Leukemia, Myelodysplasia, Transplantation

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Pills

Credit: FDA

SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.

This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.

Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.

The drug appeared to be particularly active in patients with IDH mutations.

Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.

The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.

The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.

The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.

The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.

The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.

Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.

No patients died as a result of treatment-related adverse events.

Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.

AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

SAN FRANCISCO – Adding a kinase inhibitor to a standard regimen for acute myeloid leukemia can prolong event-free and relapse-free survival in young adult patients, but the effect on overall survival is still unclear, investigators reported.

In a randomized controlled trial, 3-year event-free survival (EFS), the primary endpoint, was 40% among patients treated with chemotherapy and sorafenib (Nexavar), compared with 22% for patients treated with chemotherapy and a placebo (P = .013). The median EFS was 21 months and 9 months, respectively, reported Dr. Christoph Röllig of University Hospital in Dresden, Germany.

Relapse-free survival (RFS) at 3 years was 56% in the sorafenib-treated group, compared with 38% in the placebo group (P = .017). The median RFS was not reached in the sorafenib group, vs. 23 months in the placebo group, Dr. Röllig reported at the annual meeting of the American Society of Hematology.

“These data constitute the first randomized evidence that actually kinase inhibitors work in AML. What we judge is that, according to evidence-based medicine principles, a comparatory trial would be desirable in order to establish sorafenib in AML treatment,” he said at a briefing prior to his presentation of the data in a plenary session.

Dr. Röllig and colleagues in 25 centers enrolled patients from 18 to 60 years with newly diagnosed AML. Of the 276 enrolled, 267 went on to receive study treatment: 134 were assigned to sorafenib and 133 to placebo. The study drug was given along a chemotherapy regimen consisting of two cycles of induction with daunorubicin and cytarabine followed by three cycles of high-dose cytarabine consolidation. Patients who did not have a response after the first cycle of daunorubicin induction underwent a second induction attempt with cytarabine and mitoxantrone.

The assigned study medication was given on days 10-19 of induction cycles one and two, from day 8 of each consolidation cycle until 3 days before the start of the next consolidation cycle, and as maintenance for 12 months after the end of consolidation.

As noted before, EFS in an intention-to-treat analysis censored for stem-cell therapy favored the sorafenib-treated patients, as did RFS. In addition, there was evidence to suggest a benefit trend toward prolonged RFS and overall survival with sorafenib among patients positive for the FLT3-ITD mutation, which has been shown to be sensitive to kinase inhibitors.

Patients in the sorafenib arm had significantly more episodes of fever, bleeding events, and the hand-foot syndrome, but there were no significant differences in other adverse events, Dr. Röllig said.

In an interview, he said that the investigators chose sorafenib because of its good track record and its efficacy against multiple kinases. His center is also involved in clinical trials exploring whether a different kinase inhibitor, quizartinib, has similar or better efficacy against AML.

The study was supported by Bayer. Dr. Röllig reported having no relevant disclosures.

SAN FRANCISCO – Adding a kinase inhibitor to a standard regimen for acute myeloid leukemia can prolong event-free and relapse-free survival in young adult patients, but the effect on overall survival is still unclear, investigators reported.

In a randomized controlled trial, 3-year event-free survival (EFS), the primary endpoint, was 40% among patients treated with chemotherapy and sorafenib (Nexavar), compared with 22% for patients treated with chemotherapy and a placebo (P = .013). The median EFS was 21 months and 9 months, respectively, reported Dr. Christoph Röllig of University Hospital in Dresden, Germany.

Relapse-free survival (RFS) at 3 years was 56% in the sorafenib-treated group, compared with 38% in the placebo group (P = .017). The median RFS was not reached in the sorafenib group, vs. 23 months in the placebo group, Dr. Röllig reported at the annual meeting of the American Society of Hematology.

“These data constitute the first randomized evidence that actually kinase inhibitors work in AML. What we judge is that, according to evidence-based medicine principles, a comparatory trial would be desirable in order to establish sorafenib in AML treatment,” he said at a briefing prior to his presentation of the data in a plenary session.

Dr. Röllig and colleagues in 25 centers enrolled patients from 18 to 60 years with newly diagnosed AML. Of the 276 enrolled, 267 went on to receive study treatment: 134 were assigned to sorafenib and 133 to placebo. The study drug was given along a chemotherapy regimen consisting of two cycles of induction with daunorubicin and cytarabine followed by three cycles of high-dose cytarabine consolidation. Patients who did not have a response after the first cycle of daunorubicin induction underwent a second induction attempt with cytarabine and mitoxantrone.

The assigned study medication was given on days 10-19 of induction cycles one and two, from day 8 of each consolidation cycle until 3 days before the start of the next consolidation cycle, and as maintenance for 12 months after the end of consolidation.

