Myelodysplastic Syndrome

SAN DIEGO – Late-breaking results from the phase III PERSIST-2 trial may ease at least some safety concerns surrounding the use of pacritinib in patients with myelofibrosis, investigators said at the annual meeting of the American Society of Hematology.

In February 2016, the Food and Drug Administration imposed a clinical hold on studies of pacritinib in the wake of concerns about excess deaths, cardiotoxicities, and hemorrhage. But in the final data analysis presented at ASH, rates of these outcomes were low and similar among patients randomized to pacritinib once daily, pacritinib twice daily, or best available treatment for myelofibrosis, including ruxolitinib, lead investigator John Mascarenhas, MD, said.

Indeed, more patients died of progressive disease after stopping pacritinib than died of treatment-associated adverse events, said Dr. Mascarenhas of Icahn School of Medicine at Mount Sinai, New York.

Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. In the previous phase III PERSIST-1 trial, patients who received pacritinib had a fourfold greater probability of experiencing at least a 35% decrease in splenic volume than did patients who received best available treatment (P = .003).

PERSIST-2 also yielded clear efficacy signals, particularly when patients took pacritinib twice daily, said Dr. Mascarenhas. Between baseline and week 24, splenic volume dropped by at least 35% in 22% of these patients (95% confidence interval, 13%-33%), compared with 3% of patients on best available treatment (95% CI, 0.3%-10%; P = .001). Patients who took pacritinib twice daily also had a 32% (95% CI, 22%-44%) chance of experiencing at least a 50% drop in symptoms such as fatigue, bone pain, itching, and abdominal pain, compared with 14% (95% CI, 7%-24%) of patients on best available treatment (P = .01).

Demographic and disease risk characteristics did not significantly affect the chances of reaching these coprimary endpoints, Dr. Mascarenhas noted. “My humble opinion as a clinical investigator is that [pacritinib] is an effective drug, with a favorable benefit-to-risk ratio,” he said.

Several hematologists who were not involved in this trial agreed. “I don’t see why you are nervous [about presenting these results],” noted hematologist Kanti Rai, MD, of the Feinstein Institute for Medical Research in Manhasset, N.Y., told Dr. Mascarenhas during the discussion after the data were presented, prompting laughter from the audience.

It remains to be seen whether the FDA will find the data convincing enough to lift the clinical hold on pacritinib. Ruxolitinib (Jakafi) is approved to treat splenomegaly and symptom burden in myelofibrosis but is associated with dose-limiting cytopenias and cannot be used in patients with platelet counts of less than 50,000/mcL.

PERSIST-2 compared pacritinib 400 mg once daily with pacritinib 200 mg twice daily and best available treatment, including ruxolitinib, in patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL. About half of the study patients had less than 50,000 platelets/mcL, and more than 40% had previously received ruxolitinib.

When the clinical hold on pacritinib went into effect, 221 patients had reached the 24-week designated study endpoint and were included in the intention-to-treat analysis, Dr. Mascarenhas reported. Censored Kaplan-Meier curves of overall survival favored pacritinib over best available treatment, although the difference in survival rates did not reach statistical significance (hazard ratio, 0.68; 95% CI, 0.3-1.5). A total of 9% of patients in the twice-daily pacritinib group died, compared with 14% of patients receiving pacritinib once daily or best available treatment.

Twice-daily pacritinib most often led to diarrhea (48% of patients), nausea (32%), thrombocytopenia (34%), and anemia (24%). Overall rates of serious treatment-emergent adverse events were seen in 47% of the two pacritinib groups and in 31% of patients receiving best available treatment. The most common serious treatment-emergent adverse event with twice daily pacritinib was anemia (8% of patients), followed by thrombocytopenia and pneumonia (6%). Heart failure, atrial fibrillation, and cardiac arrest were rare and similar across all three treatment groups, as were epistaxis and subdural hematoma.

This is the first randomized, controlled trial of patients with myelofibrosis and thrombocytopenia, according to Dr. Mascarenhas. “This was a patient population with low platelets and at risk of poor outcomes, and they did pretty well,” he said. “There really is no therapeutic option for patients with myelofibrosis and low platelets, and [pacritinib] offers patients in this vulnerable situation an opportunity for symptom relief. I hope to see it move forward.”

CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.

SAN DIEGO – Late-breaking results from the phase III PERSIST-2 trial may ease at least some safety concerns surrounding the use of pacritinib in patients with myelofibrosis, investigators said at the annual meeting of the American Society of Hematology.

In February 2016, the Food and Drug Administration imposed a clinical hold on studies of pacritinib in the wake of concerns about excess deaths, cardiotoxicities, and hemorrhage. But in the final data analysis presented at ASH, rates of these outcomes were low and similar among patients randomized to pacritinib once daily, pacritinib twice daily, or best available treatment for myelofibrosis, including ruxolitinib, lead investigator John Mascarenhas, MD, said.

Indeed, more patients died of progressive disease after stopping pacritinib than died of treatment-associated adverse events, said Dr. Mascarenhas of Icahn School of Medicine at Mount Sinai, New York.

Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. In the previous phase III PERSIST-1 trial, patients who received pacritinib had a fourfold greater probability of experiencing at least a 35% decrease in splenic volume than did patients who received best available treatment (P = .003).

PERSIST-2 also yielded clear efficacy signals, particularly when patients took pacritinib twice daily, said Dr. Mascarenhas. Between baseline and week 24, splenic volume dropped by at least 35% in 22% of these patients (95% confidence interval, 13%-33%), compared with 3% of patients on best available treatment (95% CI, 0.3%-10%; P = .001). Patients who took pacritinib twice daily also had a 32% (95% CI, 22%-44%) chance of experiencing at least a 50% drop in symptoms such as fatigue, bone pain, itching, and abdominal pain, compared with 14% (95% CI, 7%-24%) of patients on best available treatment (P = .01).

Demographic and disease risk characteristics did not significantly affect the chances of reaching these coprimary endpoints, Dr. Mascarenhas noted. “My humble opinion as a clinical investigator is that [pacritinib] is an effective drug, with a favorable benefit-to-risk ratio,” he said.

Several hematologists who were not involved in this trial agreed. “I don’t see why you are nervous [about presenting these results],” noted hematologist Kanti Rai, MD, of the Feinstein Institute for Medical Research in Manhasset, N.Y., told Dr. Mascarenhas during the discussion after the data were presented, prompting laughter from the audience.

It remains to be seen whether the FDA will find the data convincing enough to lift the clinical hold on pacritinib. Ruxolitinib (Jakafi) is approved to treat splenomegaly and symptom burden in myelofibrosis but is associated with dose-limiting cytopenias and cannot be used in patients with platelet counts of less than 50,000/mcL.

PERSIST-2 compared pacritinib 400 mg once daily with pacritinib 200 mg twice daily and best available treatment, including ruxolitinib, in patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL. About half of the study patients had less than 50,000 platelets/mcL, and more than 40% had previously received ruxolitinib.

When the clinical hold on pacritinib went into effect, 221 patients had reached the 24-week designated study endpoint and were included in the intention-to-treat analysis, Dr. Mascarenhas reported. Censored Kaplan-Meier curves of overall survival favored pacritinib over best available treatment, although the difference in survival rates did not reach statistical significance (hazard ratio, 0.68; 95% CI, 0.3-1.5). A total of 9% of patients in the twice-daily pacritinib group died, compared with 14% of patients receiving pacritinib once daily or best available treatment.

Twice-daily pacritinib most often led to diarrhea (48% of patients), nausea (32%), thrombocytopenia (34%), and anemia (24%). Overall rates of serious treatment-emergent adverse events were seen in 47% of the two pacritinib groups and in 31% of patients receiving best available treatment. The most common serious treatment-emergent adverse event with twice daily pacritinib was anemia (8% of patients), followed by thrombocytopenia and pneumonia (6%). Heart failure, atrial fibrillation, and cardiac arrest were rare and similar across all three treatment groups, as were epistaxis and subdural hematoma.

