Myelodysplastic Syndrome

Photo by Rhoda Baer

Chemotherapy for solid tumors is associated with an increased risk of therapy-related myelodysplastic syndromes or acute myeloid leukemia (tMDS/AML), according to a retrospective analysis.

Long-term, population-based cohort data showed the risk of tMDS/AML was significantly elevated after chemotherapy for 22 solid tumor types.

The relative risk of tMDS/AML was 1.5- to 39.0-fold greater among patients treated for these tumors than among the general population.

Lindsay M. Morton, PhD, of the National Institutes of Health in Rockville, Maryland, and her colleagues reported these findings in JAMA Oncology.

“We undertook an investigation to quantify tMDS/AML risks after chemotherapy for solid tumors in the modern treatment era, 2000-2014, using United States cancer registry data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program,” the investigators wrote.

They retrospectively analyzed data from 1619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013.

Patients were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data do not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the investigators noted.

The team found the risk of developing tMDS/AML was significantly increased following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer.

The standardized incidence ratio (SIR) for tMDS/AML ranged from 1.5 to 39.0, and the excess absolute risk (EAR) ranged from 1.4 to 23.6 cases per 10,000 person-years.

SIRs were greatest in patients who received chemotherapy for malignancy of the bone (SIR=39.0, EAR=23.6), testis (SIR, 12.3, EAR=4.4), soft tissue (SIR=10.4, EAR=12.6), fallopian tube (SIR=8.7, EAR=16.0), small cell lung (SIR=8.1, EAR=19.9), peritoneum (SIR=7.5, EAR=15.8), brain or central nervous system (SIR=7.2, EAR=6.0), and ovary (SIR=5.8, EAR=8.2).

The investigators also found that patients who were given chemotherapy at a young age had the highest risk of developing tMDS/AML.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” the investigators said.

They acknowledged a key limitation of this study was the limited data on patient-specific chemotherapy and dosing information. Given these limitations, Dr. Morton and her colleagues said, “the exact magnitude of our risk estimates, including the proportions of excess cases, should therefore be interpreted cautiously.”

This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported no conflicts of interest.

Photo by Rhoda Baer

Chemotherapy for solid tumors is associated with an increased risk of therapy-related myelodysplastic syndromes or acute myeloid leukemia (tMDS/AML), according to a retrospective analysis.

Long-term, population-based cohort data showed the risk of tMDS/AML was significantly elevated after chemotherapy for 22 solid tumor types.

The relative risk of tMDS/AML was 1.5- to 39.0-fold greater among patients treated for these tumors than among the general population.

Lindsay M. Morton, PhD, of the National Institutes of Health in Rockville, Maryland, and her colleagues reported these findings in JAMA Oncology.

“We undertook an investigation to quantify tMDS/AML risks after chemotherapy for solid tumors in the modern treatment era, 2000-2014, using United States cancer registry data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program,” the investigators wrote.

They retrospectively analyzed data from 1619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013.

Patients were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data do not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the investigators noted.

The team found the risk of developing tMDS/AML was significantly increased following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer.

The standardized incidence ratio (SIR) for tMDS/AML ranged from 1.5 to 39.0, and the excess absolute risk (EAR) ranged from 1.4 to 23.6 cases per 10,000 person-years.

SIRs were greatest in patients who received chemotherapy for malignancy of the bone (SIR=39.0, EAR=23.6), testis (SIR, 12.3, EAR=4.4), soft tissue (SIR=10.4, EAR=12.6), fallopian tube (SIR=8.7, EAR=16.0), small cell lung (SIR=8.1, EAR=19.9), peritoneum (SIR=7.5, EAR=15.8), brain or central nervous system (SIR=7.2, EAR=6.0), and ovary (SIR=5.8, EAR=8.2).

The investigators also found that patients who were given chemotherapy at a young age had the highest risk of developing tMDS/AML.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” the investigators said.

They acknowledged a key limitation of this study was the limited data on patient-specific chemotherapy and dosing information. Given these limitations, Dr. Morton and her colleagues said, “the exact magnitude of our risk estimates, including the proportions of excess cases, should therefore be interpreted cautiously.”

This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported no conflicts of interest.

Photo by Rhoda Baer

Chemotherapy for solid tumors is associated with an increased risk of therapy-related myelodysplastic syndromes or acute myeloid leukemia (tMDS/AML), according to a retrospective analysis.

Long-term, population-based cohort data showed the risk of tMDS/AML was significantly elevated after chemotherapy for 22 solid tumor types.

The relative risk of tMDS/AML was 1.5- to 39.0-fold greater among patients treated for these tumors than among the general population.

Lindsay M. Morton, PhD, of the National Institutes of Health in Rockville, Maryland, and her colleagues reported these findings in JAMA Oncology.

“We undertook an investigation to quantify tMDS/AML risks after chemotherapy for solid tumors in the modern treatment era, 2000-2014, using United States cancer registry data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program,” the investigators wrote.

They retrospectively analyzed data from 1619 patients with tMDS/AML who were diagnosed with an initial primary solid tumor from 2000 to 2013.

Patients were given initial chemotherapy and lived for at least 1 year after treatment. Subsequently, Dr. Morton and her colleagues linked patient database records with Medicare insurance claim information to confirm the accuracy of chemotherapy data.

“Because registry data do not include treatment details, we used an alternative database to provide descriptive information on population-based patterns of chemotherapeutic drug use,” the investigators noted.

The team found the risk of developing tMDS/AML was significantly increased following chemotherapy administration for 22 of 23 solid tumor types, excluding colon cancer.

The standardized incidence ratio (SIR) for tMDS/AML ranged from 1.5 to 39.0, and the excess absolute risk (EAR) ranged from 1.4 to 23.6 cases per 10,000 person-years.

SIRs were greatest in patients who received chemotherapy for malignancy of the bone (SIR=39.0, EAR=23.6), testis (SIR, 12.3, EAR=4.4), soft tissue (SIR=10.4, EAR=12.6), fallopian tube (SIR=8.7, EAR=16.0), small cell lung (SIR=8.1, EAR=19.9), peritoneum (SIR=7.5, EAR=15.8), brain or central nervous system (SIR=7.2, EAR=6.0), and ovary (SIR=5.8, EAR=8.2).

The investigators also found that patients who were given chemotherapy at a young age had the highest risk of developing tMDS/AML.

“For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy,” the investigators said.

They acknowledged a key limitation of this study was the limited data on patient-specific chemotherapy and dosing information. Given these limitations, Dr. Morton and her colleagues said, “the exact magnitude of our risk estimates, including the proportions of excess cases, should therefore be interpreted cautiously.”

This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the California Department of Public Health. The authors reported no conflicts of interest.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

sworcester@mdedge.com

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

sworcester@mdedge.com

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

sworcester@mdedge.com

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

© ASH/Scott Morgan 2018

SAN DIEGO—Results of the randomized, phase 3 Medalist trial show that the erythroid maturation agent luspatercept can reduce transfusion burden in patients with anemia due to myelodysplastic syndromes (MDS) and ring sideroblasts.

Almost 38% of luspatercept-treated patients achieved red blood cell (RBC) transfusion independence for 8 weeks or more, compared with 13% of patients receiving placebo.

And 28% of luspatercept-treated patients achieved transfusion independence for 12 weeks or more, compared to 8% in the placebo group.

Investigators reported these results as abstract 1 at the 2018 ASH Annual Meeting.

Treatment with luspatercept was “very well tolerated,” and responses were durable, with approximately 40% of patients remaining transfusion-free after 1 year of therapy, said senior investigator Alan F. List, MD, of Moffitt Cancer Center in Tampa, Florida, during a press conference at the meeting.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ring sideroblasts who are red blood cell transfusion-dependent,” Dr. List affirmed.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the TGF-β superfamily, which is known to be very important in suppressing erythropoiesis in patients with MDS, Dr. List noted.

The Medalist study (NCT02631070) included patients with very low-, low-, or intermediate-risk disease and ring sideroblasts who were RBC transfusion-dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomized to receive luspatercept at 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days.

The primary endpoint was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

The primary endpoint was achieved by 37.9% of luspatercept-treated patients and 13.2% of placebo-treated patients (P<0.0001).

The luspatercept-treated patients also had a higher rate of erythroid response compared with the placebo group, at 52.9% and 11.8%, respectively (P<0.0001).

The investigators reported no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia (AML).

The safety profile was consistent with that of the phase 2 PACE-MDS study, which included treatment-related grade 3 myalgia (2%), increased blast cell count (2%), and general physical health deterioration (2%).

“This was a very clean drug and a very safe drug,” Dr. List said.