As noted before, EFS in an intention-to-treat analysis censored for stem-cell therapy favored the sorafenib-treated patients, as did RFS. In addition, there was evidence to suggest a benefit trend toward prolonged RFS and overall survival with sorafenib among patients positive for the FLT3-ITD mutation, which has been shown to be sensitive to kinase inhibitors.

Patients in the sorafenib arm had significantly more episodes of fever, bleeding events, and the hand-foot syndrome, but there were no significant differences in other adverse events, Dr. Röllig said.

In an interview, he said that the investigators chose sorafenib because of its good track record and its efficacy against multiple kinases. His center is also involved in clinical trials exploring whether a different kinase inhibitor, quizartinib, has similar or better efficacy against AML.

The study was supported by Bayer. Dr. Röllig reported having no relevant disclosures.

SAN FRANCISCO – Adding a kinase inhibitor to a standard regimen for acute myeloid leukemia can prolong event-free and relapse-free survival in young adult patients, but the effect on overall survival is still unclear, investigators reported.

In a randomized controlled trial, 3-year event-free survival (EFS), the primary endpoint, was 40% among patients treated with chemotherapy and sorafenib (Nexavar), compared with 22% for patients treated with chemotherapy and a placebo (P = .013). The median EFS was 21 months and 9 months, respectively, reported Dr. Christoph Röllig of University Hospital in Dresden, Germany.

Relapse-free survival (RFS) at 3 years was 56% in the sorafenib-treated group, compared with 38% in the placebo group (P = .017). The median RFS was not reached in the sorafenib group, vs. 23 months in the placebo group, Dr. Röllig reported at the annual meeting of the American Society of Hematology.

“These data constitute the first randomized evidence that actually kinase inhibitors work in AML. What we judge is that, according to evidence-based medicine principles, a comparatory trial would be desirable in order to establish sorafenib in AML treatment,” he said at a briefing prior to his presentation of the data in a plenary session.

Dr. Röllig and colleagues in 25 centers enrolled patients from 18 to 60 years with newly diagnosed AML. Of the 276 enrolled, 267 went on to receive study treatment: 134 were assigned to sorafenib and 133 to placebo. The study drug was given along a chemotherapy regimen consisting of two cycles of induction with daunorubicin and cytarabine followed by three cycles of high-dose cytarabine consolidation. Patients who did not have a response after the first cycle of daunorubicin induction underwent a second induction attempt with cytarabine and mitoxantrone.

The assigned study medication was given on days 10-19 of induction cycles one and two, from day 8 of each consolidation cycle until 3 days before the start of the next consolidation cycle, and as maintenance for 12 months after the end of consolidation.

As noted before, EFS in an intention-to-treat analysis censored for stem-cell therapy favored the sorafenib-treated patients, as did RFS. In addition, there was evidence to suggest a benefit trend toward prolonged RFS and overall survival with sorafenib among patients positive for the FLT3-ITD mutation, which has been shown to be sensitive to kinase inhibitors.

Patients in the sorafenib arm had significantly more episodes of fever, bleeding events, and the hand-foot syndrome, but there were no significant differences in other adverse events, Dr. Röllig said.

In an interview, he said that the investigators chose sorafenib because of its good track record and its efficacy against multiple kinases. His center is also involved in clinical trials exploring whether a different kinase inhibitor, quizartinib, has similar or better efficacy against AML.

The study was supported by Bayer. Dr. Röllig reported having no relevant disclosures.

SAN FRANCISCO– Teens and young adults don’t like being treated like children, but they should make an exception when it comes to acute lymphoblastic leukemia therapy, because pediatric ALL regimens are associated with significantly better event-free and overall survival among patients with ALL from the ages of 16 to 40 years.

Those findings come from a clinical trial 14 years in the making, in which 296 adolescents and young adults (AYA) with ALL were treated with an intensive pediatric chemotherapy combination regiment rather than a less-intensive adult regimen. At 2-year follow-up, the rate of overall survival (OS) was 78%, with the median overall survival not yet reached, and the event-free survival (EFS) rate was 66%, reported Dr. Wendy Stock from the University of Chicago Medical Center.

In contrast, EFS rates among AYA treated with adult regimens have historically ranged from 35-40%, Dr. Stock said at a press briefing at the annual meeting of the American Society of Hematology.

“These data really started 14 years ago at this ASH meeting when we presented data showing that young adults ages 16 to 20 who were treated on adult cooperative group studies in the United States fared much worse than the same age group who were treated on pediatric studies,” she said.

