Leukemia, Myelodysplasia, Transplantation

Doctor consults with a family

Credit: Rhoda Baer

A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.

Other variables, such as the child’s age, did not predict the risk as accurately.

And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.

Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.

The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.

Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.

The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.

General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.

The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.

Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.

“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor

children and their families and to minimize negative long-term effects in children,” she said.

Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.

Doctor consults with a family

Credit: Rhoda Baer

A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.

Other variables, such as the child’s age, did not predict the risk as accurately.

And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.

Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.

The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.

Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.

The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.

General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.

The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.

Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.

“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor

children and their families and to minimize negative long-term effects in children,” she said.

Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.

Doctor consults with a family

Credit: Rhoda Baer

A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.

Other variables, such as the child’s age, did not predict the risk as accurately.

And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.

Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.

The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.

Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.

The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.

General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.

The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.

Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.

“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor

children and their families and to minimize negative long-term effects in children,” she said.

Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Attendees at EHA 2014

Photo courtesy of EHA

MILAN—The IDH2 inhibitor AG-221 is well-tolerated and exhibits durable clinical activity in patients with hematologic disorders, results of a phase 1 study suggest.

The drug prompted responses in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML).

Fourteen of 25 patients achieved a response, and 12 of those responses are ongoing.

Most adverse events (AEs) were grade 1 or 2 in nature. However, 4 patients did have serious AEs that were possibly related to treatment.

Stéphane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France, presented these results at the 19th Annual Congress of the European Hematology Association (EHA) as abstract LB2434.

Dr de Botton and his colleagues enrolled 35 patients who had a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at 30 mg BID (n=7), 50 mg BID (n=7), 75 mg BID (n=6), 100 mg QD (n=5), 100 mg BID (n=5), or 150 mg QD (n=5). Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

Safety data

“AG-221 was remarkable well-tolerated, and the [maximum tolerated dose] has not been reached,” Dr de Botton said. “The majority of adverse events were grade 1 and 2.”

Eighteen patients were evaluable for safety. AEs of all grades included nausea (n=4), pyrexia (n=4), thrombocytopenia (n=4), anemia (n=3), dizziness (n=3), febrile neutropenia (n=3), peripheral edema (n=3), sepsis (n=3), cough (n=2), diarrhea (n=2), fatigue (n=2), leukocytosis (n=2), neutropenia (n=2), petechiae (n=2), and rash (n=2).

Grade 3 or higher AEs included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1). Dr de Botton noted that diarrhea and rash were not expected events.

Four patients had serious AEs possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Seven patients died within 30 days of study drug termination: 4 in the 30-mg cohort, 2 in the 50-mg cohort, and 1 in the 100-mg-BID cohort.

Five deaths were due to complications of disease-related sepsis (all in cycle 1), 1 complication of a humeral fracture, and 1 complication of a stroke.

Activity and response data

The researchers observed high AG-221 accumulation after multiple doses. And results were “really very similar” between the 30-mg-BID cohort and the 100-mg-QD cohort, Dr de Botton noted.

He also said AG-221 was “very efficient” at inhibiting 2-HG in the plasma. 2-HG was inhibited up to 100% in subjects with R140Q mutations and up to 60% in subjects with R172K mutations.

Twenty-five patients were evaluable for response. The remaining 10 patients did not have day-28 marrow assessments, either due to early termination (n=7) or receiving less than 28 days of treatment although they were still on the study (n=3).

In all, there were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery (CRps), 1 CR with incomplete hematologic recovery (CRi), and 5 partial responses (PRs). Five patients had stable disease (SD), and 6 had progressive disease (PD).

The most responses occurred in the 50-mg group, which had 3 CRs, 1 CRi, and 1 PR. This was followed by the 30-mg group, which had 2 CRs, 1 CRp, and 1 PR.

“The majority of responses occurred in cycle 1,” Dr de Botton noted, “except in the first cohort [30 mg], where responses occurred late, at the end of cycle 3 and cycle 4.”

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CRp, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with SD remain on study.

This study is sponsored by Celgene Corporation and Agios Pharmaceuticals Inc., the companies developing AG-221.

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.

Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.

The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.

And the researchers said financial toxicity can be considered another side effect of cancer care.

“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.

“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”

Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.

The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.

“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”

All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”

For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”

Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.

All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.

The researchers expected that financial toxicity would correlate with income.

“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”

The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.

“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.

Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.

The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.

And the researchers said financial toxicity can be considered another side effect of cancer care.

“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.

“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”

Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.

The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.

“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”

All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”

For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”

Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.

