Leukemia, Myelodysplasia, Transplantation

DNA methylation

Image by Christoph Bock

A new study helps explain how the anticancer drug decitabine reverses cell damage and has revealed a potential biomarker that could indicate a

patient’s cancer stage and response to treatment.

Investigators found that decitabine combats some of cancer’s effects by taking the place of the nucleotide cytosine at specific locations on a replicating DNA strand.

In mimicking cytosine, the drug helps “tame” cancerous cells by turning on tumor suppressors and turning off oncogenes.

The investigators also found that decitabine causes an unexpected boost in the amount of a molecule known as 5-hydroxymethylcytosine (5hmC). Because many types of cancer cause 5hmC levels to plummet, an uptick in 5hmC could be a sign that cancer treatments are working.

“We think that the expression of 5hmC could be used as a biomarker to define the stage or the aggressiveness of cancer and to possibly indicate the effectiveness of cancer treatment,” said Joseph Irudayaraj, PhD, of Purdue University in West Lafayette, Indiana. “This could help us monitor the clinical success of patients receiving decitabine.”

Dr Irudayaraj and his colleagues reported these findings in Nature Scientific Reports.

Decitabine, one of the first epigenetic drugs, helps reverse the altered methylation patterns in cancerous cells, but its precise mode of action has not been clear.

Using a combination of models, Dr Irudayaraj and his colleagues showed that decitabine is taking the place of cytosine at strategic positions on replicating strands of DNA in cancer cells.

When an enzyme tries to add a methyl group to silence decitabine, the drug traps it in place, preventing methylation. This triggers another group of enzymes to transform a methylated cytosine on the parent DNA strand into 5hmC, a molecule whose biological function is not yet known.

The investigators confirmed the increase in 5hmC levels in decitabine-treated leukemia cells.

To better explain the team’s findings, Basudev Chowdhury, PhD, also of Purdue University, likened decitabine to a text editor that restores meaning to a garbled sentence and compared conventional chemotherapy to a delete button.

“Think of nucleotides as the alphabet with which our cells compose messages,” he said. “Epigenetics helps translate those messages into actions such as the production of proteins. But cancer can jumble the messages, making them nonsensical. Decitabine helps revise the messages so they can be understood.”

DNA methylation

Image by Christoph Bock

A new study helps explain how the anticancer drug decitabine reverses cell damage and has revealed a potential biomarker that could indicate a

patient’s cancer stage and response to treatment.

Investigators found that decitabine combats some of cancer’s effects by taking the place of the nucleotide cytosine at specific locations on a replicating DNA strand.

In mimicking cytosine, the drug helps “tame” cancerous cells by turning on tumor suppressors and turning off oncogenes.

The investigators also found that decitabine causes an unexpected boost in the amount of a molecule known as 5-hydroxymethylcytosine (5hmC). Because many types of cancer cause 5hmC levels to plummet, an uptick in 5hmC could be a sign that cancer treatments are working.

“We think that the expression of 5hmC could be used as a biomarker to define the stage or the aggressiveness of cancer and to possibly indicate the effectiveness of cancer treatment,” said Joseph Irudayaraj, PhD, of Purdue University in West Lafayette, Indiana. “This could help us monitor the clinical success of patients receiving decitabine.”

Dr Irudayaraj and his colleagues reported these findings in Nature Scientific Reports.

Decitabine, one of the first epigenetic drugs, helps reverse the altered methylation patterns in cancerous cells, but its precise mode of action has not been clear.

Using a combination of models, Dr Irudayaraj and his colleagues showed that decitabine is taking the place of cytosine at strategic positions on replicating strands of DNA in cancer cells.

When an enzyme tries to add a methyl group to silence decitabine, the drug traps it in place, preventing methylation. This triggers another group of enzymes to transform a methylated cytosine on the parent DNA strand into 5hmC, a molecule whose biological function is not yet known.

The investigators confirmed the increase in 5hmC levels in decitabine-treated leukemia cells.

To better explain the team’s findings, Basudev Chowdhury, PhD, also of Purdue University, likened decitabine to a text editor that restores meaning to a garbled sentence and compared conventional chemotherapy to a delete button.

“Think of nucleotides as the alphabet with which our cells compose messages,” he said. “Epigenetics helps translate those messages into actions such as the production of proteins. But cancer can jumble the messages, making them nonsensical. Decitabine helps revise the messages so they can be understood.”

DNA methylation

Image by Christoph Bock

A new study helps explain how the anticancer drug decitabine reverses cell damage and has revealed a potential biomarker that could indicate a

patient’s cancer stage and response to treatment.

Investigators found that decitabine combats some of cancer’s effects by taking the place of the nucleotide cytosine at specific locations on a replicating DNA strand.

In mimicking cytosine, the drug helps “tame” cancerous cells by turning on tumor suppressors and turning off oncogenes.

The investigators also found that decitabine causes an unexpected boost in the amount of a molecule known as 5-hydroxymethylcytosine (5hmC). Because many types of cancer cause 5hmC levels to plummet, an uptick in 5hmC could be a sign that cancer treatments are working.

“We think that the expression of 5hmC could be used as a biomarker to define the stage or the aggressiveness of cancer and to possibly indicate the effectiveness of cancer treatment,” said Joseph Irudayaraj, PhD, of Purdue University in West Lafayette, Indiana. “This could help us monitor the clinical success of patients receiving decitabine.”

Dr Irudayaraj and his colleagues reported these findings in Nature Scientific Reports.

Decitabine, one of the first epigenetic drugs, helps reverse the altered methylation patterns in cancerous cells, but its precise mode of action has not been clear.

Using a combination of models, Dr Irudayaraj and his colleagues showed that decitabine is taking the place of cytosine at strategic positions on replicating strands of DNA in cancer cells.

When an enzyme tries to add a methyl group to silence decitabine, the drug traps it in place, preventing methylation. This triggers another group of enzymes to transform a methylated cytosine on the parent DNA strand into 5hmC, a molecule whose biological function is not yet known.

