognosis

The researchers performed genomic profiling of 1725 patients with precursor B-cell ALL, detailed genomic analyses of 154 patients with Ph-like ALL, and transcriptome sequencing for 160 patients with non-Ph-like ALL.

The team found the prevalence of Ph-like ALL increased significantly with age, from 10% among children with standard-risk B-ALL (ages 1 to 9) and 13% among those with high-risk ALL (ages 10 to 15) to 21% among adolescents (ages 16 to 20) and 27% among young adults with ALL (ages 21 to 39).

Regardless of their age, patients with Ph-like ALL were less likely than other B-ALL patients to be alive and leukemia-free 5 years after diagnosis.

Overall survival for children, adolescents, and young adults with Ph-like ALL was 62%, compared to 91% for other B-ALL patients of the same age. Leukemia-free survival was about 47% for patients with Ph-like ALL and about 83% for other patients.

Genomic alterations and TKI treatment

The researchers found that 91% of patients with Ph-like ALL had chromosomal rearrangements or other genetic alterations that activate cytokine receptor or kinase signaling.

“We identified several new subgroups of Ph-like ALL that were distinguished by the type of cytokine receptor or kinase gene alteration,” said Kathryn Roberts, PhD, also of St Jude Children’s Research Hospital.

Evidence suggests that several of these subtypes would be vulnerable to TKIs and other targeted therapies. For example, about 12% of patients had rearrangements involving the genes ABL1, ABL2, CSF1R, and PDGFRB, which are known to respond to dasatinib and related TKIs.

Other Ph-like ALL patients had gene rearrangements involving JAK2, EPOR, and other genes that can be targeted by the drug ruxolitinib.

To determine if TKIs are effective in these patients, the researchers administered TKIs to 12 patients with Ph-ALL. Follow-up is not sufficient for all of the patients, but 5 achieved remission following TKI treatment (alone, with chemotherapy, or followed by transplant), and 1 patient has been in remission for more than a year.

“We showed that Ph-like ALL is a common disease that spans the age spectrum, and we identified new genomic alterations that converge on a handful of signaling pathways that are vulnerable to treatment with tyrosine kinase inhibitors,” Dr Mullighan said. “The findings lead the way for clinical trials that could help to transform the outlook for patients, regardless of age.”

A study testing TKI therapy in children with Ph-like ALL is scheduled to begin later this year or early in 2015.

Charles Mullighan, MD, MBBS

Credit: St Jude Children’s

Research Hospital

New research indicates that Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) becomes more common with age and is associated with poor prognosis.

The study also showed that Ph-like ALL is characterized by genomic alterations that might make patients receptive to treatment with tyrosine kinase inhibitors (TKIs).

Initial tests in a small number of patients seem to support this theory, but trials are needed to verify and expand upon these results, according to researchers.

Charles Mullighan, MD, MBBS, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported the results in The New England Journal of Medicine.

Age and prognosis

The researchers performed genomic profiling of 1725 patients with precursor B-cell ALL, detailed genomic analyses of 154 patients with Ph-like ALL, and transcriptome sequencing for 160 patients with non-Ph-like ALL.

The team found the prevalence of Ph-like ALL increased significantly with age, from 10% among children with standard-risk B-ALL (ages 1 to 9) and 13% among those with high-risk ALL (ages 10 to 15) to 21% among adolescents (ages 16 to 20) and 27% among young adults with ALL (ages 21 to 39).

Regardless of their age, patients with Ph-like ALL were less likely than other B-ALL patients to be alive and leukemia-free 5 years after diagnosis.

Overall survival for children, adolescents, and young adults with Ph-like ALL was 62%, compared to 91% for other B-ALL patients of the same age. Leukemia-free survival was about 47% for patients with Ph-like ALL and about 83% for other patients.

Genomic alterations and TKI treatment

The researchers found that 91% of patients with Ph-like ALL had chromosomal rearrangements or other genetic alterations that activate cytokine receptor or kinase signaling.

“We identified several new subgroups of Ph-like ALL that were distinguished by the type of cytokine receptor or kinase gene alteration,” said Kathryn Roberts, PhD, also of St Jude Children’s Research Hospital.

Evidence suggests that several of these subtypes would be vulnerable to TKIs and other targeted therapies. For example, about 12% of patients had rearrangements involving the genes ABL1, ABL2, CSF1R, and PDGFRB, which are known to respond to dasatinib and related TKIs.

Other Ph-like ALL patients had gene rearrangements involving JAK2, EPOR, and other genes that can be targeted by the drug ruxolitinib.