All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.

The researchers expected that financial toxicity would correlate with income.

“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”

The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.

“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.

Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.

The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.

And the researchers said financial toxicity can be considered another side effect of cancer care.

“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.

“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”

Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.

The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.

“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”

All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”

For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”

Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.

All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.

The researchers expected that financial toxicity would correlate with income.

“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”

The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.

“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”

Micrograph showing

CMV infection

A new study indicates that transferring low doses of immune cells may be sufficient to protect against cytomegalovirus (CMV) infection in patients receiving allogeneic stem cell transplant.

The researchers noted that the adoptive transfer of donor-derived, virus-specific, memory T cells is a promising strategy for treating and preventing CMV infection.

But transferring too many of these cells can increase the risk of graft-vs-host disease.

So Christian Stemberger, PhD, of Technische Universitaet Muenchen in Germany, and his colleagues set out to establish a lower limit for successful adoptive T-cell therapy.

The team reported their results—observed in mice and 2 human patients—in Blood.

The researchers first conducted low-dose CD8+ T-cell transfers in the murine Listeria monocytogenes infection model.

And they found these MHC-Streptamer-enriched, antigen-specific, CD62L^hi, CD8⁺ memory T cells proliferated, differentiated, and protected against Listeria monocytogenes infections.

“The most astonishing result was that the offspring cells of just 1 transferred donor cell were enough to completely protect the animals,” Dr Stemberger said.

Next, the researchers used virus-specific T cells to treat 2 critically ill pediatric patients—1 with severe combined immunodeficiency (SCID) and the other with B-cell acute lymphoblastic leukemia.

The patients had received allogeneic transplants and subsequently developed CMV infections.

The patients received low-dose transfers of Streptamer-enriched, CMV-specific, CD8⁺ T cells—3750 cells per kilogram of body weight for the SCID patient and 5130 cells per kilogram of body weight for the leukemia patient.

In both patients, the researchers observed “strong, pathogen-specific T-cell expansion.” The CMV-specific, CD8⁺ T cells proliferated, and the CMV viral load decreased. Furthermore, neither patient developed graft-vs-host disease.

“It is a great advantage that even just a few cells can provide protection [from CMV],” said study author Michael Neuenhahn, Dr med, also of Technische Universitaet Muenchen.

“This means that the cells can be used for preventive treatment in low doses that are gentler on the organism.”

The researchers are now testing the potential of the CMV-specific, CD8⁺ T cells in a clinical study.

Micrograph showing

CMV infection

A new study indicates that transferring low doses of immune cells may be sufficient to protect against cytomegalovirus (CMV) infection in patients receiving allogeneic stem cell transplant.

The researchers noted that the adoptive transfer of donor-derived, virus-specific, memory T cells is a promising strategy for treating and preventing CMV infection.

But transferring too many of these cells can increase the risk of graft-vs-host disease.

So Christian Stemberger, PhD, of Technische Universitaet Muenchen in Germany, and his colleagues set out to establish a lower limit for successful adoptive T-cell therapy.

The team reported their results—observed in mice and 2 human patients—in Blood.

The researchers first conducted low-dose CD8+ T-cell transfers in the murine Listeria monocytogenes infection model.

And they found these MHC-Streptamer-enriched, antigen-specific, CD62L^hi, CD8⁺ memory T cells proliferated, differentiated, and protected against Listeria monocytogenes infections.

“The most astonishing result was that the offspring cells of just 1 transferred donor cell were enough to completely protect the animals,” Dr Stemberger said.

Next, the researchers used virus-specific T cells to treat 2 critically ill pediatric patients—1 with severe combined immunodeficiency (SCID) and the other with B-cell acute lymphoblastic leukemia.

The patients had received allogeneic transplants and subsequently developed CMV infections.

The patients received low-dose transfers of Streptamer-enriched, CMV-specific, CD8⁺ T cells—3750 cells per kilogram of body weight for the SCID patient and 5130 cells per kilogram of body weight for the leukemia patient.

In both patients, the researchers observed “strong, pathogen-specific T-cell expansion.” The CMV-specific, CD8⁺ T cells proliferated, and the CMV viral load decreased. Furthermore, neither patient developed graft-vs-host disease.

“It is a great advantage that even just a few cells can provide protection [from CMV],” said study author Michael Neuenhahn, Dr med, also of Technische Universitaet Muenchen.

“This means that the cells can be used for preventive treatment in low doses that are gentler on the organism.”

The researchers are now testing the potential of the CMV-specific, CD8⁺ T cells in a clinical study.

