Leukemia, Myelodysplasia, Transplantation

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Jinghui Zhang, PhD, (left)

and Xin Zhou, PhD

Photo by Peter Barta/St. Jude

Children’s Research Hospital

Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.

The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.

ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.

That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.

Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.

ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.

ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.

Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.

“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”

Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.

ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.

ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.

More information about ProteinPaint is available on the St. Jude PeCan Data Portal.

Jinghui Zhang, PhD, (left)

and Xin Zhou, PhD

Photo by Peter Barta/St. Jude

Children’s Research Hospital

Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.

The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.

ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.

That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.

Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.

ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.

ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.

Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.

“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”

Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.

ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.

ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.

More information about ProteinPaint is available on the St. Jude PeCan Data Portal.

Jinghui Zhang, PhD, (left)

and Xin Zhou, PhD

Photo by Peter Barta/St. Jude

Children’s Research Hospital

Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.

The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.

ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.

That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.

Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.

ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.

ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.

Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.

“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”

Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.

ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.

ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.

More information about ProteinPaint is available on the St. Jude PeCan Data Portal.

Preparing treatment

for a clinical trial

Photo by Esther Dyson

Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.

Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.

However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.

Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.

They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.

After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.

The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

Those 12 risk factors are:

1. The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
2. Phase 3 vs phase 2 trial (OR=1.86)
3. Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
4. Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
5. Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
6. Tissue sample required to assess eligibility (OR=1.26)
7. Investigational new drug (OR=0.34)
8. Metastatic setting (OR=1.46)
9. Sample size per 100 (OR=0.95)
10. More than one condition evaluated (OR=1.98)
11. Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
12. Interaction term (phase 3 x investigational new drug, OR=2.47).

The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.

Preparing treatment

for a clinical trial

Photo by Esther Dyson

Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.

Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.

However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.

Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.

They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.

After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.

The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

Those 12 risk factors are:

1. The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
2. Phase 3 vs phase 2 trial (OR=1.86)
3. Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
4. Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
5. Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
6. Tissue sample required to assess eligibility (OR=1.26)
7. Investigational new drug (OR=0.34)
8. Metastatic setting (OR=1.46)
9. Sample size per 100 (OR=0.95)
10. More than one condition evaluated (OR=1.98)
11. Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
12. Interaction term (phase 3 x investigational new drug, OR=2.47).

The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.

Preparing treatment

for a clinical trial

Photo by Esther Dyson

Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.

Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.

However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.

Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.

They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.

After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.

The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

Those 12 risk factors are:

1. The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
2. Phase 3 vs phase 2 trial (OR=1.86)
3. Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
4. Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
5. Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
6. Tissue sample required to assess eligibility (OR=1.26)
7. Investigational new drug (OR=0.34)
8. Metastatic setting (OR=1.46)
9. Sample size per 100 (OR=0.95)
10. More than one condition evaluated (OR=1.98)
11. Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
12. Interaction term (phase 3 x investigational new drug, OR=2.47).

The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.

Treatment for chronic myeloid leukemia (CML) entails effective but mostly noncurative long-term use of tyrosine kinase inhibitors (TKIs) that require proactive, rational approaches to minimizing cardiovascular toxicities, according to a recent review.

Survival rates of patients with newly diagnosed CML are about 90%, and in those with a complete cytogenetic response, survival is comparable to that of age-matched controls. Although second-generation TKIs have increased efficacy, survival rates are similar to those of imatinib, possibly due in part to mortality from non-CML causes.

TKIs used in CML therapy target BCR-ABL1, but their potencies vary against other kinases, including receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The relationship between off-target activities and adverse events (AEs) remains unclear, and AE management is largely empirical, said Dr. Javid Moslehi of Vanderbilt University Medical Center, Nashville, Tenn., and Dr. Michael Deininger, professor at the University of Utah Huntsman Cancer Institute, Salt Lake City.

“Reports of cardiovascular AEs with nilotinib, pulmonary arterial hypertension (PAH) on dasatinib, and frequent cardiovascular AEs with ponatinib have caused a reassessment of the situation,” they noted.

“Given the high population frequency of cardiovascular disease and the increased frequency of vascular events with nilotinib and ponatinib, cardiovascular risk assessment and, if necessary, treatment need to be integrated into the management of patients with CML on TKIs,” they wrote (J Clin Onc. 2015 Dec 10. doi: 10.1200/JCO.2015.62.4718).

Retrospective studies have indicated that imatinib may have favorable metabolic and vascular effects, but prospective controlled trials are lacking. Defining the cardiovascular baseline risk of the specific CML population under study will be crucial in future studies.

Dasatinib was approved for front-line CML treatment based on superior cytogenic response rates, compared with imatinib, but in 2011 the Food and Drug Administration warned against cardiopulmonary risks and recommended that patients be evaluated for signs and symptoms of cardiopulmonary disease before and during dasatinib treatment. Results of DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients) showed that, at 36 months of follow-up, PAH was reported in 3% of patients on dasatinib and 0% on imatinib.

Nilotinib has shown superior efficacy to imatinib and was FDA approved for first-line therapy, with recommendations for arrhythmia monitoring and avoidance of QT interval–prolonging medications. There have been no subsequent reports of ventricular arrhythmias with nilotinib, but 36% of patients on nilotinib experienced hyperglycemia in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study, compared with 20% on imatinib. Nilotinib also has been associated with hyperlipidemia and increased body mass. Recent results point to vascular toxicity with nilotinib. At the 6-year follow-up of the ENESTnd study, 10% of patients on nilotinib 300 mg twice per day and 16% on nilotinib 400 mg twice per day had cardiovascular events, compared with 2.5% of patients taking imatinib 400 mg once per day. The dose-dependent increased risk implicates a drug-dependent process.