In 2008, Dr. Stock and her colleagues published a study (Blood 2008;112:1646-54) showing that AYAs treated under Children’s Cancer Group (CCG) protocols had an overall survival rate at 7 years of 67% and an EFS rate of 63%. In contrast, AYAs treated under Cancer and Leukemia Group B (CALGB) protocols had an OS of 46% and EFS of only 34%. The risk for worse outcomes was approximately twofold among adolescents treated with adult regimens, compared with those treated with pediatric regimens. The findings were similar in studies from France, the United Kingdom, and the Netherlands, Dr. Stock noted.

The investigators determined at that time that, under the CCG regimens, the teen and young adult patients received earlier and more intensive central nervous system prophylaxis and higher doses of nonmyelosuppressive drugs, especially glucocorticoids, vincristine, and pegylated asparignase, while those on the CALGB regimens received higher doses of myelosuppressive agents such as anthracyclines.

Because their original findings came from a retrospective study, the investigators decided to launch a prospective study,US Intergroup trial C10403, designed to evaluate outcomes among patients with ALL from the ages of 16-40 years when they were treated with a pediatric regimen by adult hematologists/oncologists in the cooperative group setting.

A total of 296 eligible patients with a median age of 25 years were enrolled. The patients had newly diagnosed ALL of T-cell or B-cell lineage; patients with Burkitt’s type ALL or ALL positive for the Philadelphia chromosome were excluded. The patients were treated with a regimen identical to the Capizzi methotrexate arm of the Children’s Oncology Group AALL0232 study. The regimen consisted of four intensive courses: remission induction, remission consolidation, interim maintenance and delayed intensification, and prolonged maintenance therapy. Patients who had an M2 marrow response after remission induction (more than 5% but less than 25% lymphoblasts) received an extended remission induction course of therapy.

As noted before, the EFS rate was 66% and the median EFS duration was 59 months. The 2-year overall survival rate was 79%. EFS rates were similar between patients with B-cell lineage (65%) and T-cell lineage (68%) ALL, and there were no significant differences in EFS or OS by sex or by age.

There were five (2%) treatment-related deaths during protocol therapy, including two cases of liver failure, both occurring during induction; two infections (one in the induction phase and one in the consolidation phase); and one ventricular arrhythmia (during induction). Treatment toxicities in general were similar to those seen in the standard therapy of the COG AALL0232 trial, although patients in the current study had an increase in risk for thrombosis and early hyperbilirubinemia.

“Our outcomes are similar to other prospective international studies which apply pediatric regimens to the young adult population of acute lymphoblastic leukemia,” Dr. Stock said.

In analyses of biological factors that affect outcome, the investigators found that white blood cell counts above 30,000/uL were associated with worse EFS and OS, and that the presence of a BCR-ABL1-like signature and overexpression of the gene CRLF2 were common and associated with significantly worse survival.

The investigators plan to use the study as a basis for future studies incorporating target antibodies and kinase inhibitors in an attempt to improve survival further by eradicating minimal residual disease, Dr. Stock said.

SAN FRANCISCO– Teens and young adults don’t like being treated like children, but they should make an exception when it comes to acute lymphoblastic leukemia therapy, because pediatric ALL regimens are associated with significantly better event-free and overall survival among patients with ALL from the ages of 16 to 40 years.

Those findings come from a clinical trial 14 years in the making, in which 296 adolescents and young adults (AYA) with ALL were treated with an intensive pediatric chemotherapy combination regiment rather than a less-intensive adult regimen. At 2-year follow-up, the rate of overall survival (OS) was 78%, with the median overall survival not yet reached, and the event-free survival (EFS) rate was 66%, reported Dr. Wendy Stock from the University of Chicago Medical Center.

In contrast, EFS rates among AYA treated with adult regimens have historically ranged from 35-40%, Dr. Stock said at a press briefing at the annual meeting of the American Society of Hematology.

“These data really started 14 years ago at this ASH meeting when we presented data showing that young adults ages 16 to 20 who were treated on adult cooperative group studies in the United States fared much worse than the same age group who were treated on pediatric studies,” she said.

In 2008, Dr. Stock and her colleagues published a study (Blood 2008;112:1646-54) showing that AYAs treated under Children’s Cancer Group (CCG) protocols had an overall survival rate at 7 years of 67% and an EFS rate of 63%. In contrast, AYAs treated under Cancer and Leukemia Group B (CALGB) protocols had an OS of 46% and EFS of only 34%. The risk for worse outcomes was approximately twofold among adolescents treated with adult regimens, compared with those treated with pediatric regimens. The findings were similar in studies from France, the United Kingdom, and the Netherlands, Dr. Stock noted.

The investigators determined at that time that, under the CCG regimens, the teen and young adult patients received earlier and more intensive central nervous system prophylaxis and higher doses of nonmyelosuppressive drugs, especially glucocorticoids, vincristine, and pegylated asparignase, while those on the CALGB regimens received higher doses of myelosuppressive agents such as anthracyclines.