The decision to study luspatercept in patients with ring sideroblasts was based on results of the phase 2 PACE study showing a higher response rate in that subset of MDS patients, according to Dr. List.

The PACE study also included a small number of patients who had not previously received an ESA.

Currently underway is a phase 3 trial (NCT03682536) investigating luspatercept in ESA-naïve lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, which represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

“It’s been 12 years since we had an FDA-approved drug in MDS, and there have been 7 in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

The Medalist study was sponsored by Celgene in collaboration with Acceleron Pharma, Inc.

Dr. List reported research funding from Celgene. 

© ASH/Scott Morgan 2018

SAN DIEGO—Results of the randomized, phase 3 Medalist trial show that the erythroid maturation agent luspatercept can reduce transfusion burden in patients with anemia due to myelodysplastic syndromes (MDS) and ring sideroblasts.

Almost 38% of luspatercept-treated patients achieved red blood cell (RBC) transfusion independence for 8 weeks or more, compared with 13% of patients receiving placebo.

And 28% of luspatercept-treated patients achieved transfusion independence for 12 weeks or more, compared to 8% in the placebo group.

Investigators reported these results as abstract 1 at the 2018 ASH Annual Meeting.

Treatment with luspatercept was “very well tolerated,” and responses were durable, with approximately 40% of patients remaining transfusion-free after 1 year of therapy, said senior investigator Alan F. List, MD, of Moffitt Cancer Center in Tampa, Florida, during a press conference at the meeting.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ring sideroblasts who are red blood cell transfusion-dependent,” Dr. List affirmed.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the TGF-β superfamily, which is known to be very important in suppressing erythropoiesis in patients with MDS, Dr. List noted.

The Medalist study (NCT02631070) included patients with very low-, low-, or intermediate-risk disease and ring sideroblasts who were RBC transfusion-dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomized to receive luspatercept at 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days.

The primary endpoint was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

The primary endpoint was achieved by 37.9% of luspatercept-treated patients and 13.2% of placebo-treated patients (P<0.0001).

The luspatercept-treated patients also had a higher rate of erythroid response compared with the placebo group, at 52.9% and 11.8%, respectively (P<0.0001).

The investigators reported no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia (AML).

The safety profile was consistent with that of the phase 2 PACE-MDS study, which included treatment-related grade 3 myalgia (2%), increased blast cell count (2%), and general physical health deterioration (2%).

“This was a very clean drug and a very safe drug,” Dr. List said.

The decision to study luspatercept in patients with ring sideroblasts was based on results of the phase 2 PACE study showing a higher response rate in that subset of MDS patients, according to Dr. List.

The PACE study also included a small number of patients who had not previously received an ESA.

Currently underway is a phase 3 trial (NCT03682536) investigating luspatercept in ESA-naïve lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, which represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

“It’s been 12 years since we had an FDA-approved drug in MDS, and there have been 7 in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

The Medalist study was sponsored by Celgene in collaboration with Acceleron Pharma, Inc.

Dr. List reported research funding from Celgene. 

© ASH/Scott Morgan 2018

SAN DIEGO—Results of the randomized, phase 3 Medalist trial show that the erythroid maturation agent luspatercept can reduce transfusion burden in patients with anemia due to myelodysplastic syndromes (MDS) and ring sideroblasts.

Almost 38% of luspatercept-treated patients achieved red blood cell (RBC) transfusion independence for 8 weeks or more, compared with 13% of patients receiving placebo.

And 28% of luspatercept-treated patients achieved transfusion independence for 12 weeks or more, compared to 8% in the placebo group.

Investigators reported these results as abstract 1 at the 2018 ASH Annual Meeting.

Treatment with luspatercept was “very well tolerated,” and responses were durable, with approximately 40% of patients remaining transfusion-free after 1 year of therapy, said senior investigator Alan F. List, MD, of Moffitt Cancer Center in Tampa, Florida, during a press conference at the meeting.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ring sideroblasts who are red blood cell transfusion-dependent,” Dr. List affirmed.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the TGF-β superfamily, which is known to be very important in suppressing erythropoiesis in patients with MDS, Dr. List noted.

The Medalist study (NCT02631070) included patients with very low-, low-, or intermediate-risk disease and ring sideroblasts who were RBC transfusion-dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomized to receive luspatercept at 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days.

The primary endpoint was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

The primary endpoint was achieved by 37.9% of luspatercept-treated patients and 13.2% of placebo-treated patients (P<0.0001).

The luspatercept-treated patients also had a higher rate of erythroid response compared with the placebo group, at 52.9% and 11.8%, respectively (P<0.0001).

The investigators reported no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia (AML).

The safety profile was consistent with that of the phase 2 PACE-MDS study, which included treatment-related grade 3 myalgia (2%), increased blast cell count (2%), and general physical health deterioration (2%).

“This was a very clean drug and a very safe drug,” Dr. List said.

The decision to study luspatercept in patients with ring sideroblasts was based on results of the phase 2 PACE study showing a higher response rate in that subset of MDS patients, according to Dr. List.

The PACE study also included a small number of patients who had not previously received an ESA.

Currently underway is a phase 3 trial (NCT03682536) investigating luspatercept in ESA-naïve lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, which represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

“It’s been 12 years since we had an FDA-approved drug in MDS, and there have been 7 in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

The Medalist study was sponsored by Celgene in collaboration with Acceleron Pharma, Inc.

Dr. List reported research funding from Celgene. 

SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.

Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.

The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).

There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.

The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.

That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

Dr. List reported research funding from Celgene.

SOURCE: List AF et al. ASH 2018, Abstract 1.

SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.

Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.

The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).

There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.

The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.

That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

Dr. List reported research funding from Celgene.

SOURCE: List AF et al. ASH 2018, Abstract 1.

SAN DIEGO – A novel erythroid maturation agent significantly reduced transfusion burden versus placebo in patients with anemia caused by myelodysplastic syndromes (MDS) and ringed sideroblasts, results of a randomized, phase 3 trial demonstrate.

Luspatercept was “very well tolerated” and responses were durable, with approximately 40% of patients remaining transfusion free after 1 year of therapy, said Alan F. List, MD, of Moffitt Cancer Center, Tampa.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ringed sideroblasts who are red blood cell transfusion–dependent,” said Dr. List, senior author of the MEDALIST trial, said in a press conference at the annual meeting of the American Society of Hematology.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

In a separate randomized, placebo-controlled, phase 3 study presented at ASH 2018, Maria Domenica Cappellini, MD, of the University of Milan, reported that, in beta-thalassemia patients who were transfusion dependent, luspatercept treatment resulted in a statistically significant reductions in transfusion burden versus placebo, and was generally well tolerated.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the transforming growth factor–beta superfamily, which is known to be important in suppressing erythropoiesis in patients with MDS, Dr. List said.

The MDS study included patients with very low–, low-, or intermediate-risk disease and ringed sideroblasts who were RBC transfusion–dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomly allocated to luspatercept 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days. The primary end point was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

A total of 37.9% of luspatercept-treated patients achieved that primary endpoint, compared with 13.2% of placebo-treated patient (P less than .0001), Dr. List reported. The luspatercept-treated patients also had a 52.9% rate of erythroid response, compared with 11.8% in the placebo group (P less than .0001).

There were no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia. “This was a very clean drug and a very safe drug,” he said.

The decision to study luspatercept in patients with ringed sideroblasts was based on results of a large, phase 2 European study showing a higher response rate in that subset of MDS patients, according to Dr. List.

That study also included a small number of patients who had not previously received an ESA. Currently underway is a phase 3 trial looking at luspatercept in ESA-naive, lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, who represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

“It’s been 12 years since we had an FDA [Food and Drug Administration]-approved drug in MDS, and there have been seven in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

Dr. List reported research funding from Celgene.

SOURCE: List AF et al. ASH 2018, Abstract 1.

With more than 3,000 scientific abstracts at the 2018 annual meeting of the American Society of Hematology, it can be tough to figure out what research is most relevant to practice. But the editorial advisory board of Hematology News is making it easier this year with their picks for what to watch and why.

Lymphomas

Brian T. Hill, MD, of the Cleveland Clinic, offered his top picks in lymphoma research. Results of the phase 3 international Alliance North American Intergroup Study A041202 will be presented during the ASH plenary session at 2 p.m. PT on Sunday, Dec. 2 in Hall AB of the San Diego Convention Center (Abstract 6). The study compared bendamustine plus rituximab with ibrutinib and the combination of ibrutinib plus rituximab to see if the ibrutinib-containing therapies would have superior progression-free survival (PFS) in chronic lymphocytic leukemia (CLL), compared with chemoimmunotherapy. Results indicate that ibrutinib had superior PFS in older patients with CLL and could be a standard of care in this population.

