Leukemia, Myelodysplasia, Transplantation

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved decitabine for injection, a generic version of Dacogen, to treat patients with myelodysplastic syndromes (MDS).

Decitabine is indicated for previously treated and untreated patients with de novo and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia—as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Decitabine will be marketed in 20 mL single-dose glass vials containing 50 mg decitabine—the same size and strength as the brand name drug. The dosing regimen is identical as well.

InnoPharma developed the generic formulation of decitabine and entered into an agreement with Sandoz Inc. Sandoz will sell, market, and distribute decitabine in the US. InnoPharma is set to be acquired by Pfizer Inc., but the transaction is subject to US regulatory approval.

The FDA approved another generic form of decitabine for the treatment of MDS in July 2013. That drug is a product of Dr Reddy’s Laboratories Limited.

Dacogen has been FDA-approved to treat MDS since May 2006. Dacogen is a registered trademark used by Eisai Inc. under license from Astex Pharmaceuticals Inc.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved decitabine for injection, a generic version of Dacogen, to treat patients with myelodysplastic syndromes (MDS).

Decitabine is indicated for previously treated and untreated patients with de novo and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia—as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Decitabine will be marketed in 20 mL single-dose glass vials containing 50 mg decitabine—the same size and strength as the brand name drug. The dosing regimen is identical as well.

InnoPharma developed the generic formulation of decitabine and entered into an agreement with Sandoz Inc. Sandoz will sell, market, and distribute decitabine in the US. InnoPharma is set to be acquired by Pfizer Inc., but the transaction is subject to US regulatory approval.

The FDA approved another generic form of decitabine for the treatment of MDS in July 2013. That drug is a product of Dr Reddy’s Laboratories Limited.

Dacogen has been FDA-approved to treat MDS since May 2006. Dacogen is a registered trademark used by Eisai Inc. under license from Astex Pharmaceuticals Inc.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved decitabine for injection, a generic version of Dacogen, to treat patients with myelodysplastic syndromes (MDS).

Decitabine is indicated for previously treated and untreated patients with de novo and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia—as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Decitabine will be marketed in 20 mL single-dose glass vials containing 50 mg decitabine—the same size and strength as the brand name drug. The dosing regimen is identical as well.

InnoPharma developed the generic formulation of decitabine and entered into an agreement with Sandoz Inc. Sandoz will sell, market, and distribute decitabine in the US. InnoPharma is set to be acquired by Pfizer Inc., but the transaction is subject to US regulatory approval.

The FDA approved another generic form of decitabine for the treatment of MDS in July 2013. That drug is a product of Dr Reddy’s Laboratories Limited.

Dacogen has been FDA-approved to treat MDS since May 2006. Dacogen is a registered trademark used by Eisai Inc. under license from Astex Pharmaceuticals Inc.

Doctor consults with patient

Credit: NIH

Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.

And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.

These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.

In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.

Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.

To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.

The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.

The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).

Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.

Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.

In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).

“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.

To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.

The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.

Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).

“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.

“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”

Doctor consults with patient

Credit: NIH

Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.

And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.

These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.

In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.

Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.

To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.

The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.

The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).

Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.

Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.

In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).

“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.

To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.

The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.

Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).

“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.

“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”

Doctor consults with patient

Credit: NIH

Results of a large study suggest major depression is common—but largely untreated—among cancer patients in Scotland.

And 2 additional studies of Scottish patients showed that a program specifically designed for individuals with cancer can treat depression and improve quality of life more effectively than current methods of care.

These studies appear in The Lancet, The Lancet Oncology, and The Lancet Psychiatry.

In The Lancet Psychiatry, researchers recounted their analysis of data from 21,151 patients treated at cancer clinics in Scotland. The team found that major depression was substantially more common in cancer patients than in the general population.

Major depression was most common in patients with lung cancer (13%) and lowest in those with genitourinary cancer (6%). Moreover, nearly three-quarters (73%) of depressed cancer patients were not receiving treatment.

To address the problem of inadequate treatment, researchers initiated the SMaRT Oncology-2 trial. They reported the results in The Lancet.

The team evaluated a new treatment program called “Depression Care for People with Cancer” (DCPC). DCPC is delivered by specially trained cancer nurses and psychiatrists, working in collaboration with the patient’s cancer team and general practitioner, and is given as part of cancer care. It is a systematic treatment program that includes both antidepressants and psychological therapy.

The trial included 500 adults with major depression and a cancer with a good prognosis (predicted survival of more than 12 months).