Because their original findings came from a retrospective study, the investigators decided to launch a prospective study,US Intergroup trial C10403, designed to evaluate outcomes among patients with ALL from the ages of 16-40 years when they were treated with a pediatric regimen by adult hematologists/oncologists in the cooperative group setting.

A total of 296 eligible patients with a median age of 25 years were enrolled. The patients had newly diagnosed ALL of T-cell or B-cell lineage; patients with Burkitt’s type ALL or ALL positive for the Philadelphia chromosome were excluded. The patients were treated with a regimen identical to the Capizzi methotrexate arm of the Children’s Oncology Group AALL0232 study. The regimen consisted of four intensive courses: remission induction, remission consolidation, interim maintenance and delayed intensification, and prolonged maintenance therapy. Patients who had an M2 marrow response after remission induction (more than 5% but less than 25% lymphoblasts) received an extended remission induction course of therapy.

As noted before, the EFS rate was 66% and the median EFS duration was 59 months. The 2-year overall survival rate was 79%. EFS rates were similar between patients with B-cell lineage (65%) and T-cell lineage (68%) ALL, and there were no significant differences in EFS or OS by sex or by age.

There were five (2%) treatment-related deaths during protocol therapy, including two cases of liver failure, both occurring during induction; two infections (one in the induction phase and one in the consolidation phase); and one ventricular arrhythmia (during induction). Treatment toxicities in general were similar to those seen in the standard therapy of the COG AALL0232 trial, although patients in the current study had an increase in risk for thrombosis and early hyperbilirubinemia.

“Our outcomes are similar to other prospective international studies which apply pediatric regimens to the young adult population of acute lymphoblastic leukemia,” Dr. Stock said.

In analyses of biological factors that affect outcome, the investigators found that white blood cell counts above 30,000/uL were associated with worse EFS and OS, and that the presence of a BCR-ABL1-like signature and overexpression of the gene CRLF2 were common and associated with significantly worse survival.

The investigators plan to use the study as a basis for future studies incorporating target antibodies and kinase inhibitors in an attempt to improve survival further by eradicating minimal residual disease, Dr. Stock said.

SAN FRANCISCO– Teens and young adults don’t like being treated like children, but they should make an exception when it comes to acute lymphoblastic leukemia therapy, because pediatric ALL regimens are associated with significantly better event-free and overall survival among patients with ALL from the ages of 16 to 40 years.

Those findings come from a clinical trial 14 years in the making, in which 296 adolescents and young adults (AYA) with ALL were treated with an intensive pediatric chemotherapy combination regiment rather than a less-intensive adult regimen. At 2-year follow-up, the rate of overall survival (OS) was 78%, with the median overall survival not yet reached, and the event-free survival (EFS) rate was 66%, reported Dr. Wendy Stock from the University of Chicago Medical Center.

In contrast, EFS rates among AYA treated with adult regimens have historically ranged from 35-40%, Dr. Stock said at a press briefing at the annual meeting of the American Society of Hematology.

“These data really started 14 years ago at this ASH meeting when we presented data showing that young adults ages 16 to 20 who were treated on adult cooperative group studies in the United States fared much worse than the same age group who were treated on pediatric studies,” she said.

In 2008, Dr. Stock and her colleagues published a study (Blood 2008;112:1646-54) showing that AYAs treated under Children’s Cancer Group (CCG) protocols had an overall survival rate at 7 years of 67% and an EFS rate of 63%. In contrast, AYAs treated under Cancer and Leukemia Group B (CALGB) protocols had an OS of 46% and EFS of only 34%. The risk for worse outcomes was approximately twofold among adolescents treated with adult regimens, compared with those treated with pediatric regimens. The findings were similar in studies from France, the United Kingdom, and the Netherlands, Dr. Stock noted.

The investigators determined at that time that, under the CCG regimens, the teen and young adult patients received earlier and more intensive central nervous system prophylaxis and higher doses of nonmyelosuppressive drugs, especially glucocorticoids, vincristine, and pegylated asparignase, while those on the CALGB regimens received higher doses of myelosuppressive agents such as anthracyclines.

Because their original findings came from a retrospective study, the investigators decided to launch a prospective study,US Intergroup trial C10403, designed to evaluate outcomes among patients with ALL from the ages of 16-40 years when they were treated with a pediatric regimen by adult hematologists/oncologists in the cooperative group setting.