The study is worth watching because it is the first report of a head-to-head trial of chemotherapy versus ibrutinib for first-line treatment of CLL, Dr. Hill said.

Two more studies offer important reports of “real world” experiences with chimeric antigen receptor (CAR) T-cell therapy.

In one multicenter retrospective study, researchers evaluated the outcomes of axicabtagene ciloleucel (axi-cel) CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma when it is used a standard care. The researchers will report that 30-day responses in the real-world setting were comparable to the best responses seen in the ZUMA-1 trial. The full results will be reported at 9:30 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 91).

Another retrospective analysis looked at the use of axi-cell and revealed some critical differences from ZUMA-1, specifically the overall response rate (ORR) and complete response (CR) rate were lower than those reported in the pivotal clinical trial. The findings will be reported at 9:45 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 92).

Researchers will also present the unblinded results from the ECHELON-2 study, which compared the efficacy and safety of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) versus standard CHOP for the treatment of patients with peripheral T-cell lymphoma. The results will be presented at 6:15 p.m. PT on Monday, Dec. 3 in room 6F of the San Diego convention center (Abstract 997).

Previously reported blinded pooled data showed that the treatment was well tolerated with 3-year PFS of 53% and OS of 73%.

“This should be a new standard of care for T-cell lymphomas,” Dr. Hill said.
 

CAR T-cell therapy

There are a number of abstracts featuring the latest results on CAR T-cell therapy. Helen Heslop, MD, of Baylor College of Medicine, Houston, recommended an updated analysis from the ELIANA study, which looked at the efficacy and safety of tisagenlecleucel in for children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

“Longer-term follow-up of the ELIANA study shows encouraging remission-duration data in pediatric and young adults with ALL without additional therapy,” Dr. Heslop said.

The findings will be presented at 4:30 p.m. PT on Monday, Dec. 3 in room 6A at the San Diego Convention Center (Abstract 895).

Another notable presentation will feature results from a phase 1B/2 trial evaluating infusion of CAR T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) after lymphodepleting chemotherapy in patients with relapsed or refractory CD30+ Hodgkin lymphoma and non-Hodgkin lymphoma.

The researchers will report that there was a significant PFS advances for who received the highest dose level of the CAR T treatment, combined with bendamustine and fludarabine.

The study will be presented at 11 a.m. PT on Monday, Dec. 3 in room 6F at the San Diego Convention Center (Abstract 681).

Dr. Heslop also recommends another study being presented in the same session, which also shows encouraging results with CD30.CAR-Ts. Dr. Heslop is one of the co-investigators on the phase 1 RELY-30 trial, which is evaluating the efficacy of CD30.CAR-Ts after lymphodepleting chemotherapy. Preliminary results suggest a substantial improvement in efficacy. The findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in room 6F of the San Diego Convention Center (Abstract 680).
 

MDS/MPN

Vikas Gupta, MD, of Princess Margaret Cancer Center in Toronto, highlighted three abstracts to watch in the areas of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN).

The phase 3 Medalist trial is a randomized double-blind placebo controlled study of luspatercept to treatment anemia in patients with MDS with ring sideroblasts who require red blood cell transfusion. The researchers will report significantly reduced transfusion burdens for luspatercept, compared with placebo.

“This is a practice-changing, pivotal trial in the field of MDS for the treatment of anemia,” Dr. Gupta said.

The findings will be presented at 2 p.m. PT on Sunday, Dec. 2 during the plenary session in Hall AB in the San Diego Convention Center (Abstract 1).

Also during the Sunday plenary session is a presentation on MPN therapy (Abstract 4). Researchers will present data on secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor (TpoR) activation, specifically in CALR-mutated cells.

“This study investigates in to the mechanistic oncogenetic aspects of mutant calreticulin, and has potential for therapeutic approaches in the future,” Dr. Gupta said.

The ASH meeting will also feature the final analysis of the MPN-RC 112 consortium trial of pegylated interferon alfa-2a versus hydroxyurea for the treatment of high-risk polycythemia vera (PV) and essential thrombocythemia (ET). The researchers will report that the CR rates at 12 and 24 months were similar in patients treated with pegylated interferon alfa-2a and hydroxyurea, but pegylated interferon alfa-2a was associated with a higher rate of serious toxicities.

“There is a continuous debate on optimal first-line cytoreductive therapy for high risk PV/ET, and this is one of the first randomized study to answer this question,” Dr. Gupta said.

The findings will be presented at 7 a.m. PT on Monday, Dec. 3 in Grand Hall D at the Manchester Grand Hyatt San Diego (Abstract 577).
 

AML

For attendees interested in the latest developments in acute myeloid leukemia, Thomas Fischer, MD, of Otto-von-Guericke-University Magdeburg (Germany), highlighted three don’t-miss sessions.

In an analysis of a large cohort of FLT3-ITD mutated AML patients in the RATIFY trial, researchers looked at the prognostic impact of ITD insertion site.

“Interestingly, in this large cohort of 452 FLT3-ITD mutated AML, the negative prognostic impact of beta1-sheet insertion site of FLT3-ITD could be confirmed,” Dr. Fischer said. “Further analysis of a potential predictive effect on outcome of midostaurin treatment is ongoing and will be very interesting.”

The findings will be presented at 5 p.m. PT on Sunday, Dec. 2 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 435).

Another notable presentation features results from the phase 2 RADIUS trial, a randomized study comparing standard of care, with and without midostaurin, after allogeneic stem cell transplant in FLT3-ITD–mutated AML.

“Here, efficacy and toxicity of midostaurin was investigated in a [minimal residual disease] situation post-alloSCT,” Dr. Fischer said. “Interestingly, adding midostaurin to standard of care reduced the risk of relapse at 18 months post-alloSCT by 46%.”

The complete findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 662).

Dr. Fischer singled out another study looking at the efficacy and safety of single-agent quizartinib in patients with FLT3-ITD mutated AML. In this large, randomized trial the researchers noted a significant improvement in CR rates and survival benefit with the single agent FLT3 inhibitors, compared with salvage chemotherapy for patients with relapsed/refractory mutated AML.

The findings will be presented at 8 a.m. on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 563).
 

Notable posters

Courtesy Baylor College of Medicine

Iberia Romina Sosa, MD, PhD, of Baylor College of Medicine in Houston, suggested several posters worth visiting in the areas of thrombosis and bleeding.

Poster 1134 looks at the TNF-alpha driven inflammation and mitochondrial dysfunction in the platelet hyperreactivity of aging and MPN.

How do you know if your therapy for thrombotic thrombocytopenic purpura is working? Poster 3736 examines the measurement of cell-derived microparticles as a possible tool to monitor response to therapy.

You don’t have to be taking aspirin to have a bleeding profile characteristic with consumption of a cyclooxygenase inhibitor. Poster 1156 provides a first report of a platelet function disorder caused by autosomal recessive inheritance of PTGS1.

Poster 2477 takes a closer look at fitusiran, an antithrombin inhibitor, which improves thrombin generation in patients with hemophilia A or B. Protocol amendments for safety monitoring move fitusiran to phase 3 trials, Dr. Sosa said.

mschneider@mdedge.com

With more than 3,000 scientific abstracts at the 2018 annual meeting of the American Society of Hematology, it can be tough to figure out what research is most relevant to practice. But the editorial advisory board of Hematology News is making it easier this year with their picks for what to watch and why.

Lymphomas

Brian T. Hill, MD, of the Cleveland Clinic, offered his top picks in lymphoma research. Results of the phase 3 international Alliance North American Intergroup Study A041202 will be presented during the ASH plenary session at 2 p.m. PT on Sunday, Dec. 2 in Hall AB of the San Diego Convention Center (Abstract 6). The study compared bendamustine plus rituximab with ibrutinib and the combination of ibrutinib plus rituximab to see if the ibrutinib-containing therapies would have superior progression-free survival (PFS) in chronic lymphocytic leukemia (CLL), compared with chemoimmunotherapy. Results indicate that ibrutinib had superior PFS in older patients with CLL and could be a standard of care in this population.

The study is worth watching because it is the first report of a head-to-head trial of chemotherapy versus ibrutinib for first-line treatment of CLL, Dr. Hill said.

Two more studies offer important reports of “real world” experiences with chimeric antigen receptor (CAR) T-cell therapy.

In one multicenter retrospective study, researchers evaluated the outcomes of axicabtagene ciloleucel (axi-cel) CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma when it is used a standard care. The researchers will report that 30-day responses in the real-world setting were comparable to the best responses seen in the ZUMA-1 trial. The full results will be reported at 9:30 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 91).