Patients were randomized to receive either DCPC or “usual care,” which was provided by a patient’s general practitioner and might have included prescribing antidepressants or referring the patient to mental health services for assessment or psychological treatment.

Results showed that DCPC was more effective than usual care in reducing depression. At 6 months, 62% of patients who received DCPC responded to treatment (experiencing at least a 50% reduction in the severity of their depression), compared with 17% of those who received the usual care (P<0.0001). This benefit was sustained at 12 months.

In addition, DCPC improved anxiety, pain, fatigue, functioning, and overall quality of life (all P<0.05). The researchers also noted that the cost of providing DCPC was modest (£613 per patient).

“The huge benefit that DCPC delivers for patients with cancer and depression shows what we can achieve for patients if we take as much care with the treatment of their depression as we do with the treatment of their cancer,” said study author Michael Sharpe, MD, of the University of Oxford in the UK.

To see if patients with a poor-prognosis cancer could also benefit from DCPC, researchers initiated the SMaRT Oncology-3 trial. They reported the results in The Lancet Oncology.

The team tested a version of DCPC adapted for cancer patients with a poor prognosis. The trial included 142 patients with lung cancer and major depression.

Patients who received the modified version of DCPC had a significantly greater improvement in depression than those who received the usual care during 32 weeks of follow-up (P=0.0003). DCPC also improved patients’ anxiety (P=0.046), functioning (P=0.0019), and quality of life (P=0.018).

“Patients with lung cancer often have a poor prognosis,” said study author Jane Walker, MBChB, PhD, of the University of Oxford and Sobell House Hospice in Oxford, UK.

“If they also have major depression, that can blight the time they have left to live. This trial shows that we can effectively treat depression in patients with poor-prognosis cancers, like lung cancer, and really improve patients’ lives.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Doctor examining a child

Credit: Logan Tuttle

Weekend hospitalization can have its pitfalls, according to a study of pediatric patients newly diagnosed with leukemia.

Patients who were admitted to the hospital over the weekend had a longer length of stay, a slightly longer wait to start chemotherapy, and a higher risk for respiratory failure than patients admitted during the week.

Elizabeth K. Goodman, of the Children’s Hospital of Philadelphia, and her colleagues reported these results in JAMA Pediatrics.

The team examined adverse clinical outcomes associated with a weekend admission for the first hospitalization of pediatric patients newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

The researchers used data from the Pediatric Health Information System database, which included patients admitted to 43 children’s hospitals from 1999 through 2011.

There were 10,720 patients with ALL and 1323 with AML. Roughly 17% of these patients (n=2009) were admitted to the hospital on the weekend.

Patients hospitalized on the weekend were similar to those hospitalized during the week with regard to disease type and sex. However, weekend admissions had significantly higher percentages of patients who were younger than 5 years of age, of nonwhite race/ethnicity, and publicly insured.

Patients admitted on the weekend were also more likely to be severely ill. They were significantly more likely to require ICU-level care within the first 2 days of admission (4.8% vs 3.1%, P<0.001).

An unadjusted analysis showed that inpatient mortality was similar for patients admitted to the hospital during the week and on the weekend (0.8% and 1.0%, respectively).

However, patients admitted on the weekend had a significantly longer mean hospital stay (17.8 vs 15.8 days, P<0.001) and a longer mean wait time for chemotherapy (3.9 vs 3.5 days, P<0.001).

Patients admitted on the weekend also had an increased risk of cardiovascular failure (6.4% vs 5.0%, P=0.01), respiratory failure (8.5% vs 5.7%, P<0.001), and andrenal failure (10.2% vs 8.3%, P=0.01).

However, some of these results changed when the researchers adjusted for demographic variables (disease, sex, age, race/ethnicity, and insurance), the presence of severe illness at admission, and hospital-level factors (presence of a fellowship program, Magnet status, percentage of public payers per admissions per hospital per year, and number of oncology admissions per hospital per year).

In the adjusted analysis, weekend admission remained associated with an increase in the length of hospital stay (1.4 days) and an increase in the time to chemotherapy (0.4 days).

Weekend admission also remained associated with an increased risk of respiratory failure (odds ratio, 1.5), but it was no longer associated with an increased risk of cardiovascular or renal failure.

The researchers said these findings highlight a potential area for improvement in patient care and cost reduction. Increasing weekend resources could help reduce patients’ length of stay and ensure they receive comprehensive care.