The investigators confirmed the increase in 5hmC levels in decitabine-treated leukemia cells.

To better explain the team’s findings, Basudev Chowdhury, PhD, also of Purdue University, likened decitabine to a text editor that restores meaning to a garbled sentence and compared conventional chemotherapy to a delete button.

“Think of nucleotides as the alphabet with which our cells compose messages,” he said. “Epigenetics helps translate those messages into actions such as the production of proteins. But cancer can jumble the messages, making them nonsensical. Decitabine helps revise the messages so they can be understood.”

Vials of chemotherapy drugs

Photo by Bill Branson

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or customer.service@mylan.com, Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Vials of chemotherapy drugs

Photo by Bill Branson

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or customer.service@mylan.com, Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Vials of chemotherapy drugs

Photo by Bill Branson

The pharmaceutical company Mylan is conducting a US-wide recall of several injectable chemotherapy drugs.

Testing of retention samples revealed foreign particulate matter in lots of gemcitabine, carboplatin, methotrexate, and cytarabine. So Mylan issued a

recall of these lots to the hospital/user level.

To date, Mylan has not received any reports of adverse events related to this recall. However, administering injectables that contain foreign particulates can have severe consequences.

Intrathecal administration could result in a life-threatening adverse event or permanent impairment of a body function. Intravenous administration has the potential to damage and/or obstruct blood vessels, which could induce emboli, particularly in the lungs. Intravenous injection can also result in local inflammation, phlebitis, allergic response, and/or embolization in the body and infection.

Intra-arterial administration could result in damage to blood vessels in the distal extremities or organs. And intramuscular administration could result in foreign-body inflammatory response, with local pain, swelling, and possible long-term granuloma formation.

Recall details

The following drugs are included in this recall:

• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801396; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 67457-464-20; Lot number: 7801401; Expiration date: 08/2016
• Gemcitabine for Injection, USP 200 mg; 10 mL; NDC number: 0069-3857-10; Lot number: 7801089; Expiration date: 07/2015
• Gemcitabine for Injection, USP 2 g; 100 mL; NDC number: 67457-463-02; Lot number: 7801222; Expiration date: 03/2016
• Gemcitabine for Injection, USP 1 g; 50 mL; NDC number: 67457-462-01; Lot number: 7801273;        Expiration date: 05/2016
• Carboplatin Injection 10 mg/mL; 100 mL; NDC number: 67457-493-46; Lot number: 7801312; Expiration date: 06/2015
• Methotrexate Injection, USP 25 mg/mL; 2 mL (5 x 2 mL); NDC number: 0069-0146-02; Lot number: 7801082; Expiration date: 07/2015
• Cytarabine Injection 20 mg/mL; 5 mL (10 x 5mL); NDC number: 0069-0152-02; Lot number: 7801050; Expiration date: 05/2015.

Gemcitabine for Injection, USP 200 mg is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between February 18, 2014, and December 19, 2014, and were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801089 is packaged with a Pfizer Injectable label.

Carboplatin Injection 10 mg/mL is an intravenously administered product indicated for the treatment of advanced ovarian carcinoma. The lot was distributed in the US between August 11, 2014, and October 7, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Mylan Institutional label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between January 16, 2014, and March 25, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company, with a Pfizer Injectables label.

Cytarabine Injection can be administered intravenously or intrathecally and in combination with other approved anticancer drugs. Cytarabine is indicated for remission induction in acute non-lymphocytic leukemia in adults and pediatric patients. The lot was distributed in the US between May 02, 2014, and July 24, 2014, and was manufactured and packaged by Agila Onco Therapies Limited, a Mylan company located in Bangalore, India, and is packaged with a Pfizer Injectables label.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with the recalled products should stop using them and return them to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 1-800-796-9526 or customer.service@mylan.com, Monday through Friday from 8 am to 5 pm EST.

Consumers should contact their physicians or healthcare providers if they have experienced any problems that may be related to using these drugs.

Adverse reactions or quality problems related to the use of these product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Lab mouse

PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).

CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.

Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.

Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.

The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).

They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC_50/70/90 values were correlated with Bcl_XL and inversely correlated with Bak.

Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.

The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.

In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).

In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.

The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.

CYC065 was “strongly synergistic” with Bcl2/Bcl_XL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).

The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.

Lab mouse

PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).

CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.

Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.

Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.

The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).

They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC_50/70/90 values were correlated with Bcl_XL and inversely correlated with Bak.

Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.

The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.

In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).

In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.

The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.

CYC065 was “strongly synergistic” with Bcl2/Bcl_XL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).

The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.

Lab mouse

PHILADELPHIA—Preclinical research suggests a cyclin-dependent kinase (CDK) inhibitor is active against acute leukemias, particularly those with mixed-lineage leukemia rearrangements (MLL-r).

CYC065 selectively inhibits CDK2, which drives cell-cycle transition and activates major DNA double-strand break repair pathways; CDK5, which drives metastatic spread; and CDK9, which regulates the transcription of genes important for the proliferation and survival of malignant cells.

Experiments have shown that CYC065 exhibits activity against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with and without MLL-r.

Daniella Zheleva, PhD, and her colleagues described these experiments in a poster at the AACR Annual Meeting 2015 (abstract 1650). All of the researchers are employees of Cyclacel Ltd., the company developing CYC065.

The researchers tested CYC065 in a panel of AML cell lines with wild-type MLL (HEL, HL60, Kasumi-1, KG-1, OCI-AML5, and PL21) and MLL-r (EOL-1, ML-2, MOLM-13, MV4-11, Nomo-1, OCI-AML2, and THP-1).

They found that MLL-r cell lines were “highly sensitive” to CYC065, but the sensitivity of cell lines with wild-type MLL correlated with the level of Bcl-2 family proteins. In the wild-type cell lines, IC_50/70/90 values were correlated with Bcl_XL and inversely correlated with Bak.

Six-hour pulse treatment of CYC065 at 0.5 µM to 1 µM was sufficient to cause 90% or greater cell death in sensitive cell lines. And cell lines with reduced sensitivity to the drug could be targeted by exposure to 10-hour pulse treatments of CYC065, or to CYC065 in combination with short pulses of Bcl-2 inhibitors.