Another retrospective analysis looked at the use of axi-cell and revealed some critical differences from ZUMA-1, specifically the overall response rate (ORR) and complete response (CR) rate were lower than those reported in the pivotal clinical trial. The findings will be reported at 9:45 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 92).

Researchers will also present the unblinded results from the ECHELON-2 study, which compared the efficacy and safety of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) versus standard CHOP for the treatment of patients with peripheral T-cell lymphoma. The results will be presented at 6:15 p.m. PT on Monday, Dec. 3 in room 6F of the San Diego convention center (Abstract 997).

Previously reported blinded pooled data showed that the treatment was well tolerated with 3-year PFS of 53% and OS of 73%.

“This should be a new standard of care for T-cell lymphomas,” Dr. Hill said.
 

CAR T-cell therapy

There are a number of abstracts featuring the latest results on CAR T-cell therapy. Helen Heslop, MD, of Baylor College of Medicine, Houston, recommended an updated analysis from the ELIANA study, which looked at the efficacy and safety of tisagenlecleucel in for children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

“Longer-term follow-up of the ELIANA study shows encouraging remission-duration data in pediatric and young adults with ALL without additional therapy,” Dr. Heslop said.

The findings will be presented at 4:30 p.m. PT on Monday, Dec. 3 in room 6A at the San Diego Convention Center (Abstract 895).

Another notable presentation will feature results from a phase 1B/2 trial evaluating infusion of CAR T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) after lymphodepleting chemotherapy in patients with relapsed or refractory CD30+ Hodgkin lymphoma and non-Hodgkin lymphoma.

The researchers will report that there was a significant PFS advances for who received the highest dose level of the CAR T treatment, combined with bendamustine and fludarabine.

The study will be presented at 11 a.m. PT on Monday, Dec. 3 in room 6F at the San Diego Convention Center (Abstract 681).

Dr. Heslop also recommends another study being presented in the same session, which also shows encouraging results with CD30.CAR-Ts. Dr. Heslop is one of the co-investigators on the phase 1 RELY-30 trial, which is evaluating the efficacy of CD30.CAR-Ts after lymphodepleting chemotherapy. Preliminary results suggest a substantial improvement in efficacy. The findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in room 6F of the San Diego Convention Center (Abstract 680).
 

MDS/MPN

Vikas Gupta, MD, of Princess Margaret Cancer Center in Toronto, highlighted three abstracts to watch in the areas of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN).

The phase 3 Medalist trial is a randomized double-blind placebo controlled study of luspatercept to treatment anemia in patients with MDS with ring sideroblasts who require red blood cell transfusion. The researchers will report significantly reduced transfusion burdens for luspatercept, compared with placebo.

“This is a practice-changing, pivotal trial in the field of MDS for the treatment of anemia,” Dr. Gupta said.

The findings will be presented at 2 p.m. PT on Sunday, Dec. 2 during the plenary session in Hall AB in the San Diego Convention Center (Abstract 1).

Also during the Sunday plenary session is a presentation on MPN therapy (Abstract 4). Researchers will present data on secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor (TpoR) activation, specifically in CALR-mutated cells.

“This study investigates in to the mechanistic oncogenetic aspects of mutant calreticulin, and has potential for therapeutic approaches in the future,” Dr. Gupta said.

The ASH meeting will also feature the final analysis of the MPN-RC 112 consortium trial of pegylated interferon alfa-2a versus hydroxyurea for the treatment of high-risk polycythemia vera (PV) and essential thrombocythemia (ET). The researchers will report that the CR rates at 12 and 24 months were similar in patients treated with pegylated interferon alfa-2a and hydroxyurea, but pegylated interferon alfa-2a was associated with a higher rate of serious toxicities.

“There is a continuous debate on optimal first-line cytoreductive therapy for high risk PV/ET, and this is one of the first randomized study to answer this question,” Dr. Gupta said.

The findings will be presented at 7 a.m. PT on Monday, Dec. 3 in Grand Hall D at the Manchester Grand Hyatt San Diego (Abstract 577).
 

AML

For attendees interested in the latest developments in acute myeloid leukemia, Thomas Fischer, MD, of Otto-von-Guericke-University Magdeburg (Germany), highlighted three don’t-miss sessions.

In an analysis of a large cohort of FLT3-ITD mutated AML patients in the RATIFY trial, researchers looked at the prognostic impact of ITD insertion site.

“Interestingly, in this large cohort of 452 FLT3-ITD mutated AML, the negative prognostic impact of beta1-sheet insertion site of FLT3-ITD could be confirmed,” Dr. Fischer said. “Further analysis of a potential predictive effect on outcome of midostaurin treatment is ongoing and will be very interesting.”

The findings will be presented at 5 p.m. PT on Sunday, Dec. 2 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 435).

Another notable presentation features results from the phase 2 RADIUS trial, a randomized study comparing standard of care, with and without midostaurin, after allogeneic stem cell transplant in FLT3-ITD–mutated AML.

“Here, efficacy and toxicity of midostaurin was investigated in a [minimal residual disease] situation post-alloSCT,” Dr. Fischer said. “Interestingly, adding midostaurin to standard of care reduced the risk of relapse at 18 months post-alloSCT by 46%.”

The complete findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 662).

Dr. Fischer singled out another study looking at the efficacy and safety of single-agent quizartinib in patients with FLT3-ITD mutated AML. In this large, randomized trial the researchers noted a significant improvement in CR rates and survival benefit with the single agent FLT3 inhibitors, compared with salvage chemotherapy for patients with relapsed/refractory mutated AML.

The findings will be presented at 8 a.m. on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 563).
 

Notable posters

Courtesy Baylor College of Medicine

Iberia Romina Sosa, MD, PhD, of Baylor College of Medicine in Houston, suggested several posters worth visiting in the areas of thrombosis and bleeding.

Poster 1134 looks at the TNF-alpha driven inflammation and mitochondrial dysfunction in the platelet hyperreactivity of aging and MPN.

How do you know if your therapy for thrombotic thrombocytopenic purpura is working? Poster 3736 examines the measurement of cell-derived microparticles as a possible tool to monitor response to therapy.

You don’t have to be taking aspirin to have a bleeding profile characteristic with consumption of a cyclooxygenase inhibitor. Poster 1156 provides a first report of a platelet function disorder caused by autosomal recessive inheritance of PTGS1.

Poster 2477 takes a closer look at fitusiran, an antithrombin inhibitor, which improves thrombin generation in patients with hemophilia A or B. Protocol amendments for safety monitoring move fitusiran to phase 3 trials, Dr. Sosa said.

mschneider@mdedge.com

With more than 3,000 scientific abstracts at the 2018 annual meeting of the American Society of Hematology, it can be tough to figure out what research is most relevant to practice. But the editorial advisory board of Hematology News is making it easier this year with their picks for what to watch and why.

Lymphomas

Brian T. Hill, MD, of the Cleveland Clinic, offered his top picks in lymphoma research. Results of the phase 3 international Alliance North American Intergroup Study A041202 will be presented during the ASH plenary session at 2 p.m. PT on Sunday, Dec. 2 in Hall AB of the San Diego Convention Center (Abstract 6). The study compared bendamustine plus rituximab with ibrutinib and the combination of ibrutinib plus rituximab to see if the ibrutinib-containing therapies would have superior progression-free survival (PFS) in chronic lymphocytic leukemia (CLL), compared with chemoimmunotherapy. Results indicate that ibrutinib had superior PFS in older patients with CLL and could be a standard of care in this population.

The study is worth watching because it is the first report of a head-to-head trial of chemotherapy versus ibrutinib for first-line treatment of CLL, Dr. Hill said.

Two more studies offer important reports of “real world” experiences with chimeric antigen receptor (CAR) T-cell therapy.

In one multicenter retrospective study, researchers evaluated the outcomes of axicabtagene ciloleucel (axi-cel) CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma when it is used a standard care. The researchers will report that 30-day responses in the real-world setting were comparable to the best responses seen in the ZUMA-1 trial. The full results will be reported at 9:30 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 91).

Another retrospective analysis looked at the use of axi-cell and revealed some critical differences from ZUMA-1, specifically the overall response rate (ORR) and complete response (CR) rate were lower than those reported in the pivotal clinical trial. The findings will be reported at 9:45 a.m. PT on Saturday, Dec. 1 in Pacific Ballroom 20 of the Marriott Marquis San Diego Marina (Abstract 92).

Researchers will also present the unblinded results from the ECHELON-2 study, which compared the efficacy and safety of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) versus standard CHOP for the treatment of patients with peripheral T-cell lymphoma. The results will be presented at 6:15 p.m. PT on Monday, Dec. 3 in room 6F of the San Diego convention center (Abstract 997).

Previously reported blinded pooled data showed that the treatment was well tolerated with 3-year PFS of 53% and OS of 73%.