Ponatinib is the only clinical TKI active against the BCR-ABL1^T315I mutation. It is a potent inhibitor of numerous other kinases as well, including VEGF receptors. In the PACE (Ponatinib Ph-positive Acute Lymphoblastic Leukemia and CML Evaluation) study, 26% of patients on ponatinib developed hypertension, and traditional atherosclerosis risk factors (age, hypertension, and diabetes) predisposed patients to serious vascular AEs. Cardiovascular toxicity was shown to be dose dependent, and older patients with history of diabetes or ischemic events are the least tolerant of high dose intensity. A subset of patients will benefit from ponatinib, particularly those with BCR-ABL1^T315I, but leukemia-related and cardiovascular risks must both be assessed.

Dr. Moslehi reported financial ties with Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma. Dr. Deininger reported ties to Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Cellgene.

Treatment for chronic myeloid leukemia (CML) entails effective but mostly noncurative long-term use of tyrosine kinase inhibitors (TKIs) that require proactive, rational approaches to minimizing cardiovascular toxicities, according to a recent review.

Survival rates of patients with newly diagnosed CML are about 90%, and in those with a complete cytogenetic response, survival is comparable to that of age-matched controls. Although second-generation TKIs have increased efficacy, survival rates are similar to those of imatinib, possibly due in part to mortality from non-CML causes.

TKIs used in CML therapy target BCR-ABL1, but their potencies vary against other kinases, including receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The relationship between off-target activities and adverse events (AEs) remains unclear, and AE management is largely empirical, said Dr. Javid Moslehi of Vanderbilt University Medical Center, Nashville, Tenn., and Dr. Michael Deininger, professor at the University of Utah Huntsman Cancer Institute, Salt Lake City.

“Reports of cardiovascular AEs with nilotinib, pulmonary arterial hypertension (PAH) on dasatinib, and frequent cardiovascular AEs with ponatinib have caused a reassessment of the situation,” they noted.

“Given the high population frequency of cardiovascular disease and the increased frequency of vascular events with nilotinib and ponatinib, cardiovascular risk assessment and, if necessary, treatment need to be integrated into the management of patients with CML on TKIs,” they wrote (J Clin Onc. 2015 Dec 10. doi: 10.1200/JCO.2015.62.4718).

Retrospective studies have indicated that imatinib may have favorable metabolic and vascular effects, but prospective controlled trials are lacking. Defining the cardiovascular baseline risk of the specific CML population under study will be crucial in future studies.

Dasatinib was approved for front-line CML treatment based on superior cytogenic response rates, compared with imatinib, but in 2011 the Food and Drug Administration warned against cardiopulmonary risks and recommended that patients be evaluated for signs and symptoms of cardiopulmonary disease before and during dasatinib treatment. Results of DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients) showed that, at 36 months of follow-up, PAH was reported in 3% of patients on dasatinib and 0% on imatinib.

Nilotinib has shown superior efficacy to imatinib and was FDA approved for first-line therapy, with recommendations for arrhythmia monitoring and avoidance of QT interval–prolonging medications. There have been no subsequent reports of ventricular arrhythmias with nilotinib, but 36% of patients on nilotinib experienced hyperglycemia in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study, compared with 20% on imatinib. Nilotinib also has been associated with hyperlipidemia and increased body mass. Recent results point to vascular toxicity with nilotinib. At the 6-year follow-up of the ENESTnd study, 10% of patients on nilotinib 300 mg twice per day and 16% on nilotinib 400 mg twice per day had cardiovascular events, compared with 2.5% of patients taking imatinib 400 mg once per day. The dose-dependent increased risk implicates a drug-dependent process.

Ponatinib is the only clinical TKI active against the BCR-ABL1^T315I mutation. It is a potent inhibitor of numerous other kinases as well, including VEGF receptors. In the PACE (Ponatinib Ph-positive Acute Lymphoblastic Leukemia and CML Evaluation) study, 26% of patients on ponatinib developed hypertension, and traditional atherosclerosis risk factors (age, hypertension, and diabetes) predisposed patients to serious vascular AEs. Cardiovascular toxicity was shown to be dose dependent, and older patients with history of diabetes or ischemic events are the least tolerant of high dose intensity. A subset of patients will benefit from ponatinib, particularly those with BCR-ABL1^T315I, but leukemia-related and cardiovascular risks must both be assessed.

Dr. Moslehi reported financial ties with Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma. Dr. Deininger reported ties to Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Cellgene.

Treatment for chronic myeloid leukemia (CML) entails effective but mostly noncurative long-term use of tyrosine kinase inhibitors (TKIs) that require proactive, rational approaches to minimizing cardiovascular toxicities, according to a recent review.

Survival rates of patients with newly diagnosed CML are about 90%, and in those with a complete cytogenetic response, survival is comparable to that of age-matched controls. Although second-generation TKIs have increased efficacy, survival rates are similar to those of imatinib, possibly due in part to mortality from non-CML causes.

TKIs used in CML therapy target BCR-ABL1, but their potencies vary against other kinases, including receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The relationship between off-target activities and adverse events (AEs) remains unclear, and AE management is largely empirical, said Dr. Javid Moslehi of Vanderbilt University Medical Center, Nashville, Tenn., and Dr. Michael Deininger, professor at the University of Utah Huntsman Cancer Institute, Salt Lake City.

“Reports of cardiovascular AEs with nilotinib, pulmonary arterial hypertension (PAH) on dasatinib, and frequent cardiovascular AEs with ponatinib have caused a reassessment of the situation,” they noted.

“Given the high population frequency of cardiovascular disease and the increased frequency of vascular events with nilotinib and ponatinib, cardiovascular risk assessment and, if necessary, treatment need to be integrated into the management of patients with CML on TKIs,” they wrote (J Clin Onc. 2015 Dec 10. doi: 10.1200/JCO.2015.62.4718).