A total of 296 eligible patients with a median age of 25 years were enrolled. The patients had newly diagnosed ALL of T-cell or B-cell lineage; patients with Burkitt’s type ALL or ALL positive for the Philadelphia chromosome were excluded. The patients were treated with a regimen identical to the Capizzi methotrexate arm of the Children’s Oncology Group AALL0232 study. The regimen consisted of four intensive courses: remission induction, remission consolidation, interim maintenance and delayed intensification, and prolonged maintenance therapy. Patients who had an M2 marrow response after remission induction (more than 5% but less than 25% lymphoblasts) received an extended remission induction course of therapy.

As noted before, the EFS rate was 66% and the median EFS duration was 59 months. The 2-year overall survival rate was 79%. EFS rates were similar between patients with B-cell lineage (65%) and T-cell lineage (68%) ALL, and there were no significant differences in EFS or OS by sex or by age.

There were five (2%) treatment-related deaths during protocol therapy, including two cases of liver failure, both occurring during induction; two infections (one in the induction phase and one in the consolidation phase); and one ventricular arrhythmia (during induction). Treatment toxicities in general were similar to those seen in the standard therapy of the COG AALL0232 trial, although patients in the current study had an increase in risk for thrombosis and early hyperbilirubinemia.

“Our outcomes are similar to other prospective international studies which apply pediatric regimens to the young adult population of acute lymphoblastic leukemia,” Dr. Stock said.

In analyses of biological factors that affect outcome, the investigators found that white blood cell counts above 30,000/uL were associated with worse EFS and OS, and that the presence of a BCR-ABL1-like signature and overexpression of the gene CRLF2 were common and associated with significantly worse survival.

The investigators plan to use the study as a basis for future studies incorporating target antibodies and kinase inhibitors in an attempt to improve survival further by eradicating minimal residual disease, Dr. Stock said.

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

CLL cells

Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).

The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.

Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.

CLL cells

Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).

The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.

Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.

CLL cells

Health Canada recently approved the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) for the treatment of chronic lymphocytic leukemia (CLL).

The drug can now be used to treat CLL patients, including those with 17p deletion, who have received at least one prior therapy. It can also be used as frontline treatment in CLL patients with 17p deletion.

Health Canada’s approval of ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib is being developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen will commercialize the drug in Canada, and Janssen affiliates will commercialize it around the world, except in the US, where Pharmacyclics and Janssen Biotech, Inc. co-market it.

Doctor and patient

Credit: NIH

People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.

In a survey of about 1700 people, more than half of respondents said they had experienced at least

one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but

only 2% of them thought cancer was a possible cause.

The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.

Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.

Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.

This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.

Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.

Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.

However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.

“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.

“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”

“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”

Doctor and patient

Credit: NIH

People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.

In a survey of about 1700 people, more than half of respondents said they had experienced at least

one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but

only 2% of them thought cancer was a possible cause.

The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.

Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.

Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.

This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.

Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.

Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.

However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.

“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.

“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”

“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”

Doctor and patient

Credit: NIH

People could be putting their lives at risk by dismissing potential warning signs of cancer as less serious symptoms, according to a study published in PLOS ONE.

In a survey of about 1700 people, more than half of respondents said they had experienced at least

one red-flag cancer “alarm” symptom—such as persistent, unexplained pain or an unexplained lump—during the previous 3 months, but

only 2% of them thought cancer was a possible cause.

The survey had been sent to people aged 50 and older who were registered with 3 London general practices. The questionnaire listed 17 symptoms, including 10 widely publicized potential cancer warning signs, such as an unexplained cough, bleeding, and a persistent change in bowel or bladder habits.

Cancer was not mentioned, but the survey asked which of the symptoms subjects had experienced, what they thought caused them, if they were concerned that symptoms were serious, and whether they had consulted their doctor.

Of the 1724 subjects who responded, 53% had experienced at least one cancer “alarm” symptom in the previous 3 months.

This included unexplained cough or hoarseness; persistent change in bowel habits; persistent, unexplained pain; persistent change in bladder habits; unexplained lump; a change in the appearance of a mole; a sore that does not heal; unexplained bleeding; unexplained weight loss; and persistent difficulty swallowing.

Persistent cough (20%) and persistent change in bowel habits (18%) were the most common symptoms. Difficulty swallowing and unexplained weight loss (both 4%) were least common.

Overall, subjects appraised the cancer warning “alarm” symptoms as more serious than “non-alarm” symptoms, such as sore throat and feeling tired. Fifty-nine percent of respondents said they contacted a doctor about their “alarm” symptoms.

However, subjects rarely attributed potential signs of cancer to the disease, putting them down to other reasons, such as age, infection, arthritis, piles, and cysts.

“Most people with potential warning symptoms don’t have cancer, but some will, and others may have other diseases that would benefit from early attention,” said study author Katriina Whitaker, PhD, of University College London in the UK.