“This should be a new standard of care for T-cell lymphomas,” Dr. Hill said.
 

CAR T-cell therapy

There are a number of abstracts featuring the latest results on CAR T-cell therapy. Helen Heslop, MD, of Baylor College of Medicine, Houston, recommended an updated analysis from the ELIANA study, which looked at the efficacy and safety of tisagenlecleucel in for children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL).

“Longer-term follow-up of the ELIANA study shows encouraging remission-duration data in pediatric and young adults with ALL without additional therapy,” Dr. Heslop said.

The findings will be presented at 4:30 p.m. PT on Monday, Dec. 3 in room 6A at the San Diego Convention Center (Abstract 895).

Another notable presentation will feature results from a phase 1B/2 trial evaluating infusion of CAR T cells targeting the CD30 molecule and encoding the CD28 endodomain (CD30.CAR-Ts) after lymphodepleting chemotherapy in patients with relapsed or refractory CD30+ Hodgkin lymphoma and non-Hodgkin lymphoma.

The researchers will report that there was a significant PFS advances for who received the highest dose level of the CAR T treatment, combined with bendamustine and fludarabine.

The study will be presented at 11 a.m. PT on Monday, Dec. 3 in room 6F at the San Diego Convention Center (Abstract 681).

Dr. Heslop also recommends another study being presented in the same session, which also shows encouraging results with CD30.CAR-Ts. Dr. Heslop is one of the co-investigators on the phase 1 RELY-30 trial, which is evaluating the efficacy of CD30.CAR-Ts after lymphodepleting chemotherapy. Preliminary results suggest a substantial improvement in efficacy. The findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in room 6F of the San Diego Convention Center (Abstract 680).
 

MDS/MPN

Vikas Gupta, MD, of Princess Margaret Cancer Center in Toronto, highlighted three abstracts to watch in the areas of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN).

The phase 3 Medalist trial is a randomized double-blind placebo controlled study of luspatercept to treatment anemia in patients with MDS with ring sideroblasts who require red blood cell transfusion. The researchers will report significantly reduced transfusion burdens for luspatercept, compared with placebo.

“This is a practice-changing, pivotal trial in the field of MDS for the treatment of anemia,” Dr. Gupta said.

The findings will be presented at 2 p.m. PT on Sunday, Dec. 2 during the plenary session in Hall AB in the San Diego Convention Center (Abstract 1).

Also during the Sunday plenary session is a presentation on MPN therapy (Abstract 4). Researchers will present data on secreted mutant calreticulins as rogue cytokines trigger thrombopoietin receptor (TpoR) activation, specifically in CALR-mutated cells.

“This study investigates in to the mechanistic oncogenetic aspects of mutant calreticulin, and has potential for therapeutic approaches in the future,” Dr. Gupta said.

The ASH meeting will also feature the final analysis of the MPN-RC 112 consortium trial of pegylated interferon alfa-2a versus hydroxyurea for the treatment of high-risk polycythemia vera (PV) and essential thrombocythemia (ET). The researchers will report that the CR rates at 12 and 24 months were similar in patients treated with pegylated interferon alfa-2a and hydroxyurea, but pegylated interferon alfa-2a was associated with a higher rate of serious toxicities.

“There is a continuous debate on optimal first-line cytoreductive therapy for high risk PV/ET, and this is one of the first randomized study to answer this question,” Dr. Gupta said.

The findings will be presented at 7 a.m. PT on Monday, Dec. 3 in Grand Hall D at the Manchester Grand Hyatt San Diego (Abstract 577).
 

AML

For attendees interested in the latest developments in acute myeloid leukemia, Thomas Fischer, MD, of Otto-von-Guericke-University Magdeburg (Germany), highlighted three don’t-miss sessions.

In an analysis of a large cohort of FLT3-ITD mutated AML patients in the RATIFY trial, researchers looked at the prognostic impact of ITD insertion site.

“Interestingly, in this large cohort of 452 FLT3-ITD mutated AML, the negative prognostic impact of beta1-sheet insertion site of FLT3-ITD could be confirmed,” Dr. Fischer said. “Further analysis of a potential predictive effect on outcome of midostaurin treatment is ongoing and will be very interesting.”

The findings will be presented at 5 p.m. PT on Sunday, Dec. 2 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 435).

Another notable presentation features results from the phase 2 RADIUS trial, a randomized study comparing standard of care, with and without midostaurin, after allogeneic stem cell transplant in FLT3-ITD–mutated AML.

“Here, efficacy and toxicity of midostaurin was investigated in a [minimal residual disease] situation post-alloSCT,” Dr. Fischer said. “Interestingly, adding midostaurin to standard of care reduced the risk of relapse at 18 months post-alloSCT by 46%.”

The complete findings will be presented at 10:45 a.m. PT on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 662).

Dr. Fischer singled out another study looking at the efficacy and safety of single-agent quizartinib in patients with FLT3-ITD mutated AML. In this large, randomized trial the researchers noted a significant improvement in CR rates and survival benefit with the single agent FLT3 inhibitors, compared with salvage chemotherapy for patients with relapsed/refractory mutated AML.

The findings will be presented at 8 a.m. on Monday, Dec. 3 in Seaport Ballroom F at the Manchester Grand Hyatt San Diego (Abstract 563).
 

Notable posters

Courtesy Baylor College of Medicine

Iberia Romina Sosa, MD, PhD, of Baylor College of Medicine in Houston, suggested several posters worth visiting in the areas of thrombosis and bleeding.

Poster 1134 looks at the TNF-alpha driven inflammation and mitochondrial dysfunction in the platelet hyperreactivity of aging and MPN.

How do you know if your therapy for thrombotic thrombocytopenic purpura is working? Poster 3736 examines the measurement of cell-derived microparticles as a possible tool to monitor response to therapy.

You don’t have to be taking aspirin to have a bleeding profile characteristic with consumption of a cyclooxygenase inhibitor. Poster 1156 provides a first report of a platelet function disorder caused by autosomal recessive inheritance of PTGS1.

Poster 2477 takes a closer look at fitusiran, an antithrombin inhibitor, which improves thrombin generation in patients with hemophilia A or B. Protocol amendments for safety monitoring move fitusiran to phase 3 trials, Dr. Sosa said.

mschneider@mdedge.com

The Food and Drug Administration has approved emapalumab-lzsg (Gamifant) to treat primary hemophagocytic lymphohistiocytosis (HLH).

Emapalumab, an interferon gamma-blocking antibody, is approved to treat patients of all ages (newborn and older) with primary HLH who have refractory, recurrent, or progressive disease or who cannot tolerate conventional HLH therapy. Emapalumab is the first treatment to be FDA approved for primary HLH, and it is expected to be available in the United States in the first quarter of 2019. The FDA previously granted emapalumab priority review, breakthrough therapy designation, orphan drug designation, and rare pediatric disease designation. The FDA’s approval of emapalumab is based on results from a phase 2/3 trial (NCT01818492).

The trial included 34 patients, 27 of whom had refractory, recurrent, or progressive disease or could not tolerate conventional HLH therapy. Patients received emapalumab in combination with dexamethasone. At the end of treatment, 63% (17/27) of patients had achieved a response, which was defined as complete response (n = 7), partial response (n=8), or HLH improvement (n = 2). A total of 70% (n=19) of patients went on to hematopoietic stem cell transplant. The most common adverse events were infections (56%), hypertension (41%), infusion-related reactions (27%), and pyrexia (24%).

Results also are scheduled to be presented at the 2018 annual meeting of the American Society of Hematology in the late-breaker abstract session (Abstract LBA-6).

Emapalumab was developed by Novimmune SA. Sobi acquired global rights to the drug in August 2018.

jensmith@mdedge.com

The Food and Drug Administration has approved emapalumab-lzsg (Gamifant) to treat primary hemophagocytic lymphohistiocytosis (HLH).

Emapalumab, an interferon gamma-blocking antibody, is approved to treat patients of all ages (newborn and older) with primary HLH who have refractory, recurrent, or progressive disease or who cannot tolerate conventional HLH therapy. Emapalumab is the first treatment to be FDA approved for primary HLH, and it is expected to be available in the United States in the first quarter of 2019. The FDA previously granted emapalumab priority review, breakthrough therapy designation, orphan drug designation, and rare pediatric disease designation. The FDA’s approval of emapalumab is based on results from a phase 2/3 trial (NCT01818492).

The trial included 34 patients, 27 of whom had refractory, recurrent, or progressive disease or could not tolerate conventional HLH therapy. Patients received emapalumab in combination with dexamethasone. At the end of treatment, 63% (17/27) of patients had achieved a response, which was defined as complete response (n = 7), partial response (n=8), or HLH improvement (n = 2). A total of 70% (n=19) of patients went on to hematopoietic stem cell transplant. The most common adverse events were infections (56%), hypertension (41%), infusion-related reactions (27%), and pyrexia (24%).