The researchers observed “potent antitumor activity” when they administered CYC065 in AML xenograft models.

In an EOL-1 model, the median tumor growth inhibition on day 19 was 97% for mice that received CYC065 at 40 mg/kg (every day on days 1-5 and 8-12), 95% for mice that received CYC065 at 20 mg/kg every day on days 1-5 and 8-12), and 41% for mice that received cytarabine at 100 mg/kg (every day on days 1-5).

In the HL60 model, the median tumor growth inhibition on day 11 was 90% for mice that received CYC065 at 70 mg/kg (every day on days 1-5 and 8-12). And 2 mice achieved a complete response to treatment.

The researchers also found that CYC065 synergizes with cytarabine, particularly when CYC065 is given first. In fact, the combination could overcome the cytarabine resistance observed in the MV4-11 cell line.

CYC065 was “strongly synergistic” with Bcl2/Bcl_XL inhibitors as well, the researchers said. CYC065 synergized with ABT-199, ABT-263, and ABT-737 in both AML cell lines (THP-1 and HEL) and ALL cell lines (Jurkat and SEM).

The researchers said the potent in vitro and in vivo activity of CYC065 and the ability to combine the drug with other antileukemic agents suggest that it may have therapeutic potential in AML and ALL.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Registration area at AACR 2015

PHILADELPHIA—Withholding treatment from chronic lymphocytic leukemia (CLL) patients because they are of advanced age and have comorbidities may not be in their best interest, according to research presented at the AACR Annual Meeting 2015.

Most of the patients in this prospective, single-center study had 2 or more comorbidities, and their median age was 63.

But less than a quarter of the patients died of comorbidities, and none of them died of old age.

Most patients died of CLL progression or conditions possibly related to CLL.

Paolo Strati, MD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues presented these findings in a poster at the meeting (abstract 5267).

The researchers evaluated 1174 CLL patients, starting within 9 months of CLL diagnosis, who consented to be studied between January 2002 and November 2014.

The patients’ median age was 63 (range, 23-89), 67% were male, and 98% were Caucasian. Fifty-two percent had a Rai stage of 0, 44% had stage I-II, and 4% had stage III-IV disease. Forty-four percent of patients were IGHV-unmutated, 40% had del13q, 9% had del11q, 5% had del17p.

“The baseline characteristics are what you generally see in a CLL population,” Dr Strati noted. “Most patients did have some form of other medical condition aside from CLL. In particular, 82% of patients, at the time of CLL diagnosis, had 2 or more comorbidities.”

Comorbidities included rheumatologic conditions (42%), hyperlipidemia (41%), hypertension (40%), genitourinary conditions (35%), gastrointestinal disorders (33%), obesity (32%), cardiac conditions (28%), other cancers (20%), respiratory conditions (18%), psychiatric diseases (17%), endocrine disorders (14%), diabetes (10%), substance abuse (5%), stroke (3%), venous thromboembolism (3%), and sexually transmitted infections (3%).

“If you are an average physician of CLL patients and see that they are old, with 2 or more comorbidities, you are very tempted not to do anything,” Dr Strati said. “You are assuming the patients are going to die of something other than CLL, and that’s actually an assumption across several countries.”

But Dr Strati and his colleagues found that was not the case for most of the patients they studied.

The researchers were able to determine the cause of death in 135 patients. Fifty-one percent of those patients died of progressive CLL, and an additional 26% died of causes potentially related to CLL, such as infections (5%) and second cancers (21%). Only 22% of patients died of comorbidities.

“We also looked into whether there was any association between baseline characteristics, baseline comorbidities, and causes of death, but there was not,” Dr Strati said, noting that this reinforces the idea that CLL patients are most likely to die of CLL progression.

Dr Strati and his colleagues are still investigating the influence of other comorbidities and clinical factors at diagnosis—such as smoking and the Charlson Comorbidity Index—on survival and the ultimate cause of death in CLL patients. The team plans to present these data at iwCLL 2015.

Still, Dr Strati said the data the researchers have collected thus far suggest physicians should consider treating CLL patients despite their advanced age and the presence of comorbidities, perhaps using biological agents if patients are unable to receive chemotherapy.

In addition, he said this research suggests patients should not be excluded from clinical trials due to advanced age or comorbidities. And he hopes these data will lead to a study comparing the outcomes of treating and not treating this patient population.

Anne Kirchoff, PhD

Photo courtesy of

Huntsman Cancer Institute

A new study indicates that childhood cancer survivors (CCSs) are more likely than individuals without a cancer history to enroll on federal programs that provide disability benefits.

CCSs diagnosed between 1970 and 1986 were about 2 to 5 times as likely as control subjects to utilize such a program.

“The long-term impact of cancer can affect other issues besides health outcomes,” said study author Anne Kirchhoff, PhD, of the Huntsman Cancer Institute at the University of Utah.

“We need to do a better job of helping people function throughout their lives, not just when they’re finishing their cancer therapy.”

Dr Kirchhoff and her colleagues conducted this research and detailed the results in the Journal of the National Cancer Institute.

The researchers looked at health insurance surveys completed in 2011 and 2012 by a random sample of 698 CCSs who were diagnosed between the ages of 0 and 20 years. Today, they range in age from 20s to early 60s.

The patients are part of a National Cancer Institute initiative, called the Childhood Cancer Survivor Study, which has followed more than 14,000 children and adolescents since 1994 who were diagnosed with cancer and survived at least 5 years after diagnosis. A comparison group of 210 siblings without cancer also responded to the survey and were used as controls.

Dr Kirchhoff and her colleagues looked at current or former enrollment on 2 federal disability programs:

• Supplemental security income (SSI), which is for people with limited income who have no prior work history
• Social security disability insurance (SSDI), which pays disability benefits to adults ages 18 years and older who have worked and paid social security taxes.