Retrospective studies have indicated that imatinib may have favorable metabolic and vascular effects, but prospective controlled trials are lacking. Defining the cardiovascular baseline risk of the specific CML population under study will be crucial in future studies.

Dasatinib was approved for front-line CML treatment based on superior cytogenic response rates, compared with imatinib, but in 2011 the Food and Drug Administration warned against cardiopulmonary risks and recommended that patients be evaluated for signs and symptoms of cardiopulmonary disease before and during dasatinib treatment. Results of DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients) showed that, at 36 months of follow-up, PAH was reported in 3% of patients on dasatinib and 0% on imatinib.

Nilotinib has shown superior efficacy to imatinib and was FDA approved for first-line therapy, with recommendations for arrhythmia monitoring and avoidance of QT interval–prolonging medications. There have been no subsequent reports of ventricular arrhythmias with nilotinib, but 36% of patients on nilotinib experienced hyperglycemia in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study, compared with 20% on imatinib. Nilotinib also has been associated with hyperlipidemia and increased body mass. Recent results point to vascular toxicity with nilotinib. At the 6-year follow-up of the ENESTnd study, 10% of patients on nilotinib 300 mg twice per day and 16% on nilotinib 400 mg twice per day had cardiovascular events, compared with 2.5% of patients taking imatinib 400 mg once per day. The dose-dependent increased risk implicates a drug-dependent process.

Ponatinib is the only clinical TKI active against the BCR-ABL1^T315I mutation. It is a potent inhibitor of numerous other kinases as well, including VEGF receptors. In the PACE (Ponatinib Ph-positive Acute Lymphoblastic Leukemia and CML Evaluation) study, 26% of patients on ponatinib developed hypertension, and traditional atherosclerosis risk factors (age, hypertension, and diabetes) predisposed patients to serious vascular AEs. Cardiovascular toxicity was shown to be dose dependent, and older patients with history of diabetes or ischemic events are the least tolerant of high dose intensity. A subset of patients will benefit from ponatinib, particularly those with BCR-ABL1^T315I, but leukemia-related and cardiovascular risks must both be assessed.

Dr. Moslehi reported financial ties with Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma. Dr. Deininger reported ties to Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Cellgene.

Micrograph showing AML

A study published in Nature Communications has shed light on the hereditary elements of 12 cancer types.

Investigators looked for rare germline mutations in genes known to be associated with cancer and found the frequency of these mutations varied widely, from 4% in the acute myeloid leukemia (AML) cases studied to 19% in cases of ovarian cancer.

The team’s analysis also revealed an unexpected inherited component to stomach cancer and provided some clarity on the consequences of certain mutations in the BRCA1 and BRCA2 genes.

Li Ding, PhD, of Washington University School of Medicine in St Louis, Missouri, and her colleagues conducted this study, analyzing genetic information from more than 4000 cancer cases included in The Cancer Genome Atlas project.

“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” Dr Ding said. “But this is the first time, on a large scale, that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”

To help tease out cancer’s inherited components, Dr Ding and her colleagues looked for germline truncations in 114 genes known to be associated with cancer.

“We looked for germline mutations in the tumor, but it was not enough for the mutations simply to be present,” Dr Ding said. “They needed to be enriched in the tumor—present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.”

The investigators found germline truncations in all 12 cancer types analyzed, but the mutations occurred in varying frequencies depending on the cancer.

The percentage of tumors with truncations in the germline was 4% for AML and glioblastoma; 5% for kidney cancer; 7% for lung adenocarcinoma and endometrial cancer; 8% for head and neck cancer, glioma, lung squamous cell carcinoma, and prostate cancer; 9% for breast cancer; 11% for stomach cancer; and 19% for ovarian cancer.

“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers, for example,” Dr Ding said. “This suggests we should pay attention to the potential involvement of these 2 genes in other cancer types.”

The investigators said they identified 13 cancer genes with significant enrichment of rare truncations. Some of these were associated with specific cancers—for example, RAD51C in AML, PALB2 in stomach cancer, and MSH6 in endometrial cancer.

And the team observed significant, tumor-specific loss of heterozygosity in 9 genes—ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2, and RAD51C/D.

Dr Ding said more research is needed to confirm these results before they can be used to advise patients making healthcare decisions.

“Our strategy of investigating germline-tumor interactions provides a good way to prioritize important mutations that we should focus on,” she said. “For the information to eventually be used in the clinic, we will need to perform this type of analysis on even larger numbers of patients.”

Micrograph showing AML

A study published in Nature Communications has shed light on the hereditary elements of 12 cancer types.

Investigators looked for rare germline mutations in genes known to be associated with cancer and found the frequency of these mutations varied widely, from 4% in the acute myeloid leukemia (AML) cases studied to 19% in cases of ovarian cancer.

The team’s analysis also revealed an unexpected inherited component to stomach cancer and provided some clarity on the consequences of certain mutations in the BRCA1 and BRCA2 genes.

Li Ding, PhD, of Washington University School of Medicine in St Louis, Missouri, and her colleagues conducted this study, analyzing genetic information from more than 4000 cancer cases included in The Cancer Genome Atlas project.

“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” Dr Ding said. “But this is the first time, on a large scale, that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”

To help tease out cancer’s inherited components, Dr Ding and her colleagues looked for germline truncations in 114 genes known to be associated with cancer.

“We looked for germline mutations in the tumor, but it was not enough for the mutations simply to be present,” Dr Ding said. “They needed to be enriched in the tumor—present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.”

The investigators found germline truncations in all 12 cancer types analyzed, but the mutations occurred in varying frequencies depending on the cancer.