“That’s why it’s important that these symptoms are checked out, especially if they don’t go away. But people could delay seeing a doctor if they don’t acknowledge cancer as a possible cause. It’s worrying that even the more obvious warning symptoms, such as unexplained lumps or changes to the appearance of a mole, were rarely attributed to cancer, although they are often well recognized in surveys that assess the public’s knowledge of the disease.”

“Even when people thought warning symptoms might be serious, cancer didn’t tend to spring to mind. This might be because people were frightened and reluctant to mention cancer, thought cancer wouldn’t happen to them, or believed other causes were more likely.”

Prescription medications

Credit: CDC

Tamoxifen, a drug used to treat breast cancer, may be effective against myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) as well, according to research published in Cell Stem Cell.

The study showed that estrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to MPNs and AML.

Tamoxifen, which targets estrogen receptors, prevented JAK2^V617F-induced MPNs in mice and enhanced the effects of chemotherapy against MLL-AF9-induced AML.

“In this study, we demonstrate that tamoxifen has specific effects on certain cells in the bone marrow: the hematopoietic stem cells and their immediate descendants, known as multipotent progenitors,” explained study author Abel Sánchez-Aguilera, PhD, of Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid.

The researchers found that, unlike in breast cancer, where tamoxifen blocks the action of estrogens, in blood cells, the drug acts by imitating the function of the hormone.

Tamoxifen induced apoptosis in short-term hematopoietic stem cells (HSCs) and multipotent progenitors. But in quiescent, long-term HSCs, the drug prompted proliferation and partial loss of function, which was reversible.

Tamoxifen also prevented polycythemia vera-like MPN from developing in mice with HSCs expressing JAK2^V617F. The drug prevented MPN-associated neutrophilia and thrombocytosis; alleviated the early increase in red cell counts, hemoglobin, and hematocrit; decreased bone marrow megakaryocytes; and reduced MPN-associated splenomegaly.

Tamoxifen worked by restoring normal levels of apoptosis in mutant cells. It also prompted apoptosis of human JAK2^V617F+ hematopoietic stem and progenitor cells (HSPCs) in a xenograft model.

In these models, tamoxifen caused little alteration in the rest of the blood cells, which were maintained at normal levels even after prolonged treatment with the drug.

“Our results suggest that tamoxifen, at a similar dose used for the treatment of other diseases, might be useful to treat myeloproliferative neoplasms at various stages, without being toxic to normal blood cells,” said study author Simón Méndez-Ferrer, PhD, also of CNIC.

In addition, tamoxifen enhanced the effects of conventional chemotherapy on cancerous cells in mice with MLL-AF9-induced AML.

Tamoxifen- and vehicle-treated mice had similar numbers of MLL-AF9+ cells and HSPCs shortly after chemotherapy. But tamoxifen delayed the reappearance of circulating leukemic cells after chemotherapy.

Tamoxifen-treated mice had fewer leukemic cells in the bone marrow, spleen, and blood, although they ultimately died of their disease.

Nevertheless, the researchers concluded that tamoxifen could be a feasible treatment option for patients with MPNs or AML. And the fact that tamoxifen is already approved for clinical use increases the chances of these results leading to a clinical trial.

Prescription medications

Credit: CDC

Tamoxifen, a drug used to treat breast cancer, may be effective against myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) as well, according to research published in Cell Stem Cell.

The study showed that estrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to MPNs and AML.

Tamoxifen, which targets estrogen receptors, prevented JAK2^V617F-induced MPNs in mice and enhanced the effects of chemotherapy against MLL-AF9-induced AML.

“In this study, we demonstrate that tamoxifen has specific effects on certain cells in the bone marrow: the hematopoietic stem cells and their immediate descendants, known as multipotent progenitors,” explained study author Abel Sánchez-Aguilera, PhD, of Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid.

The researchers found that, unlike in breast cancer, where tamoxifen blocks the action of estrogens, in blood cells, the drug acts by imitating the function of the hormone.

Tamoxifen induced apoptosis in short-term hematopoietic stem cells (HSCs) and multipotent progenitors. But in quiescent, long-term HSCs, the drug prompted proliferation and partial loss of function, which was reversible.

Tamoxifen also prevented polycythemia vera-like MPN from developing in mice with HSCs expressing JAK2^V617F. The drug prevented MPN-associated neutrophilia and thrombocytosis; alleviated the early increase in red cell counts, hemoglobin, and hematocrit; decreased bone marrow megakaryocytes; and reduced MPN-associated splenomegaly.

Tamoxifen worked by restoring normal levels of apoptosis in mutant cells. It also prompted apoptosis of human JAK2^V617F+ hematopoietic stem and progenitor cells (HSPCs) in a xenograft model.

