Leukemia, Myelodysplasia, Transplantation

Henrique Orlandi Mourao

Researchers say they have found ways to identify patients with a high risk of developing acute myeloid leukemia (AML).

The researchers used basic clinical and laboratory data to identify patients 6 to 12 months before AML presentation.

Using genetic information, the researchers were able to identify high-risk patients several years before AML presentation.

“This long time window gives us the first opportunity to think about how to prevent AML,” said John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

However, Dr Dick and his colleagues noted that neither the genetic method nor the clinical data method were entirely accurate in identifying patients who would develop AML.

The researchers described both methods in Nature.

The team’s work began with the goal of distinguishing patients who will develop AML from patients who simply develop age-related clonal hematopoiesis.

“We wanted to know if there was any difference between these 2 groups in the genetics of their ‘normal’ blood samples taken at enrollment,” Dr Dick said. “To find out, we developed a gene-sequencing tool that captured the most common genes that get altered in AML and sequenced all the 500 blood samples.”

The researchers analyzed samples from 95 patients who ultimately developed AML and 414 age- and gender-matched controls. The samples from AML patients were obtained an average of 6.3 years before AML diagnosis.

The researchers found that pre-AML cases had more mutations per sample, higher variant allele frequencies, and a higher frequency of certain mutations than controls. Specifically, pre-AML cases had a significantly greater frequency of DNMT3A, TET2, SRSF2, ASXL1, TP53, U2AF1, JAK2, RUNX1, and IDH2 mutations.

The researchers used these findings to develop a model for predicting AML. They tested the model in a validation cohort of 29 pre-AML cases and 262 controls, as well as in a cohort combining the validation and discovery cohorts. The model predicted AML development with 41.9% sensitivity and 95.7% specificity.

However, the researchers said widespread use of this model would not be practical because AML is so rare. The team said millions of people would need to undergo screening to identify a few pre-AML cases, and there would be “many” false-positives.

Therefore, the researchers developed a model using clinical information from electronic health records—particularly blood counts. This model was able to predict AML development 6 to 12 months before diagnosis with a sensitivity of 25.7% and specificity of 98.2%.

The researchers said these results suggest clinical data can be used to identify patients with a high risk of AML who may benefit from targeted genetic screening. And combining clinical and genetic information in a single model could improve predictive accuracy.

“Our study provides, for the first time, evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease,” said study author George Vassiliou, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that, one day, AML prevention would provide a compelling alternative to treatment.”

Henrique Orlandi Mourao

Researchers say they have found ways to identify patients with a high risk of developing acute myeloid leukemia (AML).

The researchers used basic clinical and laboratory data to identify patients 6 to 12 months before AML presentation.

Using genetic information, the researchers were able to identify high-risk patients several years before AML presentation.

“This long time window gives us the first opportunity to think about how to prevent AML,” said John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

However, Dr Dick and his colleagues noted that neither the genetic method nor the clinical data method were entirely accurate in identifying patients who would develop AML.

The researchers described both methods in Nature.

The team’s work began with the goal of distinguishing patients who will develop AML from patients who simply develop age-related clonal hematopoiesis.

“We wanted to know if there was any difference between these 2 groups in the genetics of their ‘normal’ blood samples taken at enrollment,” Dr Dick said. “To find out, we developed a gene-sequencing tool that captured the most common genes that get altered in AML and sequenced all the 500 blood samples.”

The researchers analyzed samples from 95 patients who ultimately developed AML and 414 age- and gender-matched controls. The samples from AML patients were obtained an average of 6.3 years before AML diagnosis.

The researchers found that pre-AML cases had more mutations per sample, higher variant allele frequencies, and a higher frequency of certain mutations than controls. Specifically, pre-AML cases had a significantly greater frequency of DNMT3A, TET2, SRSF2, ASXL1, TP53, U2AF1, JAK2, RUNX1, and IDH2 mutations.

The researchers used these findings to develop a model for predicting AML. They tested the model in a validation cohort of 29 pre-AML cases and 262 controls, as well as in a cohort combining the validation and discovery cohorts. The model predicted AML development with 41.9% sensitivity and 95.7% specificity.

However, the researchers said widespread use of this model would not be practical because AML is so rare. The team said millions of people would need to undergo screening to identify a few pre-AML cases, and there would be “many” false-positives.

Therefore, the researchers developed a model using clinical information from electronic health records—particularly blood counts. This model was able to predict AML development 6 to 12 months before diagnosis with a sensitivity of 25.7% and specificity of 98.2%.