In all, 13.5% of CCSs reported being enrolled on SSI in the past or present, and 10% of survivors reported being enrolled on SSDI at some point. This was substantially higher than for the comparison group, in which 2.6% of patients reported SSI enrollment and 5.4% reported SSDI enrollment.

In addition, CCSs reported current enrollment in SSI more frequently than the US population, at rates of 7.3% and 2.5%, respectively.

Dr Kirchoff and her colleagues also identified survivor socio-demographic and treatment characteristics that were associated with a higher rate of enrollment in federal support programs.

“Survivors that were younger at diagnosis, age 4 or under, were about 7 times more likely to be on SSI than we see with survivors that were diagnosed in their adolescence,” she said.

SSI enrollment was more likely for female CCSs and for survivors with a history of cranial radiation treatment as well.

Dr Kirchhoff noted that, over the years, research on CCSs has caused hospitals to rethink how to better care for cancer survivors.

“There’s really a growing strategy to support survivors in the long-term,” she said. “For example, here at Huntsman Cancer Institute, we have a pediatric cancer late-effects clinic, which helps manage issues that might come up with childhood cancer survivors in the long term, including health-management support, health-behavior support, and access to providers to help them with other issues.”

Anne Kirchoff, PhD

Photo courtesy of

Huntsman Cancer Institute

A new study indicates that childhood cancer survivors (CCSs) are more likely than individuals without a cancer history to enroll on federal programs that provide disability benefits.

CCSs diagnosed between 1970 and 1986 were about 2 to 5 times as likely as control subjects to utilize such a program.

“The long-term impact of cancer can affect other issues besides health outcomes,” said study author Anne Kirchhoff, PhD, of the Huntsman Cancer Institute at the University of Utah.

“We need to do a better job of helping people function throughout their lives, not just when they’re finishing their cancer therapy.”

Dr Kirchhoff and her colleagues conducted this research and detailed the results in the Journal of the National Cancer Institute.

The researchers looked at health insurance surveys completed in 2011 and 2012 by a random sample of 698 CCSs who were diagnosed between the ages of 0 and 20 years. Today, they range in age from 20s to early 60s.

The patients are part of a National Cancer Institute initiative, called the Childhood Cancer Survivor Study, which has followed more than 14,000 children and adolescents since 1994 who were diagnosed with cancer and survived at least 5 years after diagnosis. A comparison group of 210 siblings without cancer also responded to the survey and were used as controls.

Dr Kirchhoff and her colleagues looked at current or former enrollment on 2 federal disability programs:

• Supplemental security income (SSI), which is for people with limited income who have no prior work history
• Social security disability insurance (SSDI), which pays disability benefits to adults ages 18 years and older who have worked and paid social security taxes.

In all, 13.5% of CCSs reported being enrolled on SSI in the past or present, and 10% of survivors reported being enrolled on SSDI at some point. This was substantially higher than for the comparison group, in which 2.6% of patients reported SSI enrollment and 5.4% reported SSDI enrollment.

In addition, CCSs reported current enrollment in SSI more frequently than the US population, at rates of 7.3% and 2.5%, respectively.

Dr Kirchoff and her colleagues also identified survivor socio-demographic and treatment characteristics that were associated with a higher rate of enrollment in federal support programs.

“Survivors that were younger at diagnosis, age 4 or under, were about 7 times more likely to be on SSI than we see with survivors that were diagnosed in their adolescence,” she said.

SSI enrollment was more likely for female CCSs and for survivors with a history of cranial radiation treatment as well.

Dr Kirchhoff noted that, over the years, research on CCSs has caused hospitals to rethink how to better care for cancer survivors.

“There’s really a growing strategy to support survivors in the long-term,” she said. “For example, here at Huntsman Cancer Institute, we have a pediatric cancer late-effects clinic, which helps manage issues that might come up with childhood cancer survivors in the long term, including health-management support, health-behavior support, and access to providers to help them with other issues.”

Anne Kirchoff, PhD

Photo courtesy of

Huntsman Cancer Institute

A new study indicates that childhood cancer survivors (CCSs) are more likely than individuals without a cancer history to enroll on federal programs that provide disability benefits.

CCSs diagnosed between 1970 and 1986 were about 2 to 5 times as likely as control subjects to utilize such a program.

“The long-term impact of cancer can affect other issues besides health outcomes,” said study author Anne Kirchhoff, PhD, of the Huntsman Cancer Institute at the University of Utah.

“We need to do a better job of helping people function throughout their lives, not just when they’re finishing their cancer therapy.”

Dr Kirchhoff and her colleagues conducted this research and detailed the results in the Journal of the National Cancer Institute.

The researchers looked at health insurance surveys completed in 2011 and 2012 by a random sample of 698 CCSs who were diagnosed between the ages of 0 and 20 years. Today, they range in age from 20s to early 60s.

The patients are part of a National Cancer Institute initiative, called the Childhood Cancer Survivor Study, which has followed more than 14,000 children and adolescents since 1994 who were diagnosed with cancer and survived at least 5 years after diagnosis. A comparison group of 210 siblings without cancer also responded to the survey and were used as controls.

Dr Kirchhoff and her colleagues looked at current or former enrollment on 2 federal disability programs:

• Supplemental security income (SSI), which is for people with limited income who have no prior work history
• Social security disability insurance (SSDI), which pays disability benefits to adults ages 18 years and older who have worked and paid social security taxes.

In all, 13.5% of CCSs reported being enrolled on SSI in the past or present, and 10% of survivors reported being enrolled on SSDI at some point. This was substantially higher than for the comparison group, in which 2.6% of patients reported SSI enrollment and 5.4% reported SSDI enrollment.

In addition, CCSs reported current enrollment in SSI more frequently than the US population, at rates of 7.3% and 2.5%, respectively.

Dr Kirchoff and her colleagues also identified survivor socio-demographic and treatment characteristics that were associated with a higher rate of enrollment in federal support programs.

“Survivors that were younger at diagnosis, age 4 or under, were about 7 times more likely to be on SSI than we see with survivors that were diagnosed in their adolescence,” she said.