In these models, tamoxifen caused little alteration in the rest of the blood cells, which were maintained at normal levels even after prolonged treatment with the drug.

“Our results suggest that tamoxifen, at a similar dose used for the treatment of other diseases, might be useful to treat myeloproliferative neoplasms at various stages, without being toxic to normal blood cells,” said study author Simón Méndez-Ferrer, PhD, also of CNIC.

In addition, tamoxifen enhanced the effects of conventional chemotherapy on cancerous cells in mice with MLL-AF9-induced AML.

Tamoxifen- and vehicle-treated mice had similar numbers of MLL-AF9+ cells and HSPCs shortly after chemotherapy. But tamoxifen delayed the reappearance of circulating leukemic cells after chemotherapy.

Tamoxifen-treated mice had fewer leukemic cells in the bone marrow, spleen, and blood, although they ultimately died of their disease.

Nevertheless, the researchers concluded that tamoxifen could be a feasible treatment option for patients with MPNs or AML. And the fact that tamoxifen is already approved for clinical use increases the chances of these results leading to a clinical trial.

Prescription medications

Credit: CDC

Tamoxifen, a drug used to treat breast cancer, may be effective against myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) as well, according to research published in Cell Stem Cell.

The study showed that estrogens regulate the survival, proliferation, and self-renewal of stem cells that give rise to MPNs and AML.

Tamoxifen, which targets estrogen receptors, prevented JAK2^V617F-induced MPNs in mice and enhanced the effects of chemotherapy against MLL-AF9-induced AML.

“In this study, we demonstrate that tamoxifen has specific effects on certain cells in the bone marrow: the hematopoietic stem cells and their immediate descendants, known as multipotent progenitors,” explained study author Abel Sánchez-Aguilera, PhD, of Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid.

The researchers found that, unlike in breast cancer, where tamoxifen blocks the action of estrogens, in blood cells, the drug acts by imitating the function of the hormone.

Tamoxifen induced apoptosis in short-term hematopoietic stem cells (HSCs) and multipotent progenitors. But in quiescent, long-term HSCs, the drug prompted proliferation and partial loss of function, which was reversible.

Tamoxifen also prevented polycythemia vera-like MPN from developing in mice with HSCs expressing JAK2^V617F. The drug prevented MPN-associated neutrophilia and thrombocytosis; alleviated the early increase in red cell counts, hemoglobin, and hematocrit; decreased bone marrow megakaryocytes; and reduced MPN-associated splenomegaly.

Tamoxifen worked by restoring normal levels of apoptosis in mutant cells. It also prompted apoptosis of human JAK2^V617F+ hematopoietic stem and progenitor cells (HSPCs) in a xenograft model.

In these models, tamoxifen caused little alteration in the rest of the blood cells, which were maintained at normal levels even after prolonged treatment with the drug.

“Our results suggest that tamoxifen, at a similar dose used for the treatment of other diseases, might be useful to treat myeloproliferative neoplasms at various stages, without being toxic to normal blood cells,” said study author Simón Méndez-Ferrer, PhD, also of CNIC.

In addition, tamoxifen enhanced the effects of conventional chemotherapy on cancerous cells in mice with MLL-AF9-induced AML.

Tamoxifen- and vehicle-treated mice had similar numbers of MLL-AF9+ cells and HSPCs shortly after chemotherapy. But tamoxifen delayed the reappearance of circulating leukemic cells after chemotherapy.

Tamoxifen-treated mice had fewer leukemic cells in the bone marrow, spleen, and blood, although they ultimately died of their disease.

Nevertheless, the researchers concluded that tamoxifen could be a feasible treatment option for patients with MPNs or AML. And the fact that tamoxifen is already approved for clinical use increases the chances of these results leading to a clinical trial.

Monoclonal antibodies

Credit: Linda Bartlett

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance that recommends obinutuzumab, marketed by Roche as Gazyvaro, for certain patients with untreated chronic lymphocytic leukemia (CLL).

In an earlier preliminary guidance, NICE said it could not recommend the drug due to uncertainties in the company’s submission.

In response, Roche submitted revised cost-effectiveness analyses and a patient access scheme.

This prompted NICE to recommend obinutuzumab in combination with chlorambucil as an option for adults with untreated CLL who have comorbidities that make them ineligible for full-dose fludarabine-based therapy.

But NICE is only recommending this as an option if bendamustine-based therapy has been deemed unsuitable and if Roche provides obinutuzumab with the discount agreed in the patient access scheme.

“We are pleased that Roche responded to our consultation and provided further analyses to allow us to propose recommending obinutuzumab as a treatment option for untreated chronic lymphocytic leukemia,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Half of the people who need treatment for their condition are not able to use the standard first-line treatment of fludarabine combination therapy. NICE recommends alternative treatment with bendamustine, but there are some patients for whom this is also unsuitable. Obinutuzumab is a clinically effective treatment which is associated with fewer adverse events and provides another option to help prevent people’s disease from progressing.”