The researchers said these results suggest clinical data can be used to identify patients with a high risk of AML who may benefit from targeted genetic screening. And combining clinical and genetic information in a single model could improve predictive accuracy.

“Our study provides, for the first time, evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease,” said study author George Vassiliou, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that, one day, AML prevention would provide a compelling alternative to treatment.”

Henrique Orlandi Mourao

Researchers say they have found ways to identify patients with a high risk of developing acute myeloid leukemia (AML).

The researchers used basic clinical and laboratory data to identify patients 6 to 12 months before AML presentation.

Using genetic information, the researchers were able to identify high-risk patients several years before AML presentation.

“This long time window gives us the first opportunity to think about how to prevent AML,” said John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

However, Dr Dick and his colleagues noted that neither the genetic method nor the clinical data method were entirely accurate in identifying patients who would develop AML.

The researchers described both methods in Nature.

The team’s work began with the goal of distinguishing patients who will develop AML from patients who simply develop age-related clonal hematopoiesis.

“We wanted to know if there was any difference between these 2 groups in the genetics of their ‘normal’ blood samples taken at enrollment,” Dr Dick said. “To find out, we developed a gene-sequencing tool that captured the most common genes that get altered in AML and sequenced all the 500 blood samples.”

The researchers analyzed samples from 95 patients who ultimately developed AML and 414 age- and gender-matched controls. The samples from AML patients were obtained an average of 6.3 years before AML diagnosis.

The researchers found that pre-AML cases had more mutations per sample, higher variant allele frequencies, and a higher frequency of certain mutations than controls. Specifically, pre-AML cases had a significantly greater frequency of DNMT3A, TET2, SRSF2, ASXL1, TP53, U2AF1, JAK2, RUNX1, and IDH2 mutations.

The researchers used these findings to develop a model for predicting AML. They tested the model in a validation cohort of 29 pre-AML cases and 262 controls, as well as in a cohort combining the validation and discovery cohorts. The model predicted AML development with 41.9% sensitivity and 95.7% specificity.

However, the researchers said widespread use of this model would not be practical because AML is so rare. The team said millions of people would need to undergo screening to identify a few pre-AML cases, and there would be “many” false-positives.

Therefore, the researchers developed a model using clinical information from electronic health records—particularly blood counts. This model was able to predict AML development 6 to 12 months before diagnosis with a sensitivity of 25.7% and specificity of 98.2%.

The researchers said these results suggest clinical data can be used to identify patients with a high risk of AML who may benefit from targeted genetic screening. And combining clinical and genetic information in a single model could improve predictive accuracy.

“Our study provides, for the first time, evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease,” said study author George Vassiliou, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that, one day, AML prevention would provide a compelling alternative to treatment.”

Photo courtesy of NIH

A group of experts has called for improvements in reporting adverse events (AEs) that occur in patients with hematologic malignancies.

The group highlighted deficiencies in capturing chronic, cumulative, and late AEs; collecting patient-reported outcomes (PROs); reporting AEs associated with hematopoietic stem cell transplant (HSCT); assessing long-term toxicity in survivors; reporting AEs to regulatory agencies; and tracking AEs that occur in routine clinical practice.

The experts discussed these problems and made recommendations for fixing them in The Lancet Haematology.

“The success in outcomes and survival in many hematological malignancies is historically unparalleled and fueled by scientific discovery and implementation,” said author Gita Thanarajasingam, MD, of the Mayo Clinic in Rochester, Minnesota.

“Patients are now living with the challenge of managing not just their hematological malignancy but also managing chronic therapy for their illness, with new types of acute, chronic, cumulative, and late toxicities. Measures to address the broad facets of toxicity assessment must be prioritized and further developed to ultimately enhance accurate, comprehensive, patient-centered toxicity reporting that will meaningfully inform the care of patients with blood cancers.”

Dr Thanarajasingam and a group of clinicians, investigators, regulators, biostatisticians, and patient advocates analyzed the evidence on AEs and proposed recommendations to policy makers, researchers, industry, and regulators.

First, the group noted that chronic, delayed, and cumulative AEs may go unreported in patients with hematologic malignancies. Therefore, longitudinal methods for AE analysis are needed, and phase 1 trials should have longer periods for evaluating dose-limiting toxicity.

The experts also said PROs are often overlooked, but it should be standard to assess PROs in clinical trials of patients with hematologic malignancies.

Another of the group’s concerns is the “cumbersome” reporting of AEs associated with HSCT acting as a barrier to clinical trials. The experts recommended using registry data to develop a consensus on expected AEs after HSCT.