This is the first randomized, controlled trial of patients with myelofibrosis and thrombocytopenia, according to Dr. Mascarenhas. “This was a patient population with low platelets and at risk of poor outcomes, and they did pretty well,” he said. “There really is no therapeutic option for patients with myelofibrosis and low platelets, and [pacritinib] offers patients in this vulnerable situation an opportunity for symptom relief. I hope to see it move forward.”

CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.

SAN DIEGO – Late-breaking results from the phase III PERSIST-2 trial may ease at least some safety concerns surrounding the use of pacritinib in patients with myelofibrosis, investigators said at the annual meeting of the American Society of Hematology.

In February 2016, the Food and Drug Administration imposed a clinical hold on studies of pacritinib in the wake of concerns about excess deaths, cardiotoxicities, and hemorrhage. But in the final data analysis presented at ASH, rates of these outcomes were low and similar among patients randomized to pacritinib once daily, pacritinib twice daily, or best available treatment for myelofibrosis, including ruxolitinib, lead investigator John Mascarenhas, MD, said.

Indeed, more patients died of progressive disease after stopping pacritinib than died of treatment-associated adverse events, said Dr. Mascarenhas of Icahn School of Medicine at Mount Sinai, New York.

Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. In the previous phase III PERSIST-1 trial, patients who received pacritinib had a fourfold greater probability of experiencing at least a 35% decrease in splenic volume than did patients who received best available treatment (P = .003).

PERSIST-2 also yielded clear efficacy signals, particularly when patients took pacritinib twice daily, said Dr. Mascarenhas. Between baseline and week 24, splenic volume dropped by at least 35% in 22% of these patients (95% confidence interval, 13%-33%), compared with 3% of patients on best available treatment (95% CI, 0.3%-10%; P = .001). Patients who took pacritinib twice daily also had a 32% (95% CI, 22%-44%) chance of experiencing at least a 50% drop in symptoms such as fatigue, bone pain, itching, and abdominal pain, compared with 14% (95% CI, 7%-24%) of patients on best available treatment (P = .01).

Demographic and disease risk characteristics did not significantly affect the chances of reaching these coprimary endpoints, Dr. Mascarenhas noted. “My humble opinion as a clinical investigator is that [pacritinib] is an effective drug, with a favorable benefit-to-risk ratio,” he said.

Several hematologists who were not involved in this trial agreed. “I don’t see why you are nervous [about presenting these results],” noted hematologist Kanti Rai, MD, of the Feinstein Institute for Medical Research in Manhasset, N.Y., told Dr. Mascarenhas during the discussion after the data were presented, prompting laughter from the audience.

It remains to be seen whether the FDA will find the data convincing enough to lift the clinical hold on pacritinib. Ruxolitinib (Jakafi) is approved to treat splenomegaly and symptom burden in myelofibrosis but is associated with dose-limiting cytopenias and cannot be used in patients with platelet counts of less than 50,000/mcL.

PERSIST-2 compared pacritinib 400 mg once daily with pacritinib 200 mg twice daily and best available treatment, including ruxolitinib, in patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL. About half of the study patients had less than 50,000 platelets/mcL, and more than 40% had previously received ruxolitinib.

When the clinical hold on pacritinib went into effect, 221 patients had reached the 24-week designated study endpoint and were included in the intention-to-treat analysis, Dr. Mascarenhas reported. Censored Kaplan-Meier curves of overall survival favored pacritinib over best available treatment, although the difference in survival rates did not reach statistical significance (hazard ratio, 0.68; 95% CI, 0.3-1.5). A total of 9% of patients in the twice-daily pacritinib group died, compared with 14% of patients receiving pacritinib once daily or best available treatment.

Twice-daily pacritinib most often led to diarrhea (48% of patients), nausea (32%), thrombocytopenia (34%), and anemia (24%). Overall rates of serious treatment-emergent adverse events were seen in 47% of the two pacritinib groups and in 31% of patients receiving best available treatment. The most common serious treatment-emergent adverse event with twice daily pacritinib was anemia (8% of patients), followed by thrombocytopenia and pneumonia (6%). Heart failure, atrial fibrillation, and cardiac arrest were rare and similar across all three treatment groups, as were epistaxis and subdural hematoma.