NICE recommends obinutuzumab on the basis that Roche provides the treatment to the National Health Service (NHS) at a reduced price. The company has agreed with the Department of Health that the size of the discount is to be confidential.

The list price of obinutuzumab is £3312 per 1000 mg vial (excluding value-added tax). According to Roche, a course of treatment costs £26,496 (£9936 for cycle 1 and £3312 for cycles 2 to 6, excluding tax).

Consultees, including the company, healthcare professionals, and members of the public, have until Tuesday, January 6, 2015, to comment on the preliminary recommendations via the NICE website.

NICE has not yet issued the final guidance to the NHS. Until then, NHS bodies should make decisions locally on the funding of specific treatments.

Monoclonal antibodies

Credit: Linda Bartlett

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance that recommends obinutuzumab, marketed by Roche as Gazyvaro, for certain patients with untreated chronic lymphocytic leukemia (CLL).

In an earlier preliminary guidance, NICE said it could not recommend the drug due to uncertainties in the company’s submission.

In response, Roche submitted revised cost-effectiveness analyses and a patient access scheme.

This prompted NICE to recommend obinutuzumab in combination with chlorambucil as an option for adults with untreated CLL who have comorbidities that make them ineligible for full-dose fludarabine-based therapy.

But NICE is only recommending this as an option if bendamustine-based therapy has been deemed unsuitable and if Roche provides obinutuzumab with the discount agreed in the patient access scheme.

“We are pleased that Roche responded to our consultation and provided further analyses to allow us to propose recommending obinutuzumab as a treatment option for untreated chronic lymphocytic leukemia,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Half of the people who need treatment for their condition are not able to use the standard first-line treatment of fludarabine combination therapy. NICE recommends alternative treatment with bendamustine, but there are some patients for whom this is also unsuitable. Obinutuzumab is a clinically effective treatment which is associated with fewer adverse events and provides another option to help prevent people’s disease from progressing.”

NICE recommends obinutuzumab on the basis that Roche provides the treatment to the National Health Service (NHS) at a reduced price. The company has agreed with the Department of Health that the size of the discount is to be confidential.

The list price of obinutuzumab is £3312 per 1000 mg vial (excluding value-added tax). According to Roche, a course of treatment costs £26,496 (£9936 for cycle 1 and £3312 for cycles 2 to 6, excluding tax).

Consultees, including the company, healthcare professionals, and members of the public, have until Tuesday, January 6, 2015, to comment on the preliminary recommendations via the NICE website.

NICE has not yet issued the final guidance to the NHS. Until then, NHS bodies should make decisions locally on the funding of specific treatments.

Monoclonal antibodies

Credit: Linda Bartlett

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance that recommends obinutuzumab, marketed by Roche as Gazyvaro, for certain patients with untreated chronic lymphocytic leukemia (CLL).

In an earlier preliminary guidance, NICE said it could not recommend the drug due to uncertainties in the company’s submission.

In response, Roche submitted revised cost-effectiveness analyses and a patient access scheme.

This prompted NICE to recommend obinutuzumab in combination with chlorambucil as an option for adults with untreated CLL who have comorbidities that make them ineligible for full-dose fludarabine-based therapy.

But NICE is only recommending this as an option if bendamustine-based therapy has been deemed unsuitable and if Roche provides obinutuzumab with the discount agreed in the patient access scheme.

“We are pleased that Roche responded to our consultation and provided further analyses to allow us to propose recommending obinutuzumab as a treatment option for untreated chronic lymphocytic leukemia,” said Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Half of the people who need treatment for their condition are not able to use the standard first-line treatment of fludarabine combination therapy. NICE recommends alternative treatment with bendamustine, but there are some patients for whom this is also unsuitable. Obinutuzumab is a clinically effective treatment which is associated with fewer adverse events and provides another option to help prevent people’s disease from progressing.”

NICE recommends obinutuzumab on the basis that Roche provides the treatment to the National Health Service (NHS) at a reduced price. The company has agreed with the Department of Health that the size of the discount is to be confidential.

The list price of obinutuzumab is £3312 per 1000 mg vial (excluding value-added tax). According to Roche, a course of treatment costs £26,496 (£9936 for cycle 1 and £3312 for cycles 2 to 6, excluding tax).

Consultees, including the company, healthcare professionals, and members of the public, have until Tuesday, January 6, 2015, to comment on the preliminary recommendations via the NICE website.

NICE has not yet issued the final guidance to the NHS. Until then, NHS bodies should make decisions locally on the funding of specific treatments.