The percentage of tumors with truncations in the germline was 4% for AML and glioblastoma; 5% for kidney cancer; 7% for lung adenocarcinoma and endometrial cancer; 8% for head and neck cancer, glioma, lung squamous cell carcinoma, and prostate cancer; 9% for breast cancer; 11% for stomach cancer; and 19% for ovarian cancer.

“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers, for example,” Dr Ding said. “This suggests we should pay attention to the potential involvement of these 2 genes in other cancer types.”

The investigators said they identified 13 cancer genes with significant enrichment of rare truncations. Some of these were associated with specific cancers—for example, RAD51C in AML, PALB2 in stomach cancer, and MSH6 in endometrial cancer.

And the team observed significant, tumor-specific loss of heterozygosity in 9 genes—ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2, and RAD51C/D.

Dr Ding said more research is needed to confirm these results before they can be used to advise patients making healthcare decisions.

“Our strategy of investigating germline-tumor interactions provides a good way to prioritize important mutations that we should focus on,” she said. “For the information to eventually be used in the clinic, we will need to perform this type of analysis on even larger numbers of patients.”

Micrograph showing AML

A study published in Nature Communications has shed light on the hereditary elements of 12 cancer types.

Investigators looked for rare germline mutations in genes known to be associated with cancer and found the frequency of these mutations varied widely, from 4% in the acute myeloid leukemia (AML) cases studied to 19% in cases of ovarian cancer.

The team’s analysis also revealed an unexpected inherited component to stomach cancer and provided some clarity on the consequences of certain mutations in the BRCA1 and BRCA2 genes.

Li Ding, PhD, of Washington University School of Medicine in St Louis, Missouri, and her colleagues conducted this study, analyzing genetic information from more than 4000 cancer cases included in The Cancer Genome Atlas project.

“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” Dr Ding said. “But this is the first time, on a large scale, that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”

To help tease out cancer’s inherited components, Dr Ding and her colleagues looked for germline truncations in 114 genes known to be associated with cancer.

“We looked for germline mutations in the tumor, but it was not enough for the mutations simply to be present,” Dr Ding said. “They needed to be enriched in the tumor—present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.”

The investigators found germline truncations in all 12 cancer types analyzed, but the mutations occurred in varying frequencies depending on the cancer.

The percentage of tumors with truncations in the germline was 4% for AML and glioblastoma; 5% for kidney cancer; 7% for lung adenocarcinoma and endometrial cancer; 8% for head and neck cancer, glioma, lung squamous cell carcinoma, and prostate cancer; 9% for breast cancer; 11% for stomach cancer; and 19% for ovarian cancer.

“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers, for example,” Dr Ding said. “This suggests we should pay attention to the potential involvement of these 2 genes in other cancer types.”

The investigators said they identified 13 cancer genes with significant enrichment of rare truncations. Some of these were associated with specific cancers—for example, RAD51C in AML, PALB2 in stomach cancer, and MSH6 in endometrial cancer.

And the team observed significant, tumor-specific loss of heterozygosity in 9 genes—ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2, and RAD51C/D.

Dr Ding said more research is needed to confirm these results before they can be used to advise patients making healthcare decisions.

“Our strategy of investigating germline-tumor interactions provides a good way to prioritize important mutations that we should focus on,” she said. “For the information to eventually be used in the clinic, we will need to perform this type of analysis on even larger numbers of patients.”

Doctor and cancer patient

Photo courtesy of NCI

and Matthews Media Group

A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.

After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.

Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.

“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.

“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”

Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.

The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.

PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.

For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.

Results

Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.

Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).

Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).

Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.

Financial concerns

During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.

These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.

“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”

“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”

The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.

Doctor and cancer patient

Photo courtesy of NCI

and Matthews Media Group

A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.

After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.

Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.

“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.

“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”

Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.

The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.

PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.

For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.

Results

Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.

Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).

Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).

Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.

Financial concerns

During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.

These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.

“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”

“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”

The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.

Doctor and cancer patient

Photo courtesy of NCI

and Matthews Media Group

A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.

After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.

Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.

“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.

“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”

Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.

The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.

PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.

For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.

Results

Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.

Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).

Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).

Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.

Financial concerns

During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.

These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.

“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”

“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”

The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.

Ashok Deniz, PhD

Photo courtesy of The

Scripps Research Institute

New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.

This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.

Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.

Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.

Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.

Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.

The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.

These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.

This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.

However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.

The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.

The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.

“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.

He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins. 

Ashok Deniz, PhD

Photo courtesy of The

Scripps Research Institute

New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.

This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.

Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.

Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.

Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.

Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.

The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.

These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.

This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.

However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.

The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.

The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.

“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.

He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins. 

Ashok Deniz, PhD

Photo courtesy of The

Scripps Research Institute

New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.

This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.

Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.

Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.

Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.

Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.

The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.

These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.

This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.

However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.

The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.

The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.

“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.

He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins. 

Doctor and cancer patient

Photo courtesy of the

National Cancer Institute

and Mathews Media Group

End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.

The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,

which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.

So it may not be clear that a patient has entered the EOL phase.

Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.

The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.

Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.

Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.

Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).

When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.

The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.

Doctor and cancer patient

Photo courtesy of the

National Cancer Institute

and Mathews Media Group

End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.

The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,

which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.

So it may not be clear that a patient has entered the EOL phase.

Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.

The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.

Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.

Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.

Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).

When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.

The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.

Doctor and cancer patient

Photo courtesy of the

National Cancer Institute

and Mathews Media Group

End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.

The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,

which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.

So it may not be clear that a patient has entered the EOL phase.

Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.

The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.

Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.

Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.

Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).

When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.

The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.

Micrograph showing CLL

Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).

Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.

But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.

Investigators reported these results in The Journal of Clinical Investigation.

They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.

“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.