Micrograph showing

CMV infection

A new study indicates that transferring low doses of immune cells may be sufficient to protect against cytomegalovirus (CMV) infection in patients receiving allogeneic stem cell transplant.

The researchers noted that the adoptive transfer of donor-derived, virus-specific, memory T cells is a promising strategy for treating and preventing CMV infection.

But transferring too many of these cells can increase the risk of graft-vs-host disease.

So Christian Stemberger, PhD, of Technische Universitaet Muenchen in Germany, and his colleagues set out to establish a lower limit for successful adoptive T-cell therapy.

The team reported their results—observed in mice and 2 human patients—in Blood.

The researchers first conducted low-dose CD8+ T-cell transfers in the murine Listeria monocytogenes infection model.

And they found these MHC-Streptamer-enriched, antigen-specific, CD62L^hi, CD8⁺ memory T cells proliferated, differentiated, and protected against Listeria monocytogenes infections.

“The most astonishing result was that the offspring cells of just 1 transferred donor cell were enough to completely protect the animals,” Dr Stemberger said.

Next, the researchers used virus-specific T cells to treat 2 critically ill pediatric patients—1 with severe combined immunodeficiency (SCID) and the other with B-cell acute lymphoblastic leukemia.

The patients had received allogeneic transplants and subsequently developed CMV infections.

The patients received low-dose transfers of Streptamer-enriched, CMV-specific, CD8⁺ T cells—3750 cells per kilogram of body weight for the SCID patient and 5130 cells per kilogram of body weight for the leukemia patient.

In both patients, the researchers observed “strong, pathogen-specific T-cell expansion.” The CMV-specific, CD8⁺ T cells proliferated, and the CMV viral load decreased. Furthermore, neither patient developed graft-vs-host disease.

“It is a great advantage that even just a few cells can provide protection [from CMV],” said study author Michael Neuenhahn, Dr med, also of Technische Universitaet Muenchen.

“This means that the cells can be used for preventive treatment in low doses that are gentler on the organism.”

The researchers are now testing the potential of the CMV-specific, CD8⁺ T cells in a clinical study.

Lab mouse

Scientists say they’ve identified a tumor-associated lipid that successfully stimulates T cells to kill leukemia cells in vitro and in vivo.

The team noted that certain T cells can recognize the presentation of self-derived lipids on the CD1c protein.

These T cells are commonly found in healthy individuals and are known to kill transformed hematopoietic cells.

However, their antigen specificity and potential antileukemic effects have not been well characterized.

So Gennaro De Libero, MD, PhD, of the University Hospital Basel in Switzerland, and his colleagues analyzed these cells and reported their findings in The Journal of Experimental Medicine.

The researchers discovered that CD1c self-reactive T cells recognize a novel class of self-lipids called methyl-lysophosphatidic acids (mLPAs), which were abundant in several human leukemias.

These mLPAs are the first example of lipid tumor-associated antigens (TAAs). TAAs are produced by tumors and stimulate T cells that can kill leukemia cells.

However, protein TAA accumulation can be drastically reduced by variant leukemia cells. And some TAAs may change their structure, which prevents recognition by T cells and facilitates tumor evasion.

mLPAs, on the other hand, do not change their structure and remain abundant in leukemia cells.

Furthermore, Dr De Libero and his colleagues found they could isolate the T cells that recognize and kill mLPA-expressing leukemia cells in in vitro tests.

And when the team transplanted the T cells into mice, the cells displayed therapeutic efficacy against leukemia cells.

The researchers noted that this type of immunotherapy, if proven effective in humans, could be used to help prevent leukemia relapse after chemotherapy or stem cell transplant.

Lab mouse

Scientists say they’ve identified a tumor-associated lipid that successfully stimulates T cells to kill leukemia cells in vitro and in vivo.

The team noted that certain T cells can recognize the presentation of self-derived lipids on the CD1c protein.

These T cells are commonly found in healthy individuals and are known to kill transformed hematopoietic cells.

However, their antigen specificity and potential antileukemic effects have not been well characterized.

So Gennaro De Libero, MD, PhD, of the University Hospital Basel in Switzerland, and his colleagues analyzed these cells and reported their findings in The Journal of Experimental Medicine.

The researchers discovered that CD1c self-reactive T cells recognize a novel class of self-lipids called methyl-lysophosphatidic acids (mLPAs), which were abundant in several human leukemias.