Results also are scheduled to be presented at the 2018 annual meeting of the American Society of Hematology in the late-breaker abstract session (Abstract LBA-6).

Emapalumab was developed by Novimmune SA. Sobi acquired global rights to the drug in August 2018.

jensmith@mdedge.com

The Food and Drug Administration has approved emapalumab-lzsg (Gamifant) to treat primary hemophagocytic lymphohistiocytosis (HLH).

Emapalumab, an interferon gamma-blocking antibody, is approved to treat patients of all ages (newborn and older) with primary HLH who have refractory, recurrent, or progressive disease or who cannot tolerate conventional HLH therapy. Emapalumab is the first treatment to be FDA approved for primary HLH, and it is expected to be available in the United States in the first quarter of 2019. The FDA previously granted emapalumab priority review, breakthrough therapy designation, orphan drug designation, and rare pediatric disease designation. The FDA’s approval of emapalumab is based on results from a phase 2/3 trial (NCT01818492).

The trial included 34 patients, 27 of whom had refractory, recurrent, or progressive disease or could not tolerate conventional HLH therapy. Patients received emapalumab in combination with dexamethasone. At the end of treatment, 63% (17/27) of patients had achieved a response, which was defined as complete response (n = 7), partial response (n=8), or HLH improvement (n = 2). A total of 70% (n=19) of patients went on to hematopoietic stem cell transplant. The most common adverse events were infections (56%), hypertension (41%), infusion-related reactions (27%), and pyrexia (24%).

Results also are scheduled to be presented at the 2018 annual meeting of the American Society of Hematology in the late-breaker abstract session (Abstract LBA-6).

Emapalumab was developed by Novimmune SA. Sobi acquired global rights to the drug in August 2018.

jensmith@mdedge.com

Micrograph showing MDS

The U.S. Food and Drug Administration has approved Lupin’s decitabine product, a generic version of Otsuka Pharmaceutical Co. Ltd.’s Dacogen, to treat patients with myelodysplastic syndromes (MDS).

Lupin’s decitabine for injection (50 mg, single-dose vial) is approved to treat patients with intermediate-1, intermediate-2, and high-risk MDS.

This includes previously treated, untreated, de novo, and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

Micrograph showing MDS

The U.S. Food and Drug Administration has approved Lupin’s decitabine product, a generic version of Otsuka Pharmaceutical Co. Ltd.’s Dacogen, to treat patients with myelodysplastic syndromes (MDS).

Lupin’s decitabine for injection (50 mg, single-dose vial) is approved to treat patients with intermediate-1, intermediate-2, and high-risk MDS.

This includes previously treated, untreated, de novo, and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

Micrograph showing MDS

The U.S. Food and Drug Administration has approved Lupin’s decitabine product, a generic version of Otsuka Pharmaceutical Co. Ltd.’s Dacogen, to treat patients with myelodysplastic syndromes (MDS).

Lupin’s decitabine for injection (50 mg, single-dose vial) is approved to treat patients with intermediate-1, intermediate-2, and high-risk MDS.

This includes previously treated, untreated, de novo, and secondary MDS of all French-American-British subtypes—refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

Photo by Petr Kratochvil

An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.

Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.

Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.

These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.

The report is based on data from the Truven Health MarketScan commercial claims databases.

The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:

• 1,468 patients with lymphoma
• 286 with chronic leukemia
• 282 with multiple myeloma
• 148 with acute leukemia
• 148 with bone marrow disorders (myelodysplastic syndromes).

The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:

• $156,845 overall
• $463,414 for acute leukemia
• $213,879 for multiple myeloma
• $133,744 for bone marrow disorders
• $130,545 for lymphoma
• $88,913 for chronic leukemia.

Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.

Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:

• $3,877 overall
• $5,147 for acute leukemia
• $4,849 for multiple myeloma
• $3,695 for lymphoma
• $3,480 for chronic leukemia
• $3,336 for bone marrow disorders.

Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.

The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.

The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.

The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.

Photo by Petr Kratochvil

An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.

Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.

Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.

These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.

The report is based on data from the Truven Health MarketScan commercial claims databases.

The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:

• 1,468 patients with lymphoma
• 286 with chronic leukemia
• 282 with multiple myeloma
• 148 with acute leukemia
• 148 with bone marrow disorders (myelodysplastic syndromes).

The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:

• $156,845 overall
• $463,414 for acute leukemia
• $213,879 for multiple myeloma
• $133,744 for bone marrow disorders
• $130,545 for lymphoma
• $88,913 for chronic leukemia.

Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.

Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:

• $3,877 overall
• $5,147 for acute leukemia
• $4,849 for multiple myeloma
• $3,695 for lymphoma
• $3,480 for chronic leukemia
• $3,336 for bone marrow disorders.

Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.

The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.

The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.

The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.

Photo by Petr Kratochvil

An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.

Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.

Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.

These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.

The report is based on data from the Truven Health MarketScan commercial claims databases.

The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:

• 1,468 patients with lymphoma
• 286 with chronic leukemia
• 282 with multiple myeloma
• 148 with acute leukemia
• 148 with bone marrow disorders (myelodysplastic syndromes).

The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:

• $156,845 overall
• $463,414 for acute leukemia
• $213,879 for multiple myeloma
• $133,744 for bone marrow disorders
• $130,545 for lymphoma
• $88,913 for chronic leukemia.

Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.

Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:

• $3,877 overall
• $5,147 for acute leukemia
• $4,849 for multiple myeloma
• $3,695 for lymphoma
• $3,480 for chronic leukemia
• $3,336 for bone marrow disorders.

Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.

The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.

The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.

The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.

Photo courtesy of GSK

Results from the phase 3 SUPPORT trial suggest there is no role for the combination of eltrombopag and azacitidine in patients with intermediate- or high-risk myelodysplastic syndromes (MDS), according to investigators.

Adding eltrombopag to azacitidine worsened platelet recovery, reduced the overall response rate, and did not improve overall or progression-free survival when compared to azacitidine plus placebo.

Investigators had hypothesized that eltrombopag would reduce the thrombocytopenia exacerbated by azacitidine treatment.

Not only was this not the case, but the investigators observed a trend toward increased progression to acute myeloid leukemia (AML) in eltrombopag-treated patients.

An independent monitoring committee recommended the trial be terminated early.

Michael Dickinson, MBBS, of Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, and his colleagues reported results from the trial in Blood.

The investigators conducted the SUPPORT study (NCT02158936) to investigate the efficacy and safety of eltrombopag as platelet supportive care in patients with intermediate- to high-risk MDS and thrombocytopenia who were receiving azacitidine.

Study design

Investigators randomized patients 1:1 to eltrombopag or placebo in combination with azacitidine. Patients had to have at least one platelet count less than 75 x 10⁹/L within 28 days prior to the first azacitidine dose.

Patients received azacitidine subcutaneously at a dose of 75 mg/m² once daily on 7 consecutive days for 28 days.

Patients received eltrombopag or placebo at a starting dose of 200 mg/day (100 mg/day for East Asians), adjusted by 100 mg increments (50 mg increments for East Asians) to a maximum of 300 mg/day (150 mg/day for East Asians).

Patient disposition

Investigators enrolled 356 patients from 30 countries between June 2014 and December 2015, randomizing 179 patients to eltrombopag and 177 to placebo.

Patients were a median age of 70, 66% were male, 83% were white, and 47% had platelet counts between 20 and 50 x 10⁹/L.

At the start of the trial, 19% of patients (n=66) were platelet transfusion-dependent—16% (29/179) in the eltrombopag group and 21% (37/177) in the placebo group.

Treatment exposure

Patients received eltrombopag for a median of 83 days (range, 60 to 148) and placebo for a median of 149 days (range, 8 to 503).

For non-East Asian patients, the mean dose of eltrombopag was 205 mg/day (range, 65 to 293), and the mean dose of placebo was 245 mg/day (range, 107 to 316).

Sixty-eight patients (38%) in the eltrombopag arm received the recommended number of six or more azacitidine cycles, compared to 91 (51%) in the placebo arm.

Two patients in the eltrombopag arm did not receive treatment. Therefore, the safety analyses were conducted on the 177 treated patients in each arm.

Safety

The most common reason for treatment discontinuation was termination of the study. Thirty-two percent of patients in the eltrombopag cohort and 44% in the placebo cohort discontinued for this reason.

Patients had to discontinue eltrombopag or placebo if azacitidine was discontinued, and this occurred in 30% of patients in the eltrombopag group and 26% in the placebo group.