“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”

The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.

In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.

In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.

In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.

In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.

In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.

In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.

The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.

Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.

Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.

But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.

Micrograph showing CLL

Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).

Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.

But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.

Investigators reported these results in The Journal of Clinical Investigation.

They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.

“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.

“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”

The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.

In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.

In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.

In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.

In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.

In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.

In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.

The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.

Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.

Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.

But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.

Micrograph showing CLL

Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).

Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.

But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.

Investigators reported these results in The Journal of Clinical Investigation.

They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.

“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.

“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”

The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.

In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.

In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.

In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.

In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.

In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.

In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.

The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.

Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.

Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.

But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.

Exhibit hall at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—ABL001, an allosteric inhibitor of BCR-ABL1, has shown early evidence of single-agent activity in a multicenter, first-in-human, first-in-class trial of heavily treated patients with chronic myeloid leukemia (CML) that is resistant to or intolerant of prior tyrosine kinase inhibitors (TKIs), even at the lowest dose evaluated.

ABL001 and classical TKIs exhibit complementary mutation profiles, with ABL001 showing activity against TKI resistance mutations.

When combined with nilotinib in a mouse model of CML, ABL001 prevented the emergence of resistant disease even after treatment was discontinued.

“This produces a new therapeutic concept—that of allosteric inhibition,” said Oliver G. Ottmann, MD, of Cardiff University in the UK.

The ABL001 binding site is located in a region remote from the kinase domain and has the potential to combine with TKIs for greater pharmacologic control of BCR-ABL1.

“This obviously has the opportunity both for combining different treatments and for overcoming resistance to one or the other,” Dr Ottmann added.

Based on preliminary pharmacokinetic data and preclinical evidence, investigators proceeded to evaluate ABL001 in a phase 1 dose-escalation and dose-expansion study.

Their primary objective was to determine the maximum tolerated dose (MTD) in humans and the recommended dose for expansion (RDE). Secondary objectives were to evaluate the safety, tolerability, preliminary anti-CML activity, and pharmacokinetic and pharmacodynamic profile.

Dr Ottmann presented the findings during the 2015 ASH Annual Meeting as abstract 138.*

Study design

Patients received ABL001 orally as a single agent twice a day (BID) continuously until disease progression, unacceptable toxicity, consent withdrawal, or death.

The dose-escalation schema followed a Bayesian logistic regression model based on dose-limiting toxicities during cycle 1. Doses ranged from 10 mg to 200 mg BID.

A subsequent dose-expansion phase was planned to augment the data generated in the dose-escalation phase and to include patients with Ph-positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy.

Dr Ottmann noted that there were 2 protocol amendments. The first amendment was made to include a once-daily (QD) dosing of ABL001 at 120 mg and 200 mg. The second amendment was made to evaluate the combination of 40 mg of ABL001 BID with nilotinib at 300 mg BID.

Inclusion/exclusion criteria

Patients had to be at least 18 years old with CML in chronic or accelerated phase. They had to have failed at least 2 prior TKIs or be intolerant of TKIs. Their performance status had to be 0–2.

Patients were excluded from the trial if they had an absolute neutrophil count less than 500/mm³, a platelet count less than 50,000/mm³, bilirubin level more than 1.5 x the upper limit of normal (ULN) or more than 3.0 x ULN in patients with Gilberts syndrome.

Their aspartate aminotransferase or alanine aminotransferase could not be above 3 x ULN, and creatinine could not be above 1.5 x ULN.

Patients were also excluded if they needed treatment with strong inhibitors or inducers of CYP3A4 or its substrates with narrow therapeutic index.

Patient demographics

Fifty-nine patients were enrolled on the trial at the time of the presentation and they had “typical” characteristics of patients at this stage, Dr Ottmann said.

Their median age was 56 (range, 23–78). Almost two-thirds (61%) were male and 39% female.

All but 1 patient had an ECOG performance status of 0, and patients had a median of 3.5 (range, 2–5) prior lines of therapy. Twenty-four patients (41%) had 2 prior TKIs, and 35 (59%) had 3 or more TKIs. Forty-five patients (76%) were resistant and 14 (24%) were intolerant to their prior TKI.

All but 1 patient had chronic phase CML, 18 (31%) were TKD nonmutated, 14 (24%) were mutated, and 17 (46%) were not evaluable.

Patient disposition

Of the 43 patients in the monotherapy BID cohort, 1 was treated at the 10 mg dose level, 5 at the 20 mg level, 12 at the 40 mg level, 12 at the 80 mg level, 8 at the 150 mg level, and 5 at the 200 mg level. They had a median duration of drug exposure ranging from 25 weeks to 67 weeks.

Of the 11 patients in the monotherapy QD group, 5 were treated at the 120 mg dose level and 6 at the 200 mg level. Their drug exposure was a median of 26 weeks for those receiving 120 mg and 9.8 weeks for those receiving the 200 mg dose.

And the 5 patients in the ABL001-plus-nilotinib group had a median of 6.3 weeks of drug exposure.

“We had a remarkably low rate of discontinuation to date,” Dr Ottmann pointed out.

Ten patients discontinued therapy, all in the monotherapy BID group, 1 at 10 mg, 2 at 40 mg, 2 at 80 mg, 3 at 150 mg, and 2 at 200 mg.

Seven patients discontinued for adverse events. Two patients withdrew consent, and 1 patient in the 40 mg group had disease progression, which is “quite remarkable in a phase 1,” Dr Ottmann said.

Pharmacokinetic profile

ABL001 is rapidly absorbed in a median of 2 to 3 hours, and there is a dose-proportional increase in exposure following single and repeated dosing.

The drug has an approximately 2-fold or lower accumulation on repeated dosing and a short elimination half-life of 5 to 6 hours.