These mLPAs are the first example of lipid tumor-associated antigens (TAAs). TAAs are produced by tumors and stimulate T cells that can kill leukemia cells.

However, protein TAA accumulation can be drastically reduced by variant leukemia cells. And some TAAs may change their structure, which prevents recognition by T cells and facilitates tumor evasion.

mLPAs, on the other hand, do not change their structure and remain abundant in leukemia cells.

Furthermore, Dr De Libero and his colleagues found they could isolate the T cells that recognize and kill mLPA-expressing leukemia cells in in vitro tests.

And when the team transplanted the T cells into mice, the cells displayed therapeutic efficacy against leukemia cells.

The researchers noted that this type of immunotherapy, if proven effective in humans, could be used to help prevent leukemia relapse after chemotherapy or stem cell transplant.

Lab mouse

Scientists say they’ve identified a tumor-associated lipid that successfully stimulates T cells to kill leukemia cells in vitro and in vivo.

The team noted that certain T cells can recognize the presentation of self-derived lipids on the CD1c protein.

These T cells are commonly found in healthy individuals and are known to kill transformed hematopoietic cells.

However, their antigen specificity and potential antileukemic effects have not been well characterized.

So Gennaro De Libero, MD, PhD, of the University Hospital Basel in Switzerland, and his colleagues analyzed these cells and reported their findings in The Journal of Experimental Medicine.

The researchers discovered that CD1c self-reactive T cells recognize a novel class of self-lipids called methyl-lysophosphatidic acids (mLPAs), which were abundant in several human leukemias.

These mLPAs are the first example of lipid tumor-associated antigens (TAAs). TAAs are produced by tumors and stimulate T cells that can kill leukemia cells.

However, protein TAA accumulation can be drastically reduced by variant leukemia cells. And some TAAs may change their structure, which prevents recognition by T cells and facilitates tumor evasion.

mLPAs, on the other hand, do not change their structure and remain abundant in leukemia cells.

Furthermore, Dr De Libero and his colleagues found they could isolate the T cells that recognize and kill mLPA-expressing leukemia cells in in vitro tests.

And when the team transplanted the T cells into mice, the cells displayed therapeutic efficacy against leukemia cells.

The researchers noted that this type of immunotherapy, if proven effective in humans, could be used to help prevent leukemia relapse after chemotherapy or stem cell transplant.

Investigators Grace Liu

and Ross Dickins, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

Results of preclinical research suggest B-progenitor acute lymphoblastic leukemia (B-ALL) can be “reversed” by coaxing leukemic cells back into normal development.

Researchers found that switching off the gene Pax5 could induce B-ALL in mice, but restoring Pax5 function could prompt disease remission.

Grace Liu, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and her colleagues detailed this research in Genes & Development.

“Pax5 is essential for normal development of [B cells],” Liu said. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous.”

The researchers used transgenic RNAi to suppress endogenous Pax5 expression in the hematopoietic compartment of mice, and this induced B-ALL.

“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” Liu said. “However, we showed, for the first time, that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukemia.”

The team found that restoring endogenous Pax5 expression triggered immunophenotypic maturation and durable disease remission.

Even brief Pax5 restoration disabled B-ALL cells’ leukemia-initiating capacity in mice. And the researchers observed similar results in human B-ALL cell lines.

“This work shows how inactivating the tumor suppressor gene Pax5 contributes to B-ALL development and how leukemia cells become addicted to low Pax5 levels to continue proliferating,” said study author Ross Dickins, PhD, also of the Walter and Eliza Hall Institute of Medical Research.

“Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumor cells to resume normal development and lose their cancerous properties.”

Dr Dickins added that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia. However, genes lost in tumor cells are not traditionally considered suitable drug targets.

“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr Dickins said. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”

Investigators Grace Liu

and Ross Dickins, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

Results of preclinical research suggest B-progenitor acute lymphoblastic leukemia (B-ALL) can be “reversed” by coaxing leukemic cells back into normal development.

Researchers found that switching off the gene Pax5 could induce B-ALL in mice, but restoring Pax5 function could prompt disease remission.

Grace Liu, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and her colleagues detailed this research in Genes & Development.

“Pax5 is essential for normal development of [B cells],” Liu said. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous.”

The researchers used transgenic RNAi to suppress endogenous Pax5 expression in the hematopoietic compartment of mice, and this induced B-ALL.

“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” Liu said. “However, we showed, for the first time, that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukemia.”

The team found that restoring endogenous Pax5 expression triggered immunophenotypic maturation and durable disease remission.