The group also highlighted deficiencies in the “description and management” of cumulative and late toxicities in survivors of hematologic malignancies. Potential solutions to this problem include developing infrastructure to collect data for adult survivors and standardizing the use and content of survivorship care plans.

The experts said “meaningful” AEs are often underreported to regulatory agencies, so better systems are needed for collecting and analyzing AE data, and the electronic submission of AEs should be simplified.

Finally, the group said AEs occurring in routine clinical practice are difficult to capture and analyze on a large scale. This suggests a need to optimize the systematic, objective collection of toxicity data at multiple points in real-world databases, according to the experts.

Additional details and recommendations are available in the full report.

Photo courtesy of NIH

A group of experts has called for improvements in reporting adverse events (AEs) that occur in patients with hematologic malignancies.

The group highlighted deficiencies in capturing chronic, cumulative, and late AEs; collecting patient-reported outcomes (PROs); reporting AEs associated with hematopoietic stem cell transplant (HSCT); assessing long-term toxicity in survivors; reporting AEs to regulatory agencies; and tracking AEs that occur in routine clinical practice.

The experts discussed these problems and made recommendations for fixing them in The Lancet Haematology.

“The success in outcomes and survival in many hematological malignancies is historically unparalleled and fueled by scientific discovery and implementation,” said author Gita Thanarajasingam, MD, of the Mayo Clinic in Rochester, Minnesota.

“Patients are now living with the challenge of managing not just their hematological malignancy but also managing chronic therapy for their illness, with new types of acute, chronic, cumulative, and late toxicities. Measures to address the broad facets of toxicity assessment must be prioritized and further developed to ultimately enhance accurate, comprehensive, patient-centered toxicity reporting that will meaningfully inform the care of patients with blood cancers.”

Dr Thanarajasingam and a group of clinicians, investigators, regulators, biostatisticians, and patient advocates analyzed the evidence on AEs and proposed recommendations to policy makers, researchers, industry, and regulators.

First, the group noted that chronic, delayed, and cumulative AEs may go unreported in patients with hematologic malignancies. Therefore, longitudinal methods for AE analysis are needed, and phase 1 trials should have longer periods for evaluating dose-limiting toxicity.

The experts also said PROs are often overlooked, but it should be standard to assess PROs in clinical trials of patients with hematologic malignancies.

Another of the group’s concerns is the “cumbersome” reporting of AEs associated with HSCT acting as a barrier to clinical trials. The experts recommended using registry data to develop a consensus on expected AEs after HSCT.

The group also highlighted deficiencies in the “description and management” of cumulative and late toxicities in survivors of hematologic malignancies. Potential solutions to this problem include developing infrastructure to collect data for adult survivors and standardizing the use and content of survivorship care plans.

The experts said “meaningful” AEs are often underreported to regulatory agencies, so better systems are needed for collecting and analyzing AE data, and the electronic submission of AEs should be simplified.

Finally, the group said AEs occurring in routine clinical practice are difficult to capture and analyze on a large scale. This suggests a need to optimize the systematic, objective collection of toxicity data at multiple points in real-world databases, according to the experts.

Additional details and recommendations are available in the full report.

Photo courtesy of NIH

A group of experts has called for improvements in reporting adverse events (AEs) that occur in patients with hematologic malignancies.

The group highlighted deficiencies in capturing chronic, cumulative, and late AEs; collecting patient-reported outcomes (PROs); reporting AEs associated with hematopoietic stem cell transplant (HSCT); assessing long-term toxicity in survivors; reporting AEs to regulatory agencies; and tracking AEs that occur in routine clinical practice.

The experts discussed these problems and made recommendations for fixing them in The Lancet Haematology.

“The success in outcomes and survival in many hematological malignancies is historically unparalleled and fueled by scientific discovery and implementation,” said author Gita Thanarajasingam, MD, of the Mayo Clinic in Rochester, Minnesota.

“Patients are now living with the challenge of managing not just their hematological malignancy but also managing chronic therapy for their illness, with new types of acute, chronic, cumulative, and late toxicities. Measures to address the broad facets of toxicity assessment must be prioritized and further developed to ultimately enhance accurate, comprehensive, patient-centered toxicity reporting that will meaningfully inform the care of patients with blood cancers.”

Dr Thanarajasingam and a group of clinicians, investigators, regulators, biostatisticians, and patient advocates analyzed the evidence on AEs and proposed recommendations to policy makers, researchers, industry, and regulators.

First, the group noted that chronic, delayed, and cumulative AEs may go unreported in patients with hematologic malignancies. Therefore, longitudinal methods for AE analysis are needed, and phase 1 trials should have longer periods for evaluating dose-limiting toxicity.