Safety

“We have excellent tolerability,” Dr Ottmann said, with a small number of grade 3/4 adverse events (AEs).

Grade 3/4 AEs considered to be drug-related were mostly associated with hematologic suppression. Four patients (7%) had thrombocytopenia, 4 (7%) neutropenia, 3 (5%) anemia, 4 (7%) lipase increase, and 1 (2%) hypercholesterolemia.

AEs of all grades suspected of being related to the study drug and occurring in 5% or more of patients included thrombocytopenia (19%), neutropenia (15%), anemia (10%), nausea/vomiting/diarrhea (29%), arthralgia/myalgia (20%), rash (17%), fatigue (15%), lipase increase (14%), headache (14%), pruritus (10%), dry skin (7%), hypophosphatemia (7%), and acute pancreatitis (5%).

“The pancreatitis was reversible upon interruption or discontinuation of the drug,” Dr Ottmann explained.

There were 5 dose-limiting toxicities. Two patients had grade 3 lipase elevation in the 40 mg BID and 200 mg QD cohorts. One patient had grade 2 myalgia/arthralgia at 80 mg BID, 1 patient had a grade 3 acute coronary event at 150 mg BID, and 1 patient had a grade 3 bronchospasm at 200 mg BID.

No deaths occurred on the study, and the dose escalation is still ongoing.

Response

Twenty-nine patients with 3 months or more of follow-up were evaluable for response.

Twelve patients, who at baseline had hematologic relapse, achieved complete hematologic response within 2 months, and 8 who had cytogenetic relapse at baseline achieved a complete cytogenetic response within 3 to 6 months.

Of the 29 patients who had molecular relapse at baseline, 10 (34.5%) achieved a molecular response within 6 months, 7 (24.1%) had 1 log or more reduction in BCR-ABL1, 9 (31.0%) had less than a log reduction, and 3 (10.3%) had no reduction.

“The obvious question from the preclinical data,” Dr Ottmann said, “is do the mutations respond?”

And ABL001 has shown clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H.

“So to conclude,” he said, “we have a new class, a new therapeutic category of drug, ABL001, which is quite well tolerated in extremely heavily treated patients with CML. We do consider this a promising approach.”

The trial was sponsored by Novartis.

*Data in the abstract differ from the presentation.

Exhibit hall at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—ABL001, an allosteric inhibitor of BCR-ABL1, has shown early evidence of single-agent activity in a multicenter, first-in-human, first-in-class trial of heavily treated patients with chronic myeloid leukemia (CML) that is resistant to or intolerant of prior tyrosine kinase inhibitors (TKIs), even at the lowest dose evaluated.

ABL001 and classical TKIs exhibit complementary mutation profiles, with ABL001 showing activity against TKI resistance mutations.

When combined with nilotinib in a mouse model of CML, ABL001 prevented the emergence of resistant disease even after treatment was discontinued.

“This produces a new therapeutic concept—that of allosteric inhibition,” said Oliver G. Ottmann, MD, of Cardiff University in the UK.

The ABL001 binding site is located in a region remote from the kinase domain and has the potential to combine with TKIs for greater pharmacologic control of BCR-ABL1.

“This obviously has the opportunity both for combining different treatments and for overcoming resistance to one or the other,” Dr Ottmann added.

Based on preliminary pharmacokinetic data and preclinical evidence, investigators proceeded to evaluate ABL001 in a phase 1 dose-escalation and dose-expansion study.

Their primary objective was to determine the maximum tolerated dose (MTD) in humans and the recommended dose for expansion (RDE). Secondary objectives were to evaluate the safety, tolerability, preliminary anti-CML activity, and pharmacokinetic and pharmacodynamic profile.

Dr Ottmann presented the findings during the 2015 ASH Annual Meeting as abstract 138.*

Study design

Patients received ABL001 orally as a single agent twice a day (BID) continuously until disease progression, unacceptable toxicity, consent withdrawal, or death.

The dose-escalation schema followed a Bayesian logistic regression model based on dose-limiting toxicities during cycle 1. Doses ranged from 10 mg to 200 mg BID.

A subsequent dose-expansion phase was planned to augment the data generated in the dose-escalation phase and to include patients with Ph-positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy.

Dr Ottmann noted that there were 2 protocol amendments. The first amendment was made to include a once-daily (QD) dosing of ABL001 at 120 mg and 200 mg. The second amendment was made to evaluate the combination of 40 mg of ABL001 BID with nilotinib at 300 mg BID.

Inclusion/exclusion criteria

Patients had to be at least 18 years old with CML in chronic or accelerated phase. They had to have failed at least 2 prior TKIs or be intolerant of TKIs. Their performance status had to be 0–2.

Patients were excluded from the trial if they had an absolute neutrophil count less than 500/mm³, a platelet count less than 50,000/mm³, bilirubin level more than 1.5 x the upper limit of normal (ULN) or more than 3.0 x ULN in patients with Gilberts syndrome.

Their aspartate aminotransferase or alanine aminotransferase could not be above 3 x ULN, and creatinine could not be above 1.5 x ULN.

Patients were also excluded if they needed treatment with strong inhibitors or inducers of CYP3A4 or its substrates with narrow therapeutic index.

Patient demographics

Fifty-nine patients were enrolled on the trial at the time of the presentation and they had “typical” characteristics of patients at this stage, Dr Ottmann said.

Their median age was 56 (range, 23–78). Almost two-thirds (61%) were male and 39% female.

All but 1 patient had an ECOG performance status of 0, and patients had a median of 3.5 (range, 2–5) prior lines of therapy. Twenty-four patients (41%) had 2 prior TKIs, and 35 (59%) had 3 or more TKIs. Forty-five patients (76%) were resistant and 14 (24%) were intolerant to their prior TKI.