SSI enrollment was more likely for female CCSs and for survivors with a history of cranial radiation treatment as well.

Dr Kirchhoff noted that, over the years, research on CCSs has caused hospitals to rethink how to better care for cancer survivors.

“There’s really a growing strategy to support survivors in the long-term,” she said. “For example, here at Huntsman Cancer Institute, we have a pediatric cancer late-effects clinic, which helps manage issues that might come up with childhood cancer survivors in the long term, including health-management support, health-behavior support, and access to providers to help them with other issues.”

Javier Di Noia, PhD

Photo courtesy of IRCM

Researchers say they have uncovered a mechanism that could aid the development of therapies for lymphomas and leukemias.

The group’s research shed new light on a mechanism affecting activation-induced deaminase (AID), an enzyme that has proven crucial for immune response.

Javier Di Noia, PhD, of Institut de Recherches Cliniques de Montreal (IRCM) in Quebec, Canada, and his colleagues described this mechanism in The Journal of Experimental Medicine.

Dr Di Noia noted that, although AID is crucial for an efficient antibody response, high levels of the enzyme can have harmful effects and lead to cancer-causing mutations.

“The objective is to find the perfect level of AID activity to maximize the protection it provides to the body while reducing the risk of damage it can cause to cells,” he said.

Dr Di Noia and his colleagues previously found that heat-shock protein 90 (Hsp90) maintains the levels of AID by stabilizing it while it is still immature. In fact, they discovered that inhibiting Hsp90 significantly reduces the levels of AID in the cell.

“Through this new study, we identified another mechanism, controlled by the protein eEF1a [elongation factor eukaryotic elongation factor 1 α], that has the opposite effect,” said Stephen P. Methot, a PhD student in Dr Di Noia’s lab.

“The protein eEF1a retains AID in the cell’s cytoplasm, away from the genome. However, unlike Hsp90, it maintains AID in a ready-to-act state. We discovered that blocking the interaction between AID and eEF1a helps AID access the cell nucleus and thereby boosts AID activity. As a result, this could increase immune response and help fight infections, for instance.”

“We found the eEF1a mechanism is necessary to restrict AID activity in the cell. It acts as a buffer by allowing the cell to accumulate enough AID to be efficient but limits its activity to prevent the oncogenic or toxic effects that could result if too much AID is in continuous contact with the genome.”

The researchers also identified 2 existing drugs that can act on the eEF1a mechanism to release AID into the cell. The team said these drugs could potentially be used to boost AID activity and, thus, immune responses.

“With this discovery, we now understand mechanisms that can both reduce and increase the activity of AID by targeting different proteins,” Dr Di Noia said.

“This knowledge could eventually lead to new treatments to boost the immune system and help our aging population fight influenza, for example, as AID activity in our cells decreases with age. On the other hand, therapies could also be developed to lower toxic levels of AID in certain cancers such as B-cell lymphoma and leukemia.”

Javier Di Noia, PhD

Photo courtesy of IRCM

Researchers say they have uncovered a mechanism that could aid the development of therapies for lymphomas and leukemias.

The group’s research shed new light on a mechanism affecting activation-induced deaminase (AID), an enzyme that has proven crucial for immune response.

Javier Di Noia, PhD, of Institut de Recherches Cliniques de Montreal (IRCM) in Quebec, Canada, and his colleagues described this mechanism in The Journal of Experimental Medicine.

Dr Di Noia noted that, although AID is crucial for an efficient antibody response, high levels of the enzyme can have harmful effects and lead to cancer-causing mutations.

“The objective is to find the perfect level of AID activity to maximize the protection it provides to the body while reducing the risk of damage it can cause to cells,” he said.

Dr Di Noia and his colleagues previously found that heat-shock protein 90 (Hsp90) maintains the levels of AID by stabilizing it while it is still immature. In fact, they discovered that inhibiting Hsp90 significantly reduces the levels of AID in the cell.

“Through this new study, we identified another mechanism, controlled by the protein eEF1a [elongation factor eukaryotic elongation factor 1 α], that has the opposite effect,” said Stephen P. Methot, a PhD student in Dr Di Noia’s lab.

“The protein eEF1a retains AID in the cell’s cytoplasm, away from the genome. However, unlike Hsp90, it maintains AID in a ready-to-act state. We discovered that blocking the interaction between AID and eEF1a helps AID access the cell nucleus and thereby boosts AID activity. As a result, this could increase immune response and help fight infections, for instance.”

“We found the eEF1a mechanism is necessary to restrict AID activity in the cell. It acts as a buffer by allowing the cell to accumulate enough AID to be efficient but limits its activity to prevent the oncogenic or toxic effects that could result if too much AID is in continuous contact with the genome.”

The researchers also identified 2 existing drugs that can act on the eEF1a mechanism to release AID into the cell. The team said these drugs could potentially be used to boost AID activity and, thus, immune responses.

“With this discovery, we now understand mechanisms that can both reduce and increase the activity of AID by targeting different proteins,” Dr Di Noia said.

“This knowledge could eventually lead to new treatments to boost the immune system and help our aging population fight influenza, for example, as AID activity in our cells decreases with age. On the other hand, therapies could also be developed to lower toxic levels of AID in certain cancers such as B-cell lymphoma and leukemia.”

Javier Di Noia, PhD

Photo courtesy of IRCM

Researchers say they have uncovered a mechanism that could aid the development of therapies for lymphomas and leukemias.

The group’s research shed new light on a mechanism affecting activation-induced deaminase (AID), an enzyme that has proven crucial for immune response.

Javier Di Noia, PhD, of Institut de Recherches Cliniques de Montreal (IRCM) in Quebec, Canada, and his colleagues described this mechanism in The Journal of Experimental Medicine.

Dr Di Noia noted that, although AID is crucial for an efficient antibody response, high levels of the enzyme can have harmful effects and lead to cancer-causing mutations.

“The objective is to find the perfect level of AID activity to maximize the protection it provides to the body while reducing the risk of damage it can cause to cells,” he said.