Even brief Pax5 restoration disabled B-ALL cells’ leukemia-initiating capacity in mice. And the researchers observed similar results in human B-ALL cell lines.

“This work shows how inactivating the tumor suppressor gene Pax5 contributes to B-ALL development and how leukemia cells become addicted to low Pax5 levels to continue proliferating,” said study author Ross Dickins, PhD, also of the Walter and Eliza Hall Institute of Medical Research.

“Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumor cells to resume normal development and lose their cancerous properties.”

Dr Dickins added that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia. However, genes lost in tumor cells are not traditionally considered suitable drug targets.

“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr Dickins said. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”

Investigators Grace Liu

and Ross Dickins, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

Results of preclinical research suggest B-progenitor acute lymphoblastic leukemia (B-ALL) can be “reversed” by coaxing leukemic cells back into normal development.

Researchers found that switching off the gene Pax5 could induce B-ALL in mice, but restoring Pax5 function could prompt disease remission.

Grace Liu, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and her colleagues detailed this research in Genes & Development.

“Pax5 is essential for normal development of [B cells],” Liu said. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous.”

The researchers used transgenic RNAi to suppress endogenous Pax5 expression in the hematopoietic compartment of mice, and this induced B-ALL.

“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” Liu said. “However, we showed, for the first time, that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukemia.”

The team found that restoring endogenous Pax5 expression triggered immunophenotypic maturation and durable disease remission.

Even brief Pax5 restoration disabled B-ALL cells’ leukemia-initiating capacity in mice. And the researchers observed similar results in human B-ALL cell lines.

“This work shows how inactivating the tumor suppressor gene Pax5 contributes to B-ALL development and how leukemia cells become addicted to low Pax5 levels to continue proliferating,” said study author Ross Dickins, PhD, also of the Walter and Eliza Hall Institute of Medical Research.

“Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumor cells to resume normal development and lose their cancerous properties.”

Dr Dickins added that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia. However, genes lost in tumor cells are not traditionally considered suitable drug targets.

“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr Dickins said. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”

Lab mice

Credit: Aaron Logan

Researchers say they’ve uncovered a genetic defect in acute lymphoblastic leukemia (ALL) cells that promotes their invasion of the brain.

The team believes the findings, recently published in Genes & Development, could lead to the development of therapies that specifically prevent ALL spread to the central nervous system (CNS).

Currently, curing children with ALL often requires injections of chemotherapy directly into the CNS to limit leukemia growth.

But these therapies can cause long-term health issues.

“If we can find therapies to prevent leukemia spread to the brain, instead of injecting chemotherapy into the brain, that would be huge,” said study author Cynthia Guidos, PhD, of The Hospital for Sick Children (SickKids) in Toronto, Canada.

“Our findings suggest that drugs targeting the functions controlled by a gene called Flt3 could help block leukemic cell growth in the CNS and may be less toxic than current treatments.”

Using a mouse model, the researchers found that CNS-invading leukemias expressed higher levels of Flt3 than leukemias that did not spread to the CNS.

And the CNS-invading leukemias expressed a defective version of Flt3 that cannot be turned off, suggesting that Flt3 allows the leukemic cells to invade the CNS.

The researchers transferred the defective Flt3 gene into mouse leukemia cells that don’t usually invade the brain. And this endowed them with the ability to spread to the CNS.

The team also showed that a Flt3 inhibitor halted growth of the CNS leukemia cells in vitro.

Dr Guidos said the next step for this research will be to investigate whether Flt3 also plays an important role in promoting CNS invasion of human ALL.

She and her colleagues plan to use frozen cells from the SickKids leukemia cell bank, which contains frozen samples from more than 100 patients, to do just that.

Lab mice

Credit: Aaron Logan

Researchers say they’ve uncovered a genetic defect in acute lymphoblastic leukemia (ALL) cells that promotes their invasion of the brain.

The team believes the findings, recently published in Genes & Development, could lead to the development of therapies that specifically prevent ALL spread to the central nervous system (CNS).

Currently, curing children with ALL often requires injections of chemotherapy directly into the CNS to limit leukemia growth.

But these therapies can cause long-term health issues.

“If we can find therapies to prevent leukemia spread to the brain, instead of injecting chemotherapy into the brain, that would be huge,” said study author Cynthia Guidos, PhD, of The Hospital for Sick Children (SickKids) in Toronto, Canada.

“Our findings suggest that drugs targeting the functions controlled by a gene called Flt3 could help block leukemic cell growth in the CNS and may be less toxic than current treatments.”