On the other hand, it might also raise hospital expenditures without decreasing negative outcomes. So additional research is needed to determine the most clinically and cost-effective combination of hospital resources to reduce the length of stay and improve outcomes for pediatric leukemia patients.

An editorial related to this study is available in JAMA Pediatrics.

Doctor examining a child

Credit: Logan Tuttle

Weekend hospitalization can have its pitfalls, according to a study of pediatric patients newly diagnosed with leukemia.

Patients who were admitted to the hospital over the weekend had a longer length of stay, a slightly longer wait to start chemotherapy, and a higher risk for respiratory failure than patients admitted during the week.

Elizabeth K. Goodman, of the Children’s Hospital of Philadelphia, and her colleagues reported these results in JAMA Pediatrics.

The team examined adverse clinical outcomes associated with a weekend admission for the first hospitalization of pediatric patients newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

The researchers used data from the Pediatric Health Information System database, which included patients admitted to 43 children’s hospitals from 1999 through 2011.

There were 10,720 patients with ALL and 1323 with AML. Roughly 17% of these patients (n=2009) were admitted to the hospital on the weekend.

Patients hospitalized on the weekend were similar to those hospitalized during the week with regard to disease type and sex. However, weekend admissions had significantly higher percentages of patients who were younger than 5 years of age, of nonwhite race/ethnicity, and publicly insured.

Patients admitted on the weekend were also more likely to be severely ill. They were significantly more likely to require ICU-level care within the first 2 days of admission (4.8% vs 3.1%, P<0.001).

An unadjusted analysis showed that inpatient mortality was similar for patients admitted to the hospital during the week and on the weekend (0.8% and 1.0%, respectively).

However, patients admitted on the weekend had a significantly longer mean hospital stay (17.8 vs 15.8 days, P<0.001) and a longer mean wait time for chemotherapy (3.9 vs 3.5 days, P<0.001).

Patients admitted on the weekend also had an increased risk of cardiovascular failure (6.4% vs 5.0%, P=0.01), respiratory failure (8.5% vs 5.7%, P<0.001), and andrenal failure (10.2% vs 8.3%, P=0.01).

However, some of these results changed when the researchers adjusted for demographic variables (disease, sex, age, race/ethnicity, and insurance), the presence of severe illness at admission, and hospital-level factors (presence of a fellowship program, Magnet status, percentage of public payers per admissions per hospital per year, and number of oncology admissions per hospital per year).

In the adjusted analysis, weekend admission remained associated with an increase in the length of hospital stay (1.4 days) and an increase in the time to chemotherapy (0.4 days).

Weekend admission also remained associated with an increased risk of respiratory failure (odds ratio, 1.5), but it was no longer associated with an increased risk of cardiovascular or renal failure.

The researchers said these findings highlight a potential area for improvement in patient care and cost reduction. Increasing weekend resources could help reduce patients’ length of stay and ensure they receive comprehensive care.

On the other hand, it might also raise hospital expenditures without decreasing negative outcomes. So additional research is needed to determine the most clinically and cost-effective combination of hospital resources to reduce the length of stay and improve outcomes for pediatric leukemia patients.

An editorial related to this study is available in JAMA Pediatrics.

Doctor examining a child

Credit: Logan Tuttle

Weekend hospitalization can have its pitfalls, according to a study of pediatric patients newly diagnosed with leukemia.

Patients who were admitted to the hospital over the weekend had a longer length of stay, a slightly longer wait to start chemotherapy, and a higher risk for respiratory failure than patients admitted during the week.

Elizabeth K. Goodman, of the Children’s Hospital of Philadelphia, and her colleagues reported these results in JAMA Pediatrics.

The team examined adverse clinical outcomes associated with a weekend admission for the first hospitalization of pediatric patients newly diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

The researchers used data from the Pediatric Health Information System database, which included patients admitted to 43 children’s hospitals from 1999 through 2011.

There were 10,720 patients with ALL and 1323 with AML. Roughly 17% of these patients (n=2009) were admitted to the hospital on the weekend.

Patients hospitalized on the weekend were similar to those hospitalized during the week with regard to disease type and sex. However, weekend admissions had significantly higher percentages of patients who were younger than 5 years of age, of nonwhite race/ethnicity, and publicly insured.

Patients admitted on the weekend were also more likely to be severely ill. They were significantly more likely to require ICU-level care within the first 2 days of admission (4.8% vs 3.1%, P<0.001).

An unadjusted analysis showed that inpatient mortality was similar for patients admitted to the hospital during the week and on the weekend (0.8% and 1.0%, respectively).