All but 1 patient had chronic phase CML, 18 (31%) were TKD nonmutated, 14 (24%) were mutated, and 17 (46%) were not evaluable.

Patient disposition

Of the 43 patients in the monotherapy BID cohort, 1 was treated at the 10 mg dose level, 5 at the 20 mg level, 12 at the 40 mg level, 12 at the 80 mg level, 8 at the 150 mg level, and 5 at the 200 mg level. They had a median duration of drug exposure ranging from 25 weeks to 67 weeks.

Of the 11 patients in the monotherapy QD group, 5 were treated at the 120 mg dose level and 6 at the 200 mg level. Their drug exposure was a median of 26 weeks for those receiving 120 mg and 9.8 weeks for those receiving the 200 mg dose.

And the 5 patients in the ABL001-plus-nilotinib group had a median of 6.3 weeks of drug exposure.

“We had a remarkably low rate of discontinuation to date,” Dr Ottmann pointed out.

Ten patients discontinued therapy, all in the monotherapy BID group, 1 at 10 mg, 2 at 40 mg, 2 at 80 mg, 3 at 150 mg, and 2 at 200 mg.

Seven patients discontinued for adverse events. Two patients withdrew consent, and 1 patient in the 40 mg group had disease progression, which is “quite remarkable in a phase 1,” Dr Ottmann said.

Pharmacokinetic profile

ABL001 is rapidly absorbed in a median of 2 to 3 hours, and there is a dose-proportional increase in exposure following single and repeated dosing.

The drug has an approximately 2-fold or lower accumulation on repeated dosing and a short elimination half-life of 5 to 6 hours.

Safety

“We have excellent tolerability,” Dr Ottmann said, with a small number of grade 3/4 adverse events (AEs).

Grade 3/4 AEs considered to be drug-related were mostly associated with hematologic suppression. Four patients (7%) had thrombocytopenia, 4 (7%) neutropenia, 3 (5%) anemia, 4 (7%) lipase increase, and 1 (2%) hypercholesterolemia.

AEs of all grades suspected of being related to the study drug and occurring in 5% or more of patients included thrombocytopenia (19%), neutropenia (15%), anemia (10%), nausea/vomiting/diarrhea (29%), arthralgia/myalgia (20%), rash (17%), fatigue (15%), lipase increase (14%), headache (14%), pruritus (10%), dry skin (7%), hypophosphatemia (7%), and acute pancreatitis (5%).

“The pancreatitis was reversible upon interruption or discontinuation of the drug,” Dr Ottmann explained.

There were 5 dose-limiting toxicities. Two patients had grade 3 lipase elevation in the 40 mg BID and 200 mg QD cohorts. One patient had grade 2 myalgia/arthralgia at 80 mg BID, 1 patient had a grade 3 acute coronary event at 150 mg BID, and 1 patient had a grade 3 bronchospasm at 200 mg BID.

No deaths occurred on the study, and the dose escalation is still ongoing.

Response

Twenty-nine patients with 3 months or more of follow-up were evaluable for response.

Twelve patients, who at baseline had hematologic relapse, achieved complete hematologic response within 2 months, and 8 who had cytogenetic relapse at baseline achieved a complete cytogenetic response within 3 to 6 months.

Of the 29 patients who had molecular relapse at baseline, 10 (34.5%) achieved a molecular response within 6 months, 7 (24.1%) had 1 log or more reduction in BCR-ABL1, 9 (31.0%) had less than a log reduction, and 3 (10.3%) had no reduction.

“The obvious question from the preclinical data,” Dr Ottmann said, “is do the mutations respond?”

And ABL001 has shown clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H.

“So to conclude,” he said, “we have a new class, a new therapeutic category of drug, ABL001, which is quite well tolerated in extremely heavily treated patients with CML. We do consider this a promising approach.”

The trial was sponsored by Novartis.

*Data in the abstract differ from the presentation.

Exhibit hall at the 2015

ASH Annual Meeting

Photo courtesy of ASH

ORLANDO, FL—ABL001, an allosteric inhibitor of BCR-ABL1, has shown early evidence of single-agent activity in a multicenter, first-in-human, first-in-class trial of heavily treated patients with chronic myeloid leukemia (CML) that is resistant to or intolerant of prior tyrosine kinase inhibitors (TKIs), even at the lowest dose evaluated.

ABL001 and classical TKIs exhibit complementary mutation profiles, with ABL001 showing activity against TKI resistance mutations.

When combined with nilotinib in a mouse model of CML, ABL001 prevented the emergence of resistant disease even after treatment was discontinued.

“This produces a new therapeutic concept—that of allosteric inhibition,” said Oliver G. Ottmann, MD, of Cardiff University in the UK.

The ABL001 binding site is located in a region remote from the kinase domain and has the potential to combine with TKIs for greater pharmacologic control of BCR-ABL1.

“This obviously has the opportunity both for combining different treatments and for overcoming resistance to one or the other,” Dr Ottmann added.

Based on preliminary pharmacokinetic data and preclinical evidence, investigators proceeded to evaluate ABL001 in a phase 1 dose-escalation and dose-expansion study.

Their primary objective was to determine the maximum tolerated dose (MTD) in humans and the recommended dose for expansion (RDE). Secondary objectives were to evaluate the safety, tolerability, preliminary anti-CML activity, and pharmacokinetic and pharmacodynamic profile.

Dr Ottmann presented the findings during the 2015 ASH Annual Meeting as abstract 138.*

Study design

Patients received ABL001 orally as a single agent twice a day (BID) continuously until disease progression, unacceptable toxicity, consent withdrawal, or death.