This is the first randomized, controlled trial of patients with myelofibrosis and thrombocytopenia, according to Dr. Mascarenhas. “This was a patient population with low platelets and at risk of poor outcomes, and they did pretty well,” he said. “There really is no therapeutic option for patients with myelofibrosis and low platelets, and [pacritinib] offers patients in this vulnerable situation an opportunity for symptom relief. I hope to see it move forward.”

CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.

SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.

After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.

H. Lee Moffitt Cancer Center

SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.

After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.

H. Lee Moffitt Cancer Center

SAN DIEGO – Dual therapy with lenalidomide and epoetin alfa was safe and led to freedom from transfusion significantly more often than lenalidomide alone in patients with erythropoietin-refractory, lower-risk, non-del(5q) myelodysplastic syndromes, according to a randomized phase III head-to-head trial.

After 16 weeks of treatment, 33% of patients who received both lenalidomide and epoetin alfa met International Working Group 2000 criteria for major erythroid response, compared with only 14% of patients receiving lenalidomide monotherapy (P = .03), Alan F. List, MD, reported at the annual meeting of the American Society of Hematology.

H. Lee Moffitt Cancer Center

Micrograph showing MDS

Preclinical research has revealed potential therapeutic targets for

myelodysplastic syndromes (MDS).

Investigators

found evidence to suggest that TRAF6, a toll-like receptor effector

with ubiquitin ligase activity, plays a key role in MDS.

So TRAF6 and

proteins regulated by TRAF6 may be therapeutic targets for MDS.

Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.

The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.

To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.

“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.

Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.

This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.

All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.

“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.

Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.

TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.

Micrograph showing MDS

Preclinical research has revealed potential therapeutic targets for

myelodysplastic syndromes (MDS).

Investigators

found evidence to suggest that TRAF6, a toll-like receptor effector

with ubiquitin ligase activity, plays a key role in MDS.

So TRAF6 and

proteins regulated by TRAF6 may be therapeutic targets for MDS.

Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.

The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.

To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.

“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.

Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.

This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.

All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.

“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.

Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.

TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.

Micrograph showing MDS

Preclinical research has revealed potential therapeutic targets for

myelodysplastic syndromes (MDS).

Investigators

found evidence to suggest that TRAF6, a toll-like receptor effector

with ubiquitin ligase activity, plays a key role in MDS.

So TRAF6 and

proteins regulated by TRAF6 may be therapeutic targets for MDS.

Daniel Starczynowski, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Nature Immunology.

The investigators first found that TRAF6 is overexpressed in hematopoietic stem/progenitor cells from MDS patients.

To more closely examine the role of TRAF6 in MDS, the team created mouse models in which the protein was overexpressed.

“We found that TRAF6 overexpression in mouse hematopoietic stem cells results in impaired blood cell formation and bone marrow failure,” Dr Starczynowski said.

Further investigation revealed that hnRNPA1, an RNA-binding protein and auxiliary splicing factor, is a substrate of TRAF6. And TRAF6 ubiquitination of hnRNPA1 regulates alternative splicing of Arhgap1.

This activates the GTP-binding Rho family protein Cdc42 and accounts for the defects observed in hematopoietic stem/progenitor cells that express TRAF6.

All of these proteins could be potential treatment targets for cases of MDS triggered by overexpression of TRAF6, according to Dr Starczynowski, who said future studies will test their therapeutic potential in mouse models of MDS.

“Based on our paper, a number of therapeutic approaches can be tested and directed against TRAF6 and other related proteins responsible for MDS,” he said.

Beyond the potential for new therapeutic approaches in MDS, this research revealed a new and critical immune-related function for TRAF6, according to the investigators.

TRAF6 regulates RNA isoform expression in response to various pathogens. In the context of the current study, TRAF6’s regulation of RNA isoform expression is important to the function of hematopoietic cells and reveals another dimension to how cells respond to infection, Dr Starczynowski said.