Using a mouse model, the researchers found that CNS-invading leukemias expressed higher levels of Flt3 than leukemias that did not spread to the CNS.

And the CNS-invading leukemias expressed a defective version of Flt3 that cannot be turned off, suggesting that Flt3 allows the leukemic cells to invade the CNS.

The researchers transferred the defective Flt3 gene into mouse leukemia cells that don’t usually invade the brain. And this endowed them with the ability to spread to the CNS.

The team also showed that a Flt3 inhibitor halted growth of the CNS leukemia cells in vitro.

Dr Guidos said the next step for this research will be to investigate whether Flt3 also plays an important role in promoting CNS invasion of human ALL.

She and her colleagues plan to use frozen cells from the SickKids leukemia cell bank, which contains frozen samples from more than 100 patients, to do just that.

Lab mice

Credit: Aaron Logan

Researchers say they’ve uncovered a genetic defect in acute lymphoblastic leukemia (ALL) cells that promotes their invasion of the brain.

The team believes the findings, recently published in Genes & Development, could lead to the development of therapies that specifically prevent ALL spread to the central nervous system (CNS).

Currently, curing children with ALL often requires injections of chemotherapy directly into the CNS to limit leukemia growth.

But these therapies can cause long-term health issues.

“If we can find therapies to prevent leukemia spread to the brain, instead of injecting chemotherapy into the brain, that would be huge,” said study author Cynthia Guidos, PhD, of The Hospital for Sick Children (SickKids) in Toronto, Canada.

“Our findings suggest that drugs targeting the functions controlled by a gene called Flt3 could help block leukemic cell growth in the CNS and may be less toxic than current treatments.”

Using a mouse model, the researchers found that CNS-invading leukemias expressed higher levels of Flt3 than leukemias that did not spread to the CNS.

And the CNS-invading leukemias expressed a defective version of Flt3 that cannot be turned off, suggesting that Flt3 allows the leukemic cells to invade the CNS.

The researchers transferred the defective Flt3 gene into mouse leukemia cells that don’t usually invade the brain. And this endowed them with the ability to spread to the CNS.

The team also showed that a Flt3 inhibitor halted growth of the CNS leukemia cells in vitro.

Dr Guidos said the next step for this research will be to investigate whether Flt3 also plays an important role in promoting CNS invasion of human ALL.

She and her colleagues plan to use frozen cells from the SickKids leukemia cell bank, which contains frozen samples from more than 100 patients, to do just that.

Audience at ASCO 2014

©ASCO/Phil McCarten

CHICAGO—Patients with chronic myeloid leukemia (CML) are more likely to achieve a deep molecular response if they switch to nilotinib rather than remain on imatinib, updated research suggests.

Patients with detectable disease who crossed over from imatinib to nilotinib after 24 months on the ENESTcmr study were able to achieve deep molecular responses (MR 4.5) by 36 months.

But none of the patients who remained on imatinib achieved undetectable BCR-ABL transcripts.

“Longer follow-up supports switching from imatinib to nilotinib to attain deep molecular responses,” said study investigator Nelson Spector, MD, of Federal University of Rio de Janeiro in Brazil.

“Achievement of deeper molecular responses with nilotinib therapy may increase patient eligibility for treatment-free remission trials.”

Dr Spector presented these results—an update of the ongoing, phase 3 ENESTcmr study—at the 2014 ASCO Annual Meeting (abstract 7025).

The study included 207 patients with Philadelphia-chromosome-positive CML in chronic phase who were treated with imatinib for at least 2 years and achieved complete cytogenetic response but had detectable BCR-ABL transcripts.

With 36 months’ follow-up, rates of MR 4.5 remained higher with nilotinib vs imatinib (47% vs 33%). The median time to achievement of MR 4.5 was 24 months with nilotinib and was not reached with imatinib after the 36-month follow-up.

“Patients experienced a rapid reduction in median BCR-ABL levels within the first 3 months after crossover from imatinib to nilotinib,” Dr Spector said. “No patient with detectable BCR-ABL at 24 months who remained on imatinib achieved this response with another year of follow-up.”

MR 4.5 rates were higher by 12 months in patients randomized to nilotinib (33%) than patients who crossed over from imatinib to nilotinib (21%).

“Three years follow-up shows the ability to achieve undetectable BCR-ABL status with nilotinib as we strive to achieve deep molecular responses with the potential to stop therapy,” said ASCO discussant Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York.

However, he questioned whether MR 4.5, “the last, deepest milestone of relevance, is enough to assess stopping.”