To determine if TKIs are effective in these patients, the researchers administered TKIs to 12 patients with Ph-ALL. Follow-up is not sufficient for all of the patients, but 5 achieved remission following TKI treatment (alone, with chemotherapy, or followed by transplant), and 1 patient has been in remission for more than a year.

“We showed that Ph-like ALL is a common disease that spans the age spectrum, and we identified new genomic alterations that converge on a handful of signaling pathways that are vulnerable to treatment with tyrosine kinase inhibitors,” Dr Mullighan said. “The findings lead the way for clinical trials that could help to transform the outlook for patients, regardless of age.”

A study testing TKI therapy in children with Ph-like ALL is scheduled to begin later this year or early in 2015.

Aspergillus fumigatus

WASHINGTON, DC—A new antifungal agent is as effective as an existing drug against invasive mold infection in patients with hematologic disorders, results of a phase 3 trial suggest.

Overall response and all-cause mortality rates were comparable with the newer drug, isavuconazole (ISA), and the existing drug, voriconazole (VRC).

The overall rates of treatment-emergent adverse events were comparable as well, but ISA was associated with a significantly lower incidence of several events.

Kieren Marr, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues presented these results in a subset of patients from the SECURE trial at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (poster M-1757).

Patient characteristics and safety outcomes

Of the 433 patients with a hematologic disorder enrolled in the trial, 217 had proven or probable invasive mold infection. The researchers divided patients into 2 groups according to disease: those with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) or other conditions.

In all, 102 patients had AML, and 115 had ALL (n=28) or other conditions, including non-Hodgkin lymphoma (n=19), chronic lymphocytic leukemia (n=15), refractory anemia with excess blasts (n=9), myelodysplastic syndrome (n=8), chronic myeloid leukemia (n=6), and “other” underlying conditions (n=30).

Patients were randomized to receive VRC (n=105) or ISA (N=112). Thirty patients in the ISA arm and 26 in the VRC arm had undergone allogeneic transplant prior to therapy.

The primary outcome was all-cause mortality at day 42. Overall response and safety were secondary endpoints.

The overall rates of treatment-emergent adverse events were similar between ISA and VRC arms. Ninety-seven percent of patients in the ISA arm and 98% of patients in the VRC arm reported at least 1 treatment-emergent adverse event.

However, patients in the ISA arm had significantly fewer (P<0.05) events for the cardiac disorders, eye, psychiatric disorders, renal and urinary, and vascular system organ classes.

Response and mortality

All-cause mortality rates were comparable between the ISA and VRC arms—22% and 24%, respectively—as were overall response rates—39% and 34%, respectively—and complete response rates—13% and 10%, respectively.

All-cause mortality rates among patients with AML were 18% in the ISA arm and 15% in the VRC arm. Overall response rates were 36% and 48%, respectively.

For patients with ALL or other hematologic conditions, all-cause mortality rates were 26% in the ISA arm and 32% in the VRC arm. Overall response rates were 42% and 21%, respectively.

In transplant patients, the all-cause mortality rate was 27% for both the ISA and VRC arms. The overall response rate was 27% for both arms as well.

“These results show the potential of isavuconazole as a potent antifungal in the fight against invasive mold disease,” Dr Marr said.

ISA is an investigational antifungal under development by Astellas and Basilea Pharmaceutica International Ltd. The SECURE trial was funded by Astellas.

The US Food and Drug Administration recently accepted a new drug application seeking approval for ISA for the treatment of invasive aspergillosis and invasive mucormycosis.

Aspergillus fumigatus

WASHINGTON, DC—A new antifungal agent is as effective as an existing drug against invasive mold infection in patients with hematologic disorders, results of a phase 3 trial suggest.

Overall response and all-cause mortality rates were comparable with the newer drug, isavuconazole (ISA), and the existing drug, voriconazole (VRC).

The overall rates of treatment-emergent adverse events were comparable as well, but ISA was associated with a significantly lower incidence of several events.

Kieren Marr, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues presented these results in a subset of patients from the SECURE trial at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (poster M-1757).

Patient characteristics and safety outcomes

Of the 433 patients with a hematologic disorder enrolled in the trial, 217 had proven or probable invasive mold infection. The researchers divided patients into 2 groups according to disease: those with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) or other conditions.

In all, 102 patients had AML, and 115 had ALL (n=28) or other conditions, including non-Hodgkin lymphoma (n=19), chronic lymphocytic leukemia (n=15), refractory anemia with excess blasts (n=9), myelodysplastic syndrome (n=8), chronic myeloid leukemia (n=6), and “other” underlying conditions (n=30).