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Andy Futreal, PhD

Photo courtesy of

MD Anderson Cancer Center

SAN DIEGO―Clonal hematopoiesis could be used as a predictive marker to identify cancer patients at risk of developing therapy-related myeloid neoplasms (t-MNs), according to researchers.

The team conducted a case-control study, which showed that patients who developed t-MNs—acute myeloid leukemia and myelodysplastic syndromes—were significantly more likely than patients without t-MNs to have clonal hematopoiesis at the time of primary cancer diagnosis.

“Based on these findings, we believe pre-leukemic mutations may function as a new biomarker that would predict t-MN development,” said Andy Futreal, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Futreal and his colleagues reported these findings in The Lancet Oncology.

Co-author Koichi Takashi, MD, also of MD Anderson, presented the findings at the 2016 ASH Annual Meeting (abstract 38).

Initial cohort

The researchers analyzed data on patients treated at MD Anderson from 1997 to 2015.

The 14 cases the team identified had been treated for a primary cancer and later developed t-MNs. The 54 age-matched control subjects had been treated for lymphoma, received combination chemotherapy, and did not develop t-MNs after at least 5 years of follow-up.

For both cases and controls, the researchers performed gene sequencing on pre-treatment peripheral blood samples. For cases, the researchers also performed targeted gene sequencing on bone marrow samples taken at t-MN diagnosis.

“We found that prevalence of pre-leukemic mutations was significantly higher in patients who developed t-MNs versus those who did not,” Dr Futreal said.

Clonal hematopoiesis was present in 71% of cases (n=10) and 31% of controls (n=17).

“We found genetic mutations that are present in t-MNs leukemia samples actually could be found in blood samples obtained at the time of their original cancer diagnosis,” Dr Takashi noted.

Overall, the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis than in those without it—30% and 7%, respectively (P=0.016).

Validation cohort

The researchers also assessed clonal hematopoiesis in an external cohort of 74 patients with lymphoma who were treated in a trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin.

In this cohort, 7% (n=5) of patients developed t-MNs. Eighty percent of these patients (n=4) had clonal hematopoiesis.

Of the 69 patients who did not develop t-MNs, 16% (n=11) had clonal hematopoiesis.

The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis than in those without it—29% and 0%, respectively (P=0.0009).

Multivariate analysis suggested clonal hematopoiesis significantly increased the risk of t-MNs, with a hazard ratio of 13.7 (P=0.013).

“[W]e believe the data suggest potential approaches of screening for clonal hematopoiesis in cancer patients that may identify patients at risk of developing t-MNs, although further studies are needed,” Dr Takashi concluded.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Micrograph showing MDS

Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.

“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.

“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”

In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.

With the current study, the researchers wanted to build upon those findings by identifying the underlying  mechanisms and determining their relevance to human disease.

So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).

The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.

The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.

Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.

The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9⁺ patients than niche S100A8/9^- patients.

The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)

The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.

“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”

Micrograph showing MDS

Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.

“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.

“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”

In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.

With the current study, the researchers wanted to build upon those findings by identifying the underlying  mechanisms and determining their relevance to human disease.

So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).

The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.

The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.

Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.

The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9⁺ patients than niche S100A8/9^- patients.

The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)

The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.

“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”

Micrograph showing MDS

Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.

“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.

“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”

In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.

With the current study, the researchers wanted to build upon those findings by identifying the underlying  mechanisms and determining their relevance to human disease.

So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).

The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.

The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.

Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.

The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9⁺ patients than niche S100A8/9^- patients.

The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)

The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.

“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”

Prescription medications

Photo by Steven Harbour

Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.

In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+

chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.

Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.

In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.

For more details on imatinib, see the full prescribing information.

Prescription medications

Photo by Steven Harbour

Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.

In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+

chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.

Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.

In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.

For more details on imatinib, see the full prescribing information.

Prescription medications

Photo by Steven Harbour

Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.

In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+

chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.

Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.

In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.

For more details on imatinib, see the full prescribing information.

Micrograph showing MDS

Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.

The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.

And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.

The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.

For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.

The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.

In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.

NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.

Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).

The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.