By 3 years of follow-up, 93 patients (92.1%) on nilotinib and 72 patients (69.9%) on imatinib had drug-related adverse events.

The most common events with nilotinib were headache, rash, and pruritus. With imatinib, the most common events were muscle spasms, nausea, and diarrhea. More cardiovascular events were reported in patients randomized to nilotinib compared with imatinib.

“Nilotinib-treated patients experienced adverse events early after switching from long-term imatinib therapy,” Dr Spector said. “These adverse events were expected and consistent with the safety profile of nilotinib observed in other studies.”

Audience at ASCO 2014

©ASCO/Phil McCarten

CHICAGO—Patients with chronic myeloid leukemia (CML) are more likely to achieve a deep molecular response if they switch to nilotinib rather than remain on imatinib, updated research suggests.

Patients with detectable disease who crossed over from imatinib to nilotinib after 24 months on the ENESTcmr study were able to achieve deep molecular responses (MR 4.5) by 36 months.

But none of the patients who remained on imatinib achieved undetectable BCR-ABL transcripts.

“Longer follow-up supports switching from imatinib to nilotinib to attain deep molecular responses,” said study investigator Nelson Spector, MD, of Federal University of Rio de Janeiro in Brazil.

“Achievement of deeper molecular responses with nilotinib therapy may increase patient eligibility for treatment-free remission trials.”

Dr Spector presented these results—an update of the ongoing, phase 3 ENESTcmr study—at the 2014 ASCO Annual Meeting (abstract 7025).

The study included 207 patients with Philadelphia-chromosome-positive CML in chronic phase who were treated with imatinib for at least 2 years and achieved complete cytogenetic response but had detectable BCR-ABL transcripts.

With 36 months’ follow-up, rates of MR 4.5 remained higher with nilotinib vs imatinib (47% vs 33%). The median time to achievement of MR 4.5 was 24 months with nilotinib and was not reached with imatinib after the 36-month follow-up.

“Patients experienced a rapid reduction in median BCR-ABL levels within the first 3 months after crossover from imatinib to nilotinib,” Dr Spector said. “No patient with detectable BCR-ABL at 24 months who remained on imatinib achieved this response with another year of follow-up.”

MR 4.5 rates were higher by 12 months in patients randomized to nilotinib (33%) than patients who crossed over from imatinib to nilotinib (21%).

“Three years follow-up shows the ability to achieve undetectable BCR-ABL status with nilotinib as we strive to achieve deep molecular responses with the potential to stop therapy,” said ASCO discussant Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York.

However, he questioned whether MR 4.5, “the last, deepest milestone of relevance, is enough to assess stopping.”

By 3 years of follow-up, 93 patients (92.1%) on nilotinib and 72 patients (69.9%) on imatinib had drug-related adverse events.

The most common events with nilotinib were headache, rash, and pruritus. With imatinib, the most common events were muscle spasms, nausea, and diarrhea. More cardiovascular events were reported in patients randomized to nilotinib compared with imatinib.

“Nilotinib-treated patients experienced adverse events early after switching from long-term imatinib therapy,” Dr Spector said. “These adverse events were expected and consistent with the safety profile of nilotinib observed in other studies.”

Audience at ASCO 2014

©ASCO/Phil McCarten

CHICAGO—Patients with chronic myeloid leukemia (CML) are more likely to achieve a deep molecular response if they switch to nilotinib rather than remain on imatinib, updated research suggests.

Patients with detectable disease who crossed over from imatinib to nilotinib after 24 months on the ENESTcmr study were able to achieve deep molecular responses (MR 4.5) by 36 months.

But none of the patients who remained on imatinib achieved undetectable BCR-ABL transcripts.

“Longer follow-up supports switching from imatinib to nilotinib to attain deep molecular responses,” said study investigator Nelson Spector, MD, of Federal University of Rio de Janeiro in Brazil.

“Achievement of deeper molecular responses with nilotinib therapy may increase patient eligibility for treatment-free remission trials.”

Dr Spector presented these results—an update of the ongoing, phase 3 ENESTcmr study—at the 2014 ASCO Annual Meeting (abstract 7025).

The study included 207 patients with Philadelphia-chromosome-positive CML in chronic phase who were treated with imatinib for at least 2 years and achieved complete cytogenetic response but had detectable BCR-ABL transcripts.

With 36 months’ follow-up, rates of MR 4.5 remained higher with nilotinib vs imatinib (47% vs 33%). The median time to achievement of MR 4.5 was 24 months with nilotinib and was not reached with imatinib after the 36-month follow-up.