Dr Di Noia and his colleagues previously found that heat-shock protein 90 (Hsp90) maintains the levels of AID by stabilizing it while it is still immature. In fact, they discovered that inhibiting Hsp90 significantly reduces the levels of AID in the cell.

“Through this new study, we identified another mechanism, controlled by the protein eEF1a [elongation factor eukaryotic elongation factor 1 α], that has the opposite effect,” said Stephen P. Methot, a PhD student in Dr Di Noia’s lab.

“The protein eEF1a retains AID in the cell’s cytoplasm, away from the genome. However, unlike Hsp90, it maintains AID in a ready-to-act state. We discovered that blocking the interaction between AID and eEF1a helps AID access the cell nucleus and thereby boosts AID activity. As a result, this could increase immune response and help fight infections, for instance.”

“We found the eEF1a mechanism is necessary to restrict AID activity in the cell. It acts as a buffer by allowing the cell to accumulate enough AID to be efficient but limits its activity to prevent the oncogenic or toxic effects that could result if too much AID is in continuous contact with the genome.”

The researchers also identified 2 existing drugs that can act on the eEF1a mechanism to release AID into the cell. The team said these drugs could potentially be used to boost AID activity and, thus, immune responses.

“With this discovery, we now understand mechanisms that can both reduce and increase the activity of AID by targeting different proteins,” Dr Di Noia said.

“This knowledge could eventually lead to new treatments to boost the immune system and help our aging population fight influenza, for example, as AID activity in our cells decreases with age. On the other hand, therapies could also be developed to lower toxic levels of AID in certain cancers such as B-cell lymphoma and leukemia.”

Leukemia patient

Photo by Bill Branson

Several statistical analyses have revealed higher-than-expected rates of pediatric cancers in 2 regions of Florida—the Miami metro area and an area west of the Everglades.

The anomalous rates were detected by 5 different research teams—each using different epidemiological and statistical methodology—on a data set spanning the period from 2000 to 2010 that was provided by the Florida Association of Pediatric Tumor Programs (FAPTP).

Lance A. Waller, PhD, of Emory University in Atlanta, Georgia, reviewed the different analyses and described his findings in Statistics and Public Policy.

The research groups applied different analytical approaches to achieve the same goal: detect spatio-temporal pediatric cancer clusters. The analyses used familiar methods—scan statistics, classification, and hierarchical Bayesian modeling—as well as some ideas new to disease clustering: wombling and machine learning.

During their respective analyses of the FAPTP data, the research groups found several suggestive results. For instance, each approach identified local areas in which the observed pediatric cancer rate is significantly higher than the rate expected, given the number of people at risk.

While the precise areas of high reported risk differ between methods, the groups identified a few common results that overlap but are not identical.

For example, all 5 teams identified significantly elevated rates of pediatric cancers in an urban area within collections of ZIP code tabulation areas (ZCTAs) in the Miami metro area and in an area just west of the Everglades. (ZCTAs are geographic areas defined by the US Census Bureau to provide a link between census geography—blocks, block groups, and tracts—and US Postal Service ZIP code areas.)

One analysis suggested the local increase west of the Everglades is based on 2 cases, both classified as “other” race, while another analysis indicated that this cluster is limited to the year 2000.

The observed elevated rates near Miami involved a much larger population size and many more cases, factors that complicate the identification of any shared characteristics common to cases in the cluster.

The analyses also revealed other patterns in the data. Dr Waller said an analysis that revealed a statewide increase in the baseline pediatric cancer incidence rate occurring between 2005 and 2006 merits a closer look to see whether this result represents an overall increase in risk or a change in reporting, because the statistical analysis does not reveal potential reasons for the change.

There also are subtle differences between the specific clusters identified by the various analytical approaches. Comparisons across analyses revealed characteristics of the detected patterns, including the number of cases (2), types of cancer (leukemia or brain/central nervous system cancer), and the racial composition and timing of the cluster west of the Everglades.

As the methods the researchers used don’t completely agree on the precise location, boundaries, and make-up of the detected clusters, the findings suggest a single method may not prove sufficient for such analyses, Dr Waller said.

He added that the identified clusters are geographically quite large and therefore unlikely to provide clear links between particular environmental exposures to local risks.

“While the results do not identify a ‘smoking gun’ in the form of a shared environmental exposure in high-incidence areas, the results do provide epidemiologic insight into the local demographics of the incidence of pediatric cancer cases and suggest more detailed assessment of migration patterns in the Miami area,” Dr Waller said.

“Policy-wise, the results point to responsibly responsive next steps of detailed description of the cases and the at-risk population in the detected areas to summarize local features in the data, particularly the race of cases west of the Everglades and demographic descriptors of any shifts in the at-risk population in the Miami area during the study period.”

Policy responses by local and state health officials may involve more detailed follow-up, including additional data collection, exposure surveys, or in-depth investigation of case histories within a reported cluster.

Dr Waller added that estimated cancer rates consist of the local number of cases (reported by the FAPTP) and the local number of children at risk (reported by the decennial census). Higher-than-expected rates can result from unusually high numbers of reported cases or low numbers of reported local residents.

Since Miami, like many urban areas, often experiences rapid changes in population size and composition between decennial censuses, it is important to assess the accuracy of both data components. Dr Waller suggested, as a first step, assessing the accuracy of the case counts and the inter-census population projections defining the local rates.

“State and local health departments and public health agencies regularly respond to cluster reports from the public,” he said. “Typically, a responsive and effective response is not based on a detailed new epidemiologic study but, rather, is based on education, assessments of local concentrations of demographic risk factors associated with the reported cluster, and an assessment of the distribution of numbers of cases expected given the local demographics.”

Leukemia patient

Photo by Bill Branson

Several statistical analyses have revealed higher-than-expected rates of pediatric cancers in 2 regions of Florida—the Miami metro area and an area west of the Everglades.

The anomalous rates were detected by 5 different research teams—each using different epidemiological and statistical methodology—on a data set spanning the period from 2000 to 2010 that was provided by the Florida Association of Pediatric Tumor Programs (FAPTP).