Micrograph showing MDS

Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.

The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.

And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.

The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.

For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.

The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.

In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.

NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.

Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).

The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.

Micrograph showing MDS

Next-generation sequencing (NGS) of cell-free DNA should be the method of choice to confirm the diagnosis of myelodysplastic syndromes (MDS), according to researchers.

The team found that using NGS to analyze samples from MDS patients yielded more accurate results than Sanger sequencing.

And sequencing cell-free DNA rather than peripheral blood cell DNA increased the likelihood of detecting mutations associated with MDS.

The team reported these findings in Genetic Testing and Molecular Biomarkers. This research was funded by NeoGenomics Laboratories.

For this study, the researchers performed NGS on a panel of 14 target genes using total nucleic acid extracted from the plasma of 16 patients with early MDS (blasts <5%). The team also performed Sanger sequencing and NGS on peripheral blood cell DNA from the same patients.

The researchers found that NGS of cell-free DNA confirmed the diagnosis of MDS in all 16 patients.

In addition, NGS of cell-free DNA revealed abnormalities in 5 patients (31%) that were not detected by Sanger sequencing of peripheral blood cell DNA.

NGS of peripheral blood cell DNA produced the same results as NGS of cell-free DNA for 4 of the 5 patients. However, NGS of peripheral blood cell DNA did not detect a mutation in the RUNX1 gene that was evident in cell-free DNA from 1 patient.

Overall, the researchers found that mutant allele frequency was significantly higher in cell-free DNA than cellular DNA (P=0.008).

The team therefore concluded that cell-free DNA is more reliable than peripheral blood cell DNA for detecting molecular abnormalities in patients with MDS, and NGS is more accurate than Sanger sequencing.

Preparing for radiation

Photo by Rhoda Baer

Radiologists who graduated from medical school after 1940 do not have an increased risk of dying from radiation-related causes such as cancers, according to a study published in Radiology.

However, the study suggested that male radiologists who graduated before 1940 had a higher risk of death from certain cancers, including acute myeloid leukemia and non-Hodgkin lymphoma.

Researchers said these findings point to the success of efforts to reduce occupational radiation doses over the past several decades.

The team noted that female radiologists did not have an increased risk of all-cause mortality or cancer-related mortality, regardless of when they graduated from medical school.

However, the small number of women in this study prevented the researchers from studying the subjects’ mortality rates in detail. And very few female radiologists worked during the early period of the study, when radiation exposures were likely highest.

To conduct this study, the researchers analyzed records from the American Medical Association Physician Masterfile, a database established in 1906 that has grown to include current and historical data for more than 1.4 million physicians, residents, and medical students in the US.

The team compared cancer incidence and mortality rates between 43,763 radiologists and 64,990 psychiatrists who graduated from medical school between 1916 and 2006. Psychiatrists were chosen as a comparison group because they are unlikely to have had occupational radiation exposure.

“Our most important finding is that radiologists have lower death rates from all causes of death combined, compared to psychiatrists, and had similar risks of cancer deaths overall,” said study author Martha Linet, MD, of the National Cancer Institute in Bethesda, Maryland.

Results in males

The researchers found that, among male subjects who graduated after 1940, the risk of all-cause mortality was lower for the radiologists than the psychiatrists (relative risk [RR]=0.94; 95% CI: 0.90, 0.97), and the risk of death from cancer was similar (RR=1.00; 95% CI: 0.93, 1.07).

In contrast, male radiologists who graduated before 1940 had higher mortality rates from certain cancers.

They had a higher risk of skin cancer mortality (RR=6.38; 95% CI: 1.75, 23.20) that was driven by an excess of melanoma (RR=8.75; 95% CI: 1.89, 40.53).

They had an increased risk of death from all myeloid leukemias (RR=1.43; 95% CI: 1.00, 2.05) that was driven by acute myeloid leukemia and/or myelodysplastic syndromes (RR=4.68; 95% CI: 0.91, 24.18).

And they had an increased risk of death from lymphomas (RR=2.24; 95% CI: 1.31, 3.86) that was driven by non-Hodgkin lymphoma (RR=2.69; 95% CI: 1.33, 5.45).