The experts also said PROs are often overlooked, but it should be standard to assess PROs in clinical trials of patients with hematologic malignancies.

Another of the group’s concerns is the “cumbersome” reporting of AEs associated with HSCT acting as a barrier to clinical trials. The experts recommended using registry data to develop a consensus on expected AEs after HSCT.

The group also highlighted deficiencies in the “description and management” of cumulative and late toxicities in survivors of hematologic malignancies. Potential solutions to this problem include developing infrastructure to collect data for adult survivors and standardizing the use and content of survivorship care plans.

The experts said “meaningful” AEs are often underreported to regulatory agencies, so better systems are needed for collecting and analyzing AE data, and the electronic submission of AEs should be simplified.

Finally, the group said AEs occurring in routine clinical practice are difficult to capture and analyze on a large scale. This suggests a need to optimize the systematic, objective collection of toxicity data at multiple points in real-world databases, according to the experts.

Additional details and recommendations are available in the full report.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

Photo by Rhoda Baer

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) have called for renewed political commitment to improve cancer services and reduce cancer deaths.

ASCO and ESMO issued a joint statement in which they asked heads of state and health ministers to attend the United Nations Civil Society Hearing on Non-communicable Diseases (NCDs) in September and reconfirm their commitment to “pass legislation and invest in actions that will reduce the burden of NCDs, including cancer.”

Specifically, ESMO and ASCO said governments should:

1. Implement the 2017 World Health Assembly Cancer Resolution
2. Develop and strengthen educational programs that provide lifestyle recommendations to reduce cancer risk (eg, prevent tobacco use, encourage healthy weight control, etc.)
3. Develop efficient and cost-effective primary prevention measures (eg, Helicobacter pylori eradication)
4. Ensure timely access to screening, early stage diagnosis, and treatment for all stages of cancer
5. Strengthen health systems so they can provide cancer services to all who need them
6. Provide essential secondary healthcare services that ensure an adequate number of well-trained oncology professionals who have access to necessary resources
7. Aim to reduce premature mortality by 25% by 2025 and by 33% by 2030 across all NCDs.

“Recent UN and WHO reports^1,2,3,4 note that, unless countries significantly scale-up their actions and investments, they will not meet agreed targets to reduce deaths from non-communicable diseases,” said ESMO President Josep Tabernero, MD, PhD.

“We are concerned that governments may find it easier to achieve their targets by reducing deaths from only some NCDs, leaving cancer patients behind. We believe there are cost-effective ways to improve cancer care and stand ready to assist countries in doing this by providing our expertise in cancer management to support implementation of the 2017 World Health Assembly Cancer Resolution.”

“We urge member states to consider our joint call and amendments to strengthen the political declaration to be approved during the UN high-level meeting on 27 September and thus change the future outlook for cancer patients worldwide.”

1. United Nations Report by the Secretary General, Document A_72_662, 21 December 2017: http://www.who.int/ncds/governance/high-level-commission/A_72_662.pdf

2. World Health Assembly Report by the WHO Director General, Document WHA 71.2, 26 May 2018: http://apps.who.int/gb/ebwha/pdf_files/WHA71/A71_R2-en.pdf

3. WHO Independent High-Level Commission on NCDs Report, Time to Deliver, 1 June 2018: http://apps.who.int/iris/bitstream/handle/10665/272710/9789241514163-eng.pdf?ua=1

4. WHO Report Saving Lives, Spending Less, 21 May 2018: http://apps.who.int/iris/bitstream/handle/10665/272534/WHO-NMH-NVI-18.8-eng.pdf

Photo by Rhoda Baer

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) have called for renewed political commitment to improve cancer services and reduce cancer deaths.

ASCO and ESMO issued a joint statement in which they asked heads of state and health ministers to attend the United Nations Civil Society Hearing on Non-communicable Diseases (NCDs) in September and reconfirm their commitment to “pass legislation and invest in actions that will reduce the burden of NCDs, including cancer.”

Specifically, ESMO and ASCO said governments should:

1. Implement the 2017 World Health Assembly Cancer Resolution
2. Develop and strengthen educational programs that provide lifestyle recommendations to reduce cancer risk (eg, prevent tobacco use, encourage healthy weight control, etc.)
3. Develop efficient and cost-effective primary prevention measures (eg, Helicobacter pylori eradication)
4. Ensure timely access to screening, early stage diagnosis, and treatment for all stages of cancer
5. Strengthen health systems so they can provide cancer services to all who need them
6. Provide essential secondary healthcare services that ensure an adequate number of well-trained oncology professionals who have access to necessary resources
7. Aim to reduce premature mortality by 25% by 2025 and by 33% by 2030 across all NCDs.