The dose-escalation schema followed a Bayesian logistic regression model based on dose-limiting toxicities during cycle 1. Doses ranged from 10 mg to 200 mg BID.

A subsequent dose-expansion phase was planned to augment the data generated in the dose-escalation phase and to include patients with Ph-positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy.

Dr Ottmann noted that there were 2 protocol amendments. The first amendment was made to include a once-daily (QD) dosing of ABL001 at 120 mg and 200 mg. The second amendment was made to evaluate the combination of 40 mg of ABL001 BID with nilotinib at 300 mg BID.

Inclusion/exclusion criteria

Patients had to be at least 18 years old with CML in chronic or accelerated phase. They had to have failed at least 2 prior TKIs or be intolerant of TKIs. Their performance status had to be 0–2.

Patients were excluded from the trial if they had an absolute neutrophil count less than 500/mm³, a platelet count less than 50,000/mm³, bilirubin level more than 1.5 x the upper limit of normal (ULN) or more than 3.0 x ULN in patients with Gilberts syndrome.

Their aspartate aminotransferase or alanine aminotransferase could not be above 3 x ULN, and creatinine could not be above 1.5 x ULN.

Patients were also excluded if they needed treatment with strong inhibitors or inducers of CYP3A4 or its substrates with narrow therapeutic index.

Patient demographics

Fifty-nine patients were enrolled on the trial at the time of the presentation and they had “typical” characteristics of patients at this stage, Dr Ottmann said.

Their median age was 56 (range, 23–78). Almost two-thirds (61%) were male and 39% female.

All but 1 patient had an ECOG performance status of 0, and patients had a median of 3.5 (range, 2–5) prior lines of therapy. Twenty-four patients (41%) had 2 prior TKIs, and 35 (59%) had 3 or more TKIs. Forty-five patients (76%) were resistant and 14 (24%) were intolerant to their prior TKI.

All but 1 patient had chronic phase CML, 18 (31%) were TKD nonmutated, 14 (24%) were mutated, and 17 (46%) were not evaluable.

Patient disposition

Of the 43 patients in the monotherapy BID cohort, 1 was treated at the 10 mg dose level, 5 at the 20 mg level, 12 at the 40 mg level, 12 at the 80 mg level, 8 at the 150 mg level, and 5 at the 200 mg level. They had a median duration of drug exposure ranging from 25 weeks to 67 weeks.

Of the 11 patients in the monotherapy QD group, 5 were treated at the 120 mg dose level and 6 at the 200 mg level. Their drug exposure was a median of 26 weeks for those receiving 120 mg and 9.8 weeks for those receiving the 200 mg dose.

And the 5 patients in the ABL001-plus-nilotinib group had a median of 6.3 weeks of drug exposure.

“We had a remarkably low rate of discontinuation to date,” Dr Ottmann pointed out.

Ten patients discontinued therapy, all in the monotherapy BID group, 1 at 10 mg, 2 at 40 mg, 2 at 80 mg, 3 at 150 mg, and 2 at 200 mg.

Seven patients discontinued for adverse events. Two patients withdrew consent, and 1 patient in the 40 mg group had disease progression, which is “quite remarkable in a phase 1,” Dr Ottmann said.

Pharmacokinetic profile

ABL001 is rapidly absorbed in a median of 2 to 3 hours, and there is a dose-proportional increase in exposure following single and repeated dosing.

The drug has an approximately 2-fold or lower accumulation on repeated dosing and a short elimination half-life of 5 to 6 hours.

Safety

“We have excellent tolerability,” Dr Ottmann said, with a small number of grade 3/4 adverse events (AEs).

Grade 3/4 AEs considered to be drug-related were mostly associated with hematologic suppression. Four patients (7%) had thrombocytopenia, 4 (7%) neutropenia, 3 (5%) anemia, 4 (7%) lipase increase, and 1 (2%) hypercholesterolemia.

AEs of all grades suspected of being related to the study drug and occurring in 5% or more of patients included thrombocytopenia (19%), neutropenia (15%), anemia (10%), nausea/vomiting/diarrhea (29%), arthralgia/myalgia (20%), rash (17%), fatigue (15%), lipase increase (14%), headache (14%), pruritus (10%), dry skin (7%), hypophosphatemia (7%), and acute pancreatitis (5%).

“The pancreatitis was reversible upon interruption or discontinuation of the drug,” Dr Ottmann explained.

There were 5 dose-limiting toxicities. Two patients had grade 3 lipase elevation in the 40 mg BID and 200 mg QD cohorts. One patient had grade 2 myalgia/arthralgia at 80 mg BID, 1 patient had a grade 3 acute coronary event at 150 mg BID, and 1 patient had a grade 3 bronchospasm at 200 mg BID.

No deaths occurred on the study, and the dose escalation is still ongoing.

Response

Twenty-nine patients with 3 months or more of follow-up were evaluable for response.

Twelve patients, who at baseline had hematologic relapse, achieved complete hematologic response within 2 months, and 8 who had cytogenetic relapse at baseline achieved a complete cytogenetic response within 3 to 6 months.

Of the 29 patients who had molecular relapse at baseline, 10 (34.5%) achieved a molecular response within 6 months, 7 (24.1%) had 1 log or more reduction in BCR-ABL1, 9 (31.0%) had less than a log reduction, and 3 (10.3%) had no reduction.

“The obvious question from the preclinical data,” Dr Ottmann said, “is do the mutations respond?”

And ABL001 has shown clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H.

“So to conclude,” he said, “we have a new class, a new therapeutic category of drug, ABL001, which is quite well tolerated in extremely heavily treated patients with CML. We do consider this a promising approach.”

The trial was sponsored by Novartis.

*Data in the abstract differ from the presentation.