However, patients admitted on the weekend had a significantly longer mean hospital stay (17.8 vs 15.8 days, P<0.001) and a longer mean wait time for chemotherapy (3.9 vs 3.5 days, P<0.001).

Patients admitted on the weekend also had an increased risk of cardiovascular failure (6.4% vs 5.0%, P=0.01), respiratory failure (8.5% vs 5.7%, P<0.001), and andrenal failure (10.2% vs 8.3%, P=0.01).

However, some of these results changed when the researchers adjusted for demographic variables (disease, sex, age, race/ethnicity, and insurance), the presence of severe illness at admission, and hospital-level factors (presence of a fellowship program, Magnet status, percentage of public payers per admissions per hospital per year, and number of oncology admissions per hospital per year).

In the adjusted analysis, weekend admission remained associated with an increase in the length of hospital stay (1.4 days) and an increase in the time to chemotherapy (0.4 days).

Weekend admission also remained associated with an increased risk of respiratory failure (odds ratio, 1.5), but it was no longer associated with an increased risk of cardiovascular or renal failure.

The researchers said these findings highlight a potential area for improvement in patient care and cost reduction. Increasing weekend resources could help reduce patients’ length of stay and ensure they receive comprehensive care.

On the other hand, it might also raise hospital expenditures without decreasing negative outcomes. So additional research is needed to determine the most clinically and cost-effective combination of hospital resources to reduce the length of stay and improve outcomes for pediatric leukemia patients.

An editorial related to this study is available in JAMA Pediatrics.

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

DNA repair

Credit: Tom Ellenberger

Researchers say they’ve discovered “an intimate link” between RUNX genes and Fanconi anemia, a finding that also has implications for treating acute myeloid leukemia (AML).

The group found that RUNX1 and RUNX3 interact with Fanconi anemia group D2 (FANCD2), a protein involved in the repair of DNA damage.

The RUNX proteins facilitate the recruitment of FANCD2 to sites of DNA damage in both Fanconi anemia and AML.

Motomi Osato, MD, PhD, of the Cancer Science Institute of Singapore, and his colleagues recounted these findings in Cell Reports.

The researchers began by studying RUNX deficiency in mice. They found that knockdown of both RUNX1 and RUNX3 led to bone marrow failure or myeloproliferative disorders in the mice.

These clinical manifestations are seen in inherited bone marrow failure syndromes such as Fanconi anemia, which is caused by the disruption of gene products that participate in the repair of DNA interstrand crosslinks (ICLs).

With this in mind, the researchers decided to investigate RUNX function in the ICL repair pathway. And they found RUNX proteins play a critical role in the pathway by facilitating the recruitment of FANCD2 to sites of DNA damage.

To explore the clinical relevance of RUNX participation in DNA damage repair, the team conducted experiments in Kasumi-1 and SKNO-1 cells. These AML cell lines express RUNX1-ETO, which is thought to suppress the expression and/or function of RUNX1 and RUNX3 simultaneously.

The researchers showed that Kasumi-1 and SKNO-1 cells were sensitive to the ICL-inducing agent mytomycin C, and knocking down RUNX1-ETO reduced this sensitivity. Depleting RUNX1-ETO also led to increased FANCD2 recruitment to chromatin.

The team said these results suggest that RUNX1-ETO might repress FANCD2 foci formation and ICL repair in AML cells. And they predicted that RUNX dysfunction would sensitize the cells to PARP inhibitors.

So they tested 2 PARP inhibitors—olaparib and rucaparib—in Kasumi-1 cells and observed sensitivity to both drugs. Knocking down RUNX1-ETO partially reduced this sensitivity, while adding mytomycin C increased sensitivity.

“PARP inhibitors have been with us for quite some time, but nobody has realized their application for leukemia,” Dr Osato said. “Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors, which can potentially be extended to other types of common cancers.”

The researchers are now conducting additional drug testing in xenograft models.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.

Recently, Federal Practitioner talked with Sanjai Sharma, MD, about how signaling pathways in chronic lymphocytic leukemia (CLL) is critical to the development of therapeutic agents to treat this disease. Ibrutinib and idelalisib are therapeutic agents that block signaling pathways and, therefore, inhibit the growth of CLL cells.

For more information about CLL, read "Signaling Pathways and Novel Inhibitors in Chronic Lymphocytic Leukemia," in our August 2014 issue.

Dr. Sharma is a physician at the West Los Angeles VA Medical Center and associate professor in the Department of Medicine, Hematology/Oncology at UCLA, both in California.