“Recent UN and WHO reports^1,2,3,4 note that, unless countries significantly scale-up their actions and investments, they will not meet agreed targets to reduce deaths from non-communicable diseases,” said ESMO President Josep Tabernero, MD, PhD.

“We are concerned that governments may find it easier to achieve their targets by reducing deaths from only some NCDs, leaving cancer patients behind. We believe there are cost-effective ways to improve cancer care and stand ready to assist countries in doing this by providing our expertise in cancer management to support implementation of the 2017 World Health Assembly Cancer Resolution.”

“We urge member states to consider our joint call and amendments to strengthen the political declaration to be approved during the UN high-level meeting on 27 September and thus change the future outlook for cancer patients worldwide.”

1. United Nations Report by the Secretary General, Document A_72_662, 21 December 2017: http://www.who.int/ncds/governance/high-level-commission/A_72_662.pdf

2. World Health Assembly Report by the WHO Director General, Document WHA 71.2, 26 May 2018: http://apps.who.int/gb/ebwha/pdf_files/WHA71/A71_R2-en.pdf

3. WHO Independent High-Level Commission on NCDs Report, Time to Deliver, 1 June 2018: http://apps.who.int/iris/bitstream/handle/10665/272710/9789241514163-eng.pdf?ua=1

4. WHO Report Saving Lives, Spending Less, 21 May 2018: http://apps.who.int/iris/bitstream/handle/10665/272534/WHO-NMH-NVI-18.8-eng.pdf

Photo by Rhoda Baer

The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) have called for renewed political commitment to improve cancer services and reduce cancer deaths.

ASCO and ESMO issued a joint statement in which they asked heads of state and health ministers to attend the United Nations Civil Society Hearing on Non-communicable Diseases (NCDs) in September and reconfirm their commitment to “pass legislation and invest in actions that will reduce the burden of NCDs, including cancer.”

Specifically, ESMO and ASCO said governments should:

1. Implement the 2017 World Health Assembly Cancer Resolution
2. Develop and strengthen educational programs that provide lifestyle recommendations to reduce cancer risk (eg, prevent tobacco use, encourage healthy weight control, etc.)
3. Develop efficient and cost-effective primary prevention measures (eg, Helicobacter pylori eradication)
4. Ensure timely access to screening, early stage diagnosis, and treatment for all stages of cancer
5. Strengthen health systems so they can provide cancer services to all who need them
6. Provide essential secondary healthcare services that ensure an adequate number of well-trained oncology professionals who have access to necessary resources
7. Aim to reduce premature mortality by 25% by 2025 and by 33% by 2030 across all NCDs.

“Recent UN and WHO reports^1,2,3,4 note that, unless countries significantly scale-up their actions and investments, they will not meet agreed targets to reduce deaths from non-communicable diseases,” said ESMO President Josep Tabernero, MD, PhD.

“We are concerned that governments may find it easier to achieve their targets by reducing deaths from only some NCDs, leaving cancer patients behind. We believe there are cost-effective ways to improve cancer care and stand ready to assist countries in doing this by providing our expertise in cancer management to support implementation of the 2017 World Health Assembly Cancer Resolution.”

“We urge member states to consider our joint call and amendments to strengthen the political declaration to be approved during the UN high-level meeting on 27 September and thus change the future outlook for cancer patients worldwide.”

1. United Nations Report by the Secretary General, Document A_72_662, 21 December 2017: http://www.who.int/ncds/governance/high-level-commission/A_72_662.pdf

2. World Health Assembly Report by the WHO Director General, Document WHA 71.2, 26 May 2018: http://apps.who.int/gb/ebwha/pdf_files/WHA71/A71_R2-en.pdf

3. WHO Independent High-Level Commission on NCDs Report, Time to Deliver, 1 June 2018: http://apps.who.int/iris/bitstream/handle/10665/272710/9789241514163-eng.pdf?ua=1

4. WHO Report Saving Lives, Spending Less, 21 May 2018: http://apps.who.int/iris/bitstream/handle/10665/272534/WHO-NMH-NVI-18.8-eng.pdf

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

Photo from EHA

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

The trial was sponsored by Stemline Therapeutics.

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

Efficacy

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

Safety

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

Next steps

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”

Photo from EHA

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

The trial was sponsored by Stemline Therapeutics.

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

Efficacy

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

Safety

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

Next steps

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”

Photo from EHA

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

The trial was sponsored by Stemline Therapeutics.

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

Efficacy

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

Safety

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

Next steps

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”