Twenty-two percent of eltrombopag-treated patients discontinued due to adverse events (AEs), compared with 14% in the placebo group.

The most common reasons for azacitidine discontinuation in the eltrombopag and placebo arms, respectively, were study termination (35% and 46%), AEs (25% and 19%), disease progression (15% and 14%), and patient decision (11% and 9%).

AEs with the greatest difference between the eltrombopag and placebo arms, respectively, were febrile neutropenia (31% and 21%), neutropenia (31% and 26%), nausea (31% and 26%), and diarrhea (25% and 14%).

Sixty-three of the 177 AEs in the eltrombopag group were suspected to be treatment-related, compared to 42 of 173 AEs in the placebo group.

One hundred twenty-eight (72%) serious AEs occurred in the eltrombopag arm, compared to 100 (56%) in the placebo arm.

Fifteen percent of the serious AEs were suspected to be related to eltrombopag treatment, compared to 4% of the serious AEs in the placebo group.

At the final analysis, 108 patients had died—57 (32%) in the eltrombopag group and 51 (29%) in the placebo group (hazard ratio [HR] 1.42; 95% CI 0.97, 2.08; nominal P=0.164).

The main causes of death were disease progression (28 in the eltrombopag group and 21 in the placebo group) and sepsis (18 in the eltrombopag group and 13 in the placebo group).

Efficacy

The study’s primary endpoint was the proportion of patients free of platelet transfusions during cycles one to four of azacitidine therapy.

At the final analysis, there were fewer patients in the eltrombopag arm than in the placebo arm who had achieved platelet transfusion independence—16% (28/179) and 31% (55/177), respectively. The odds ratio (OR) was 0.37 (95% CI 0.21, 0.65; two-sided P value=0.001).

Secondary efficacy endpoints included overall survival, disease response, duration of response, progression to AML, progression-free survival, and hematologic improvement.

The investigators pointed out that no formal statistical tests were performed for the secondary endpoints. Therefore, “statistical interpretation should be made with caution,” they wrote.

Overall response by IWG criteria occurred in 20% of patients in the eltrombopag group and 35% of those in the placebo group, according to investigator assessment (OR=0.51; 95% CI 0.30, 0.86; nominal P=0.005).

There was no significant difference in hematologic improvement, overall survival, or progression-free survival between the treatment arms.

The investigators found a higher rate of progression to AML in the eltrombopag arm than in the placebo arm—15% and 9%, respectively (OR=1.59; 95% CI 0.81, 3.14; nominal P=0.079).

They pointed out that these results contrasted with those of recent clinical studies of eltrombopag monotherapy^1,2,3,4 in patients with MDS.

“[T]he findings of this trial were unexpected,” the investigators wrote.

They hypothesized that eltrombopag inhibits the effects of azacitidine when the drugs are given concomitantly. The issue is being studied further with ongoing research, they said.

The authors acknowledged financial support for medical editorial assistance provided by Novartis Pharmaceuticals Corporation.

Dr. Dickinson disclosed relationships with Celgene, Novartis, Janssen, Pfizer, and Roche. Senior study author Uwe Platzbecker, MD, disclosed relationships with Amgen, Celgene, GlaxoSmithKline, and Novartis.

1. Platzbecker U, et al Lancet Haematol. 2015;2(10):e417-e426. DOI: https://doi.org/10.1016/S2352-3026(15)00149-0

2. Oliva EN, et al. Lancet Haematol. 2017;4(3):e127-e136. DOI: https://doi.org/10.1016/S2352-3026(17)30012-1

3. Mittelman M, et al. Lancet Haematol. 2017;5(1):e34-e43. DOI: https://doi.org/10.1016/S2352-3026(17)30228-4

4. Buckstein R. Lancet Haematol. 2015;2(10):e396-e397. DOI: https://doi.org/10.1016/S2352-3026(15)00200-8

Photo courtesy of GSK

Results from the phase 3 SUPPORT trial suggest there is no role for the combination of eltrombopag and azacitidine in patients with intermediate- or high-risk myelodysplastic syndromes (MDS), according to investigators.

Adding eltrombopag to azacitidine worsened platelet recovery, reduced the overall response rate, and did not improve overall or progression-free survival when compared to azacitidine plus placebo.

Investigators had hypothesized that eltrombopag would reduce the thrombocytopenia exacerbated by azacitidine treatment.

Not only was this not the case, but the investigators observed a trend toward increased progression to acute myeloid leukemia (AML) in eltrombopag-treated patients.

An independent monitoring committee recommended the trial be terminated early.

Michael Dickinson, MBBS, of Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, and his colleagues reported results from the trial in Blood.

The investigators conducted the SUPPORT study (NCT02158936) to investigate the efficacy and safety of eltrombopag as platelet supportive care in patients with intermediate- to high-risk MDS and thrombocytopenia who were receiving azacitidine.

Study design

Investigators randomized patients 1:1 to eltrombopag or placebo in combination with azacitidine. Patients had to have at least one platelet count less than 75 x 10⁹/L within 28 days prior to the first azacitidine dose.

Patients received azacitidine subcutaneously at a dose of 75 mg/m² once daily on 7 consecutive days for 28 days.

Patients received eltrombopag or placebo at a starting dose of 200 mg/day (100 mg/day for East Asians), adjusted by 100 mg increments (50 mg increments for East Asians) to a maximum of 300 mg/day (150 mg/day for East Asians).

Patient disposition

Investigators enrolled 356 patients from 30 countries between June 2014 and December 2015, randomizing 179 patients to eltrombopag and 177 to placebo.

Patients were a median age of 70, 66% were male, 83% were white, and 47% had platelet counts between 20 and 50 x 10⁹/L.

At the start of the trial, 19% of patients (n=66) were platelet transfusion-dependent—16% (29/179) in the eltrombopag group and 21% (37/177) in the placebo group.

Treatment exposure

Patients received eltrombopag for a median of 83 days (range, 60 to 148) and placebo for a median of 149 days (range, 8 to 503).

For non-East Asian patients, the mean dose of eltrombopag was 205 mg/day (range, 65 to 293), and the mean dose of placebo was 245 mg/day (range, 107 to 316).

Sixty-eight patients (38%) in the eltrombopag arm received the recommended number of six or more azacitidine cycles, compared to 91 (51%) in the placebo arm.

Two patients in the eltrombopag arm did not receive treatment. Therefore, the safety analyses were conducted on the 177 treated patients in each arm.

Safety

The most common reason for treatment discontinuation was termination of the study. Thirty-two percent of patients in the eltrombopag cohort and 44% in the placebo cohort discontinued for this reason.

Patients had to discontinue eltrombopag or placebo if azacitidine was discontinued, and this occurred in 30% of patients in the eltrombopag group and 26% in the placebo group.

Twenty-two percent of eltrombopag-treated patients discontinued due to adverse events (AEs), compared with 14% in the placebo group.

The most common reasons for azacitidine discontinuation in the eltrombopag and placebo arms, respectively, were study termination (35% and 46%), AEs (25% and 19%), disease progression (15% and 14%), and patient decision (11% and 9%).

AEs with the greatest difference between the eltrombopag and placebo arms, respectively, were febrile neutropenia (31% and 21%), neutropenia (31% and 26%), nausea (31% and 26%), and diarrhea (25% and 14%).

Sixty-three of the 177 AEs in the eltrombopag group were suspected to be treatment-related, compared to 42 of 173 AEs in the placebo group.

One hundred twenty-eight (72%) serious AEs occurred in the eltrombopag arm, compared to 100 (56%) in the placebo arm.

Fifteen percent of the serious AEs were suspected to be related to eltrombopag treatment, compared to 4% of the serious AEs in the placebo group.

At the final analysis, 108 patients had died—57 (32%) in the eltrombopag group and 51 (29%) in the placebo group (hazard ratio [HR] 1.42; 95% CI 0.97, 2.08; nominal P=0.164).

The main causes of death were disease progression (28 in the eltrombopag group and 21 in the placebo group) and sepsis (18 in the eltrombopag group and 13 in the placebo group).

Efficacy

The study’s primary endpoint was the proportion of patients free of platelet transfusions during cycles one to four of azacitidine therapy.

At the final analysis, there were fewer patients in the eltrombopag arm than in the placebo arm who had achieved platelet transfusion independence—16% (28/179) and 31% (55/177), respectively. The odds ratio (OR) was 0.37 (95% CI 0.21, 0.65; two-sided P value=0.001).

Secondary efficacy endpoints included overall survival, disease response, duration of response, progression to AML, progression-free survival, and hematologic improvement.

The investigators pointed out that no formal statistical tests were performed for the secondary endpoints. Therefore, “statistical interpretation should be made with caution,” they wrote.