Patients were randomized to receive VRC (n=105) or ISA (N=112). Thirty patients in the ISA arm and 26 in the VRC arm had undergone allogeneic transplant prior to therapy.

The primary outcome was all-cause mortality at day 42. Overall response and safety were secondary endpoints.

The overall rates of treatment-emergent adverse events were similar between ISA and VRC arms. Ninety-seven percent of patients in the ISA arm and 98% of patients in the VRC arm reported at least 1 treatment-emergent adverse event.

However, patients in the ISA arm had significantly fewer (P<0.05) events for the cardiac disorders, eye, psychiatric disorders, renal and urinary, and vascular system organ classes.

Response and mortality

All-cause mortality rates were comparable between the ISA and VRC arms—22% and 24%, respectively—as were overall response rates—39% and 34%, respectively—and complete response rates—13% and 10%, respectively.

All-cause mortality rates among patients with AML were 18% in the ISA arm and 15% in the VRC arm. Overall response rates were 36% and 48%, respectively.

For patients with ALL or other hematologic conditions, all-cause mortality rates were 26% in the ISA arm and 32% in the VRC arm. Overall response rates were 42% and 21%, respectively.

In transplant patients, the all-cause mortality rate was 27% for both the ISA and VRC arms. The overall response rate was 27% for both arms as well.

“These results show the potential of isavuconazole as a potent antifungal in the fight against invasive mold disease,” Dr Marr said.

ISA is an investigational antifungal under development by Astellas and Basilea Pharmaceutica International Ltd. The SECURE trial was funded by Astellas.

The US Food and Drug Administration recently accepted a new drug application seeking approval for ISA for the treatment of invasive aspergillosis and invasive mucormycosis.

Aspergillus fumigatus

WASHINGTON, DC—A new antifungal agent is as effective as an existing drug against invasive mold infection in patients with hematologic disorders, results of a phase 3 trial suggest.

Overall response and all-cause mortality rates were comparable with the newer drug, isavuconazole (ISA), and the existing drug, voriconazole (VRC).

The overall rates of treatment-emergent adverse events were comparable as well, but ISA was associated with a significantly lower incidence of several events.

Kieren Marr, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues presented these results in a subset of patients from the SECURE trial at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (poster M-1757).

Patient characteristics and safety outcomes

Of the 433 patients with a hematologic disorder enrolled in the trial, 217 had proven or probable invasive mold infection. The researchers divided patients into 2 groups according to disease: those with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) or other conditions.

In all, 102 patients had AML, and 115 had ALL (n=28) or other conditions, including non-Hodgkin lymphoma (n=19), chronic lymphocytic leukemia (n=15), refractory anemia with excess blasts (n=9), myelodysplastic syndrome (n=8), chronic myeloid leukemia (n=6), and “other” underlying conditions (n=30).

Patients were randomized to receive VRC (n=105) or ISA (N=112). Thirty patients in the ISA arm and 26 in the VRC arm had undergone allogeneic transplant prior to therapy.

The primary outcome was all-cause mortality at day 42. Overall response and safety were secondary endpoints.

The overall rates of treatment-emergent adverse events were similar between ISA and VRC arms. Ninety-seven percent of patients in the ISA arm and 98% of patients in the VRC arm reported at least 1 treatment-emergent adverse event.

However, patients in the ISA arm had significantly fewer (P<0.05) events for the cardiac disorders, eye, psychiatric disorders, renal and urinary, and vascular system organ classes.

Response and mortality

All-cause mortality rates were comparable between the ISA and VRC arms—22% and 24%, respectively—as were overall response rates—39% and 34%, respectively—and complete response rates—13% and 10%, respectively.

All-cause mortality rates among patients with AML were 18% in the ISA arm and 15% in the VRC arm. Overall response rates were 36% and 48%, respectively.

For patients with ALL or other hematologic conditions, all-cause mortality rates were 26% in the ISA arm and 32% in the VRC arm. Overall response rates were 42% and 21%, respectively.

In transplant patients, the all-cause mortality rate was 27% for both the ISA and VRC arms. The overall response rate was 27% for both arms as well.

“These results show the potential of isavuconazole as a potent antifungal in the fight against invasive mold disease,” Dr Marr said.

ISA is an investigational antifungal under development by Astellas and Basilea Pharmaceutica International Ltd. The SECURE trial was funded by Astellas.

The US Food and Drug Administration recently accepted a new drug application seeking approval for ISA for the treatment of invasive aspergillosis and invasive mucormycosis.