“Patients experienced a rapid reduction in median BCR-ABL levels within the first 3 months after crossover from imatinib to nilotinib,” Dr Spector said. “No patient with detectable BCR-ABL at 24 months who remained on imatinib achieved this response with another year of follow-up.”

MR 4.5 rates were higher by 12 months in patients randomized to nilotinib (33%) than patients who crossed over from imatinib to nilotinib (21%).

“Three years follow-up shows the ability to achieve undetectable BCR-ABL status with nilotinib as we strive to achieve deep molecular responses with the potential to stop therapy,” said ASCO discussant Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York.

However, he questioned whether MR 4.5, “the last, deepest milestone of relevance, is enough to assess stopping.”

By 3 years of follow-up, 93 patients (92.1%) on nilotinib and 72 patients (69.9%) on imatinib had drug-related adverse events.

The most common events with nilotinib were headache, rash, and pruritus. With imatinib, the most common events were muscle spasms, nausea, and diarrhea. More cardiovascular events were reported in patients randomized to nilotinib compared with imatinib.

“Nilotinib-treated patients experienced adverse events early after switching from long-term imatinib therapy,” Dr Spector said. “These adverse events were expected and consistent with the safety profile of nilotinib observed in other studies.”

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.

Researchers in the lab

Credit: Rhoda Baer

Researchers tested 5 anti-leukemia agents in combination with the methylation inhibitor decitabine and found that the sequential combination of decitabine and idarubicin worked synergistically to produce anti-leukemia effects.

The combination induced cell death in U937, HEL, and SKM-1 human cell lines and acute myeloid leukemia (AML) cells isolated from patients.

The researchers attributed the effects to demethylation of the Wnt/β-catenin pathway inhibitors and downregulation of the Wnt/β-catenin pathway nuclear targets.

The researchers noted that decitabine monotherapy has resulted in relatively low complete remission rates in AML and myelodysplastic syndromes (MDS). So they undertook to investigate combination therapies that would potentially improve efficacy.

Hongyan Tong, PhD, of Zhejiang University School of Medicine in Hangzhou, China, and colleagues reported their findings in the Journal of Translational Medicine.

The researchers chose 5 agents to combine, either simultaneously or sequentially, with decitabine—idarubicin, daunorubicin, aclarubicin, thalidomide, and homoharringtonine—and analyzed their effect on leukemia proliferation in the various AML cell lines mentioned above.

Using the U937 cell line first, the researchers found that when decitabine was combined simulataneously or sequentially with homharringtonine, aclarubicin, thalidomide, and daunorubicin, there was no synergistic effect. The confidence interval (CI) values of various doses were almost all over 0.8.

This was also true for the simultaneous combination of decitabine with idarubicin.

However, when they combined decitabine sequentially with idarubicin, the CI values on all 5 doses were under 0.8, indicating synergism.

In addition, when they administered decitabine twice in the sequence, the CI values were lower than a single administration.

They then confirmed the results in other AML cell lines (HEL and SKM-1) and in cells from AML patients.

Next, they confirmed the synergism of the sequential combination of decitabine and idarubicin in an AML mouse model and found that the combination inhibited tumor growth.

Tumor growth was inhibited significantly on days 4 (P<0.01), days 6 -16 (P<0.001), and started to wane by day 18 (P<0.05) after treatment.

The investigators determined that apoptosis was responsible for the combination’s decrease in leukemic cell viability. The apoptosis rates with the combination therapy were significantly increased in the U937, HEL, and SKM-1 cell lines compared with controls, (all P< 0.001).

In addition, the researchers observed that the tumor cells after treatment showed typical apoptosis characteristics, such as the absence of microvilli on cell membrane, nuclear and cell membrane blebbing, chromosome condensation, and the formation of apoptotic bodies.

The investigators used microarray expression to ascertain the differential gene expression profile of decitabine and idarubicin and found that the Wnt pathway was one of the major pathways disturbed.

Sequential treatment significantly upregulated the Wnt antagonist genes SFRP1, HDPR1, and DKK3. This in turn resulted in increased expression of these genes at the mRNA and protein levels.

In addition, treatment with idarubicin after decitabine caused significant down regulation of the expression of c-Myc, β-catenin, and cyclinD1 genes compared to treatment with decitabine or idarubicin alone.

The investigators concluded that the findings suggest clinical potential in sequential administration of decitabine and idarubicin in AML and high-risk MDS.