Overall response by IWG criteria occurred in 20% of patients in the eltrombopag group and 35% of those in the placebo group, according to investigator assessment (OR=0.51; 95% CI 0.30, 0.86; nominal P=0.005).

There was no significant difference in hematologic improvement, overall survival, or progression-free survival between the treatment arms.

The investigators found a higher rate of progression to AML in the eltrombopag arm than in the placebo arm—15% and 9%, respectively (OR=1.59; 95% CI 0.81, 3.14; nominal P=0.079).

They pointed out that these results contrasted with those of recent clinical studies of eltrombopag monotherapy^1,2,3,4 in patients with MDS.

“[T]he findings of this trial were unexpected,” the investigators wrote.

They hypothesized that eltrombopag inhibits the effects of azacitidine when the drugs are given concomitantly. The issue is being studied further with ongoing research, they said.

The authors acknowledged financial support for medical editorial assistance provided by Novartis Pharmaceuticals Corporation.

Dr. Dickinson disclosed relationships with Celgene, Novartis, Janssen, Pfizer, and Roche. Senior study author Uwe Platzbecker, MD, disclosed relationships with Amgen, Celgene, GlaxoSmithKline, and Novartis.

1. Platzbecker U, et al Lancet Haematol. 2015;2(10):e417-e426. DOI: https://doi.org/10.1016/S2352-3026(15)00149-0

2. Oliva EN, et al. Lancet Haematol. 2017;4(3):e127-e136. DOI: https://doi.org/10.1016/S2352-3026(17)30012-1

3. Mittelman M, et al. Lancet Haematol. 2017;5(1):e34-e43. DOI: https://doi.org/10.1016/S2352-3026(17)30228-4

4. Buckstein R. Lancet Haematol. 2015;2(10):e396-e397. DOI: https://doi.org/10.1016/S2352-3026(15)00200-8

Photo courtesy of GSK

Results from the phase 3 SUPPORT trial suggest there is no role for the combination of eltrombopag and azacitidine in patients with intermediate- or high-risk myelodysplastic syndromes (MDS), according to investigators.

Adding eltrombopag to azacitidine worsened platelet recovery, reduced the overall response rate, and did not improve overall or progression-free survival when compared to azacitidine plus placebo.

Investigators had hypothesized that eltrombopag would reduce the thrombocytopenia exacerbated by azacitidine treatment.

Not only was this not the case, but the investigators observed a trend toward increased progression to acute myeloid leukemia (AML) in eltrombopag-treated patients.

An independent monitoring committee recommended the trial be terminated early.

Michael Dickinson, MBBS, of Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, and his colleagues reported results from the trial in Blood.

The investigators conducted the SUPPORT study (NCT02158936) to investigate the efficacy and safety of eltrombopag as platelet supportive care in patients with intermediate- to high-risk MDS and thrombocytopenia who were receiving azacitidine.

Study design

Investigators randomized patients 1:1 to eltrombopag or placebo in combination with azacitidine. Patients had to have at least one platelet count less than 75 x 10⁹/L within 28 days prior to the first azacitidine dose.

Patients received azacitidine subcutaneously at a dose of 75 mg/m² once daily on 7 consecutive days for 28 days.

Patients received eltrombopag or placebo at a starting dose of 200 mg/day (100 mg/day for East Asians), adjusted by 100 mg increments (50 mg increments for East Asians) to a maximum of 300 mg/day (150 mg/day for East Asians).

Patient disposition

Investigators enrolled 356 patients from 30 countries between June 2014 and December 2015, randomizing 179 patients to eltrombopag and 177 to placebo.

Patients were a median age of 70, 66% were male, 83% were white, and 47% had platelet counts between 20 and 50 x 10⁹/L.

At the start of the trial, 19% of patients (n=66) were platelet transfusion-dependent—16% (29/179) in the eltrombopag group and 21% (37/177) in the placebo group.

Treatment exposure

Patients received eltrombopag for a median of 83 days (range, 60 to 148) and placebo for a median of 149 days (range, 8 to 503).

For non-East Asian patients, the mean dose of eltrombopag was 205 mg/day (range, 65 to 293), and the mean dose of placebo was 245 mg/day (range, 107 to 316).

Sixty-eight patients (38%) in the eltrombopag arm received the recommended number of six or more azacitidine cycles, compared to 91 (51%) in the placebo arm.

Two patients in the eltrombopag arm did not receive treatment. Therefore, the safety analyses were conducted on the 177 treated patients in each arm.

Safety

The most common reason for treatment discontinuation was termination of the study. Thirty-two percent of patients in the eltrombopag cohort and 44% in the placebo cohort discontinued for this reason.

Patients had to discontinue eltrombopag or placebo if azacitidine was discontinued, and this occurred in 30% of patients in the eltrombopag group and 26% in the placebo group.

Twenty-two percent of eltrombopag-treated patients discontinued due to adverse events (AEs), compared with 14% in the placebo group.

The most common reasons for azacitidine discontinuation in the eltrombopag and placebo arms, respectively, were study termination (35% and 46%), AEs (25% and 19%), disease progression (15% and 14%), and patient decision (11% and 9%).

AEs with the greatest difference between the eltrombopag and placebo arms, respectively, were febrile neutropenia (31% and 21%), neutropenia (31% and 26%), nausea (31% and 26%), and diarrhea (25% and 14%).

Sixty-three of the 177 AEs in the eltrombopag group were suspected to be treatment-related, compared to 42 of 173 AEs in the placebo group.

One hundred twenty-eight (72%) serious AEs occurred in the eltrombopag arm, compared to 100 (56%) in the placebo arm.

Fifteen percent of the serious AEs were suspected to be related to eltrombopag treatment, compared to 4% of the serious AEs in the placebo group.

At the final analysis, 108 patients had died—57 (32%) in the eltrombopag group and 51 (29%) in the placebo group (hazard ratio [HR] 1.42; 95% CI 0.97, 2.08; nominal P=0.164).

The main causes of death were disease progression (28 in the eltrombopag group and 21 in the placebo group) and sepsis (18 in the eltrombopag group and 13 in the placebo group).

Efficacy

The study’s primary endpoint was the proportion of patients free of platelet transfusions during cycles one to four of azacitidine therapy.

At the final analysis, there were fewer patients in the eltrombopag arm than in the placebo arm who had achieved platelet transfusion independence—16% (28/179) and 31% (55/177), respectively. The odds ratio (OR) was 0.37 (95% CI 0.21, 0.65; two-sided P value=0.001).

Secondary efficacy endpoints included overall survival, disease response, duration of response, progression to AML, progression-free survival, and hematologic improvement.

The investigators pointed out that no formal statistical tests were performed for the secondary endpoints. Therefore, “statistical interpretation should be made with caution,” they wrote.

Overall response by IWG criteria occurred in 20% of patients in the eltrombopag group and 35% of those in the placebo group, according to investigator assessment (OR=0.51; 95% CI 0.30, 0.86; nominal P=0.005).

There was no significant difference in hematologic improvement, overall survival, or progression-free survival between the treatment arms.

The investigators found a higher rate of progression to AML in the eltrombopag arm than in the placebo arm—15% and 9%, respectively (OR=1.59; 95% CI 0.81, 3.14; nominal P=0.079).

They pointed out that these results contrasted with those of recent clinical studies of eltrombopag monotherapy^1,2,3,4 in patients with MDS.

“[T]he findings of this trial were unexpected,” the investigators wrote.

They hypothesized that eltrombopag inhibits the effects of azacitidine when the drugs are given concomitantly. The issue is being studied further with ongoing research, they said.

The authors acknowledged financial support for medical editorial assistance provided by Novartis Pharmaceuticals Corporation.

Dr. Dickinson disclosed relationships with Celgene, Novartis, Janssen, Pfizer, and Roche. Senior study author Uwe Platzbecker, MD, disclosed relationships with Amgen, Celgene, GlaxoSmithKline, and Novartis.

1. Platzbecker U, et al Lancet Haematol. 2015;2(10):e417-e426. DOI: https://doi.org/10.1016/S2352-3026(15)00149-0

2. Oliva EN, et al. Lancet Haematol. 2017;4(3):e127-e136. DOI: https://doi.org/10.1016/S2352-3026(17)30012-1

3. Mittelman M, et al. Lancet Haematol. 2017;5(1):e34-e43. DOI: https://doi.org/10.1016/S2352-3026(17)30228-4

4. Buckstein R. Lancet Haematol. 2015;2(10):e396-e397. DOI: https://doi.org/10.1016/S2352-3026(15)00200-8

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

jensmith@mdedge.com
 

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

jensmith@mdedge.com
 

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

jensmith@mdedge.com