The researchers also found an increased risk of cerebrovascular deaths in the male radiologists who graduated before 1940 (RR=1.49; 95% CI: 1.11, 2.01).

The team said the reduced health risks for more recent radiology graduates are likely due to developments and improvements in radiation protection and monitoring, along with improvements in equipment safety.

“Most of the findings of increased risk were in the earlier radiologists,” Dr Linet noted. “We do feel there is evidence that decreases in dose in the United States and other countries seem to have paid off, reducing risks in recent graduates.”

Results in females

The researchers said there were no clear increases in mortality in the female radiologists compared with the female psychiatrists.

The risk of all-cause mortality was lower in the radiologists, as was the risk of death from circulatory diseases, but the risk of cancer-related mortality was similar between the radiologists and the psychiatrists.

However, the researchers said the relatively small number of female deaths in this study prevented detailed investigation. Only 2% of female radiologists (208/8851) and 3% of female psychiatrists (524/17,493) died, compared to 12% of male radiologists (4260/43,763) and 16% of male psychiatrists (7815/47,443).

Preparing for radiation

Photo by Rhoda Baer

Radiologists who graduated from medical school after 1940 do not have an increased risk of dying from radiation-related causes such as cancers, according to a study published in Radiology.

However, the study suggested that male radiologists who graduated before 1940 had a higher risk of death from certain cancers, including acute myeloid leukemia and non-Hodgkin lymphoma.

Researchers said these findings point to the success of efforts to reduce occupational radiation doses over the past several decades.

The team noted that female radiologists did not have an increased risk of all-cause mortality or cancer-related mortality, regardless of when they graduated from medical school.

However, the small number of women in this study prevented the researchers from studying the subjects’ mortality rates in detail. And very few female radiologists worked during the early period of the study, when radiation exposures were likely highest.

To conduct this study, the researchers analyzed records from the American Medical Association Physician Masterfile, a database established in 1906 that has grown to include current and historical data for more than 1.4 million physicians, residents, and medical students in the US.

The team compared cancer incidence and mortality rates between 43,763 radiologists and 64,990 psychiatrists who graduated from medical school between 1916 and 2006. Psychiatrists were chosen as a comparison group because they are unlikely to have had occupational radiation exposure.

“Our most important finding is that radiologists have lower death rates from all causes of death combined, compared to psychiatrists, and had similar risks of cancer deaths overall,” said study author Martha Linet, MD, of the National Cancer Institute in Bethesda, Maryland.

Results in males

The researchers found that, among male subjects who graduated after 1940, the risk of all-cause mortality was lower for the radiologists than the psychiatrists (relative risk [RR]=0.94; 95% CI: 0.90, 0.97), and the risk of death from cancer was similar (RR=1.00; 95% CI: 0.93, 1.07).

In contrast, male radiologists who graduated before 1940 had higher mortality rates from certain cancers.

They had a higher risk of skin cancer mortality (RR=6.38; 95% CI: 1.75, 23.20) that was driven by an excess of melanoma (RR=8.75; 95% CI: 1.89, 40.53).

They had an increased risk of death from all myeloid leukemias (RR=1.43; 95% CI: 1.00, 2.05) that was driven by acute myeloid leukemia and/or myelodysplastic syndromes (RR=4.68; 95% CI: 0.91, 24.18).

And they had an increased risk of death from lymphomas (RR=2.24; 95% CI: 1.31, 3.86) that was driven by non-Hodgkin lymphoma (RR=2.69; 95% CI: 1.33, 5.45).

The researchers also found an increased risk of cerebrovascular deaths in the male radiologists who graduated before 1940 (RR=1.49; 95% CI: 1.11, 2.01).

The team said the reduced health risks for more recent radiology graduates are likely due to developments and improvements in radiation protection and monitoring, along with improvements in equipment safety.

“Most of the findings of increased risk were in the earlier radiologists,” Dr Linet noted. “We do feel there is evidence that decreases in dose in the United States and other countries seem to have paid off, reducing risks in recent graduates.”