Lance A. Waller, PhD, of Emory University in Atlanta, Georgia, reviewed the different analyses and described his findings in Statistics and Public Policy.

The research groups applied different analytical approaches to achieve the same goal: detect spatio-temporal pediatric cancer clusters. The analyses used familiar methods—scan statistics, classification, and hierarchical Bayesian modeling—as well as some ideas new to disease clustering: wombling and machine learning.

During their respective analyses of the FAPTP data, the research groups found several suggestive results. For instance, each approach identified local areas in which the observed pediatric cancer rate is significantly higher than the rate expected, given the number of people at risk.

While the precise areas of high reported risk differ between methods, the groups identified a few common results that overlap but are not identical.

For example, all 5 teams identified significantly elevated rates of pediatric cancers in an urban area within collections of ZIP code tabulation areas (ZCTAs) in the Miami metro area and in an area just west of the Everglades. (ZCTAs are geographic areas defined by the US Census Bureau to provide a link between census geography—blocks, block groups, and tracts—and US Postal Service ZIP code areas.)

One analysis suggested the local increase west of the Everglades is based on 2 cases, both classified as “other” race, while another analysis indicated that this cluster is limited to the year 2000.

The observed elevated rates near Miami involved a much larger population size and many more cases, factors that complicate the identification of any shared characteristics common to cases in the cluster.

The analyses also revealed other patterns in the data. Dr Waller said an analysis that revealed a statewide increase in the baseline pediatric cancer incidence rate occurring between 2005 and 2006 merits a closer look to see whether this result represents an overall increase in risk or a change in reporting, because the statistical analysis does not reveal potential reasons for the change.

There also are subtle differences between the specific clusters identified by the various analytical approaches. Comparisons across analyses revealed characteristics of the detected patterns, including the number of cases (2), types of cancer (leukemia or brain/central nervous system cancer), and the racial composition and timing of the cluster west of the Everglades.

As the methods the researchers used don’t completely agree on the precise location, boundaries, and make-up of the detected clusters, the findings suggest a single method may not prove sufficient for such analyses, Dr Waller said.

He added that the identified clusters are geographically quite large and therefore unlikely to provide clear links between particular environmental exposures to local risks.

“While the results do not identify a ‘smoking gun’ in the form of a shared environmental exposure in high-incidence areas, the results do provide epidemiologic insight into the local demographics of the incidence of pediatric cancer cases and suggest more detailed assessment of migration patterns in the Miami area,” Dr Waller said.

“Policy-wise, the results point to responsibly responsive next steps of detailed description of the cases and the at-risk population in the detected areas to summarize local features in the data, particularly the race of cases west of the Everglades and demographic descriptors of any shifts in the at-risk population in the Miami area during the study period.”

Policy responses by local and state health officials may involve more detailed follow-up, including additional data collection, exposure surveys, or in-depth investigation of case histories within a reported cluster.

Dr Waller added that estimated cancer rates consist of the local number of cases (reported by the FAPTP) and the local number of children at risk (reported by the decennial census). Higher-than-expected rates can result from unusually high numbers of reported cases or low numbers of reported local residents.

Since Miami, like many urban areas, often experiences rapid changes in population size and composition between decennial censuses, it is important to assess the accuracy of both data components. Dr Waller suggested, as a first step, assessing the accuracy of the case counts and the inter-census population projections defining the local rates.

“State and local health departments and public health agencies regularly respond to cluster reports from the public,” he said. “Typically, a responsive and effective response is not based on a detailed new epidemiologic study but, rather, is based on education, assessments of local concentrations of demographic risk factors associated with the reported cluster, and an assessment of the distribution of numbers of cases expected given the local demographics.”

Leukemia patient

Photo by Bill Branson

Several statistical analyses have revealed higher-than-expected rates of pediatric cancers in 2 regions of Florida—the Miami metro area and an area west of the Everglades.

The anomalous rates were detected by 5 different research teams—each using different epidemiological and statistical methodology—on a data set spanning the period from 2000 to 2010 that was provided by the Florida Association of Pediatric Tumor Programs (FAPTP).

Lance A. Waller, PhD, of Emory University in Atlanta, Georgia, reviewed the different analyses and described his findings in Statistics and Public Policy.

The research groups applied different analytical approaches to achieve the same goal: detect spatio-temporal pediatric cancer clusters. The analyses used familiar methods—scan statistics, classification, and hierarchical Bayesian modeling—as well as some ideas new to disease clustering: wombling and machine learning.

During their respective analyses of the FAPTP data, the research groups found several suggestive results. For instance, each approach identified local areas in which the observed pediatric cancer rate is significantly higher than the rate expected, given the number of people at risk.

While the precise areas of high reported risk differ between methods, the groups identified a few common results that overlap but are not identical.

For example, all 5 teams identified significantly elevated rates of pediatric cancers in an urban area within collections of ZIP code tabulation areas (ZCTAs) in the Miami metro area and in an area just west of the Everglades. (ZCTAs are geographic areas defined by the US Census Bureau to provide a link between census geography—blocks, block groups, and tracts—and US Postal Service ZIP code areas.)

One analysis suggested the local increase west of the Everglades is based on 2 cases, both classified as “other” race, while another analysis indicated that this cluster is limited to the year 2000.

The observed elevated rates near Miami involved a much larger population size and many more cases, factors that complicate the identification of any shared characteristics common to cases in the cluster.

The analyses also revealed other patterns in the data. Dr Waller said an analysis that revealed a statewide increase in the baseline pediatric cancer incidence rate occurring between 2005 and 2006 merits a closer look to see whether this result represents an overall increase in risk or a change in reporting, because the statistical analysis does not reveal potential reasons for the change.

There also are subtle differences between the specific clusters identified by the various analytical approaches. Comparisons across analyses revealed characteristics of the detected patterns, including the number of cases (2), types of cancer (leukemia or brain/central nervous system cancer), and the racial composition and timing of the cluster west of the Everglades.