Results in females

The researchers said there were no clear increases in mortality in the female radiologists compared with the female psychiatrists.

The risk of all-cause mortality was lower in the radiologists, as was the risk of death from circulatory diseases, but the risk of cancer-related mortality was similar between the radiologists and the psychiatrists.

However, the researchers said the relatively small number of female deaths in this study prevented detailed investigation. Only 2% of female radiologists (208/8851) and 3% of female psychiatrists (524/17,493) died, compared to 12% of male radiologists (4260/43,763) and 16% of male psychiatrists (7815/47,443).

Preparing for radiation

Photo by Rhoda Baer

Radiologists who graduated from medical school after 1940 do not have an increased risk of dying from radiation-related causes such as cancers, according to a study published in Radiology.

However, the study suggested that male radiologists who graduated before 1940 had a higher risk of death from certain cancers, including acute myeloid leukemia and non-Hodgkin lymphoma.

Researchers said these findings point to the success of efforts to reduce occupational radiation doses over the past several decades.

The team noted that female radiologists did not have an increased risk of all-cause mortality or cancer-related mortality, regardless of when they graduated from medical school.

However, the small number of women in this study prevented the researchers from studying the subjects’ mortality rates in detail. And very few female radiologists worked during the early period of the study, when radiation exposures were likely highest.

To conduct this study, the researchers analyzed records from the American Medical Association Physician Masterfile, a database established in 1906 that has grown to include current and historical data for more than 1.4 million physicians, residents, and medical students in the US.

The team compared cancer incidence and mortality rates between 43,763 radiologists and 64,990 psychiatrists who graduated from medical school between 1916 and 2006. Psychiatrists were chosen as a comparison group because they are unlikely to have had occupational radiation exposure.

“Our most important finding is that radiologists have lower death rates from all causes of death combined, compared to psychiatrists, and had similar risks of cancer deaths overall,” said study author Martha Linet, MD, of the National Cancer Institute in Bethesda, Maryland.

Results in males

The researchers found that, among male subjects who graduated after 1940, the risk of all-cause mortality was lower for the radiologists than the psychiatrists (relative risk [RR]=0.94; 95% CI: 0.90, 0.97), and the risk of death from cancer was similar (RR=1.00; 95% CI: 0.93, 1.07).

In contrast, male radiologists who graduated before 1940 had higher mortality rates from certain cancers.

They had a higher risk of skin cancer mortality (RR=6.38; 95% CI: 1.75, 23.20) that was driven by an excess of melanoma (RR=8.75; 95% CI: 1.89, 40.53).

They had an increased risk of death from all myeloid leukemias (RR=1.43; 95% CI: 1.00, 2.05) that was driven by acute myeloid leukemia and/or myelodysplastic syndromes (RR=4.68; 95% CI: 0.91, 24.18).

And they had an increased risk of death from lymphomas (RR=2.24; 95% CI: 1.31, 3.86) that was driven by non-Hodgkin lymphoma (RR=2.69; 95% CI: 1.33, 5.45).

The researchers also found an increased risk of cerebrovascular deaths in the male radiologists who graduated before 1940 (RR=1.49; 95% CI: 1.11, 2.01).

The team said the reduced health risks for more recent radiology graduates are likely due to developments and improvements in radiation protection and monitoring, along with improvements in equipment safety.

“Most of the findings of increased risk were in the earlier radiologists,” Dr Linet noted. “We do feel there is evidence that decreases in dose in the United States and other countries seem to have paid off, reducing risks in recent graduates.”

Results in females

The researchers said there were no clear increases in mortality in the female radiologists compared with the female psychiatrists.

The risk of all-cause mortality was lower in the radiologists, as was the risk of death from circulatory diseases, but the risk of cancer-related mortality was similar between the radiologists and the psychiatrists.

However, the researchers said the relatively small number of female deaths in this study prevented detailed investigation. Only 2% of female radiologists (208/8851) and 3% of female psychiatrists (524/17,493) died, compared to 12% of male radiologists (4260/43,763) and 16% of male psychiatrists (7815/47,443).