As the methods the researchers used don’t completely agree on the precise location, boundaries, and make-up of the detected clusters, the findings suggest a single method may not prove sufficient for such analyses, Dr Waller said.

He added that the identified clusters are geographically quite large and therefore unlikely to provide clear links between particular environmental exposures to local risks.

“While the results do not identify a ‘smoking gun’ in the form of a shared environmental exposure in high-incidence areas, the results do provide epidemiologic insight into the local demographics of the incidence of pediatric cancer cases and suggest more detailed assessment of migration patterns in the Miami area,” Dr Waller said.

“Policy-wise, the results point to responsibly responsive next steps of detailed description of the cases and the at-risk population in the detected areas to summarize local features in the data, particularly the race of cases west of the Everglades and demographic descriptors of any shifts in the at-risk population in the Miami area during the study period.”

Policy responses by local and state health officials may involve more detailed follow-up, including additional data collection, exposure surveys, or in-depth investigation of case histories within a reported cluster.

Dr Waller added that estimated cancer rates consist of the local number of cases (reported by the FAPTP) and the local number of children at risk (reported by the decennial census). Higher-than-expected rates can result from unusually high numbers of reported cases or low numbers of reported local residents.

Since Miami, like many urban areas, often experiences rapid changes in population size and composition between decennial censuses, it is important to assess the accuracy of both data components. Dr Waller suggested, as a first step, assessing the accuracy of the case counts and the inter-census population projections defining the local rates.

“State and local health departments and public health agencies regularly respond to cluster reports from the public,” he said. “Typically, a responsive and effective response is not based on a detailed new epidemiologic study but, rather, is based on education, assessments of local concentrations of demographic risk factors associated with the reported cluster, and an assessment of the distribution of numbers of cases expected given the local demographics.”

An EBV-infected cell (green)

among uninfected cells (blue)

Image courtesy of NIH/

Benjamin Chaigne-Delalande

PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients

with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.

Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.

Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.

The team presented these results as abstract CT107.*

“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.

“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”

In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.

Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.

Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.

Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.

For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).

Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.

Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.

All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.

He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.

“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”

Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.

Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.

*Information in the abstract differs from that presented at the meeting. 

An EBV-infected cell (green)

among uninfected cells (blue)

Image courtesy of NIH/

Benjamin Chaigne-Delalande

PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients

with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.

Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.

Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.

The team presented these results as abstract CT107.*

“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.

“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”

In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.

Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.

Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.

Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.

For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).

Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.

Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.

All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.

He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.

“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”

Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.

Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.

*Information in the abstract differs from that presented at the meeting. 

An EBV-infected cell (green)

among uninfected cells (blue)

Image courtesy of NIH/

Benjamin Chaigne-Delalande

PHILADELPHIA—Cytotoxic T lymphocytes designed to target Epstein-Barr virus (EBV-CTLs) can elicit durable responses in patients

with EBV–associated lymphoproliferative disorder (EBV-LPD), according to data presented at the AACRAnnual Meeting 2015.

Results from two trials showed that EBV-CTLs derived from a patient’s transplant donor could produce a response rate of 62%, and EBV-CTLs derived from third-party donors could produce a response rate of 61%.

Study investigators noted that, with the achievement of complete response (CR), remission proved durable. And, unlike with chemotherapy, partial responses (PRs) to EBV-CTLs were durable as well.

The team presented these results as abstract CT107.*

“The purpose of our clinical trials was to see if giving T cells from a normal-immune individual that were expanded in culture and stimulated to respond to multiple proteins from the Epstein-Barr virus could provide a safe and effective treatment,” said Richard J. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York.

“The good news from our two clinical trials is that EBV-CTLs generated from either the patient’s transplant donor or from the bank of normal donor T cells developed at Memorial Sloan Kettering put aggressive EBV-LPD that had failed to respond to rituximab into long-lasting remission in more than 60% of patients.”

In the first trial, 26 patients with EBV-LPD received EBV-CTLs generated from their transplant donor. Thirteen of these patients had previously received rituximab, and 16 had high-risk disease.

Thirteen patients in this trial received HLA-matched, EBV-CTLs from the Memorial Sloan Kettering Cancer Center bank of EBV-CTLs generated from third-party, healthy donors. All 13 patients had high-risk disease, and 12 had received prior rituximab.

Dr O’Reilly noted that good results were observed with EBV-CTLs from both sources in this trial. And because EBV-CTLs from the bank are available immediately, he and his team used only EBV-CTLs from the bank when treating the 18 patients enrolled in the second trial.

Among the 39 patients enrolled in the first trial, 23 had a CR, none had a PR, and 2 had stable disease.

For patients who received EBV-CTLs from their primary donor, the combined rate of CR and PR was 62% (16 CRs). For patients who received third-party EBV-CTLs, the combined rate of CR and PR was 54% (7 CRs).

Sixteen of the patients who achieved a CR are still doing well, Dr O’Reilly said. Eight of these patients are alive more than 5 years after receiving EBV-CTLs, and 1 is alive more than 10 years after treatment.

Among the 18 patients enrolled in the second trial, 9 had a CR, 3 had a PR, and 1 had stable disease. The combined rate of CR and PR was 67%.

All of the patients who achieved a CR in this trial continue to do well, and the investigators will be following them long-term, Dr O’Reilly said.

He also noted that toxicities with EBV-CTLs were minimal, and there were no treatment-related deaths. None of the patients developed cytokine release syndrome or graft-vs-host disease requiring systemic therapy.

“The EBV-CTLs work well for the majority of recipients,” Dr O’Reilly said. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about 7 to 14 days. We are rigorously pursuing the development of biomarkers or other tests to predict response earlier.”

Memorial Sloan Kettering Cancer Center has entered into an option agreement with Atara Biotherapeutics to further develop EBV-CTLs for clinical use. However, the data presented at AACR were accrued prior to that agreement.

Last month, the US Food and Drug Administration granted breakthrough therapy designation to EBV-CTLs generated from third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.

*Information in the abstract differs from that presented at the meeting.