ALL

Bone marrow aspirate Photo by Chad McNeeley

The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.

ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

The clonoSEQ Assay is marketed by Adaptive Biotechnologies.

The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.

Validation in ALL

As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.

MRD as determined by MRD negativity at less than 10^-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.

Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.

Validation in MM

The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.

According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.

ClonoSEQ measurements demonstrated that MRD status at a threshold of 10^-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).

And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).

In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.

MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.

Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10^-5.

Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.

For additional information on the clonoSEQ Assay consult the Technical Information available online. 

Bone marrow aspirate Photo by Chad McNeeley

The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.

ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

The clonoSEQ Assay is marketed by Adaptive Biotechnologies.

The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.

Validation in ALL

As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.

MRD as determined by MRD negativity at less than 10^-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.

Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.

Validation in MM

The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.

According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.

ClonoSEQ measurements demonstrated that MRD status at a threshold of 10^-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).

And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).

In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.

MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.

Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10^-5.

Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.

For additional information on the clonoSEQ Assay consult the Technical Information available online. 

Bone marrow aspirate Photo by Chad McNeeley

The U.S. Food and Drug Administration has authorized the first next-generation sequencing (NGS)-based assay to be marketed for minimal residual disease (MRD) testing in patients with acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The assay, called clonoSEQ®, uses both polymerase chain reaction (PCR) and NGS to identify and quantify gene sequences in DNA from patients’ bone marrow.

ClonoSEQ Assay can detect MRD levels below 1 in 1 million cells. By comparison flow cytometry assays or PCR-based assays are capable of measuring MRD down to 1 in 10,000 or 1 in 100,000 cells.

The clonoSEQ Assay is marketed by Adaptive Biotechnologies.

The FDA based its authorization on data from three clinical studies, one with 273 ALL patients, an ongoing study of 323 MM patients, and another MM trial with 706 patients.

Validation in ALL

As described in the clonoSEQ Assay Technical Information, a subset of 273 patients originally enrolled in the Children’s Oncology Group AALL0232 (NCT00075725) and AALL0331 (NCT00103285) studies had left-over bone marrow specimens to evaluate the performance of the clonoSEQ Assay.

MRD as determined by MRD negativity at less than 10^-4 predicted improved event-free survival (EFS) irrespective of age. MRD-positive patients had a 2.74 higher event risk compared to MRD-negative patients.

Similar findings between MRD negativity and EFS in pediatric ALL using an earlier version of the assay were published in Blood.

Validation in MM

The ongoing phase 3 DFCI Study 10-106 (NCT01208662) is comparing conventional treatment with lenalidomide, bortezomib and dexamethasone to high-dose treatment with stem cell transplant as initial management of MM patients less than 65 years.

According to clonoSEQ’s technical information, bone marrow samples from 323 of the 720 patients originally enrolled were available and evaluable for MRD assessment.

ClonoSEQ measurements demonstrated that MRD status at a threshold of 10^-5 significantly predicts progression-free survival (PFS) in all patients (P=0.027).

And samples from 75 patients who had achieved complete remission (CR) showed a modest association with disease-free survival (DFS) and lower MRD levels (P=0.064).

In the phase 3 ALCYONE trial, investigators randomly assigned 706 treatment-naïve MM patients ineligible for hematopoietic stem cell transplant to bortezomib, melphalan, and prednisone with or without daratumumab.

MRD assessments were made using the clonoSEQ Assay at screening, at confirmation of CR or stringent CR, and at intervals after patients achieved a CR.

Patients who did not achieve CR were considered MRD positive. The threshold for the MRD analysis was 10^-5.

Investigators found that patients who were MRD negative by the clonoSEQ Assay had longer PFS compared to MRD-positive patients, regardless of treatment group.

For additional information on the clonoSEQ Assay consult the Technical Information available online. 

Photo by Rhoda Baer

New research suggests race, clinical trial participation, and treatment duration may influence the risk of relapse in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

The study showed that AYAs with ALL were significantly more likely to relapse than pediatric ALL patients.

Among AYAs, the risk of on-therapy relapse was higher for non-white patients and those who did not participate in clinical trials. The risk of relapse after therapy was higher for AYAs with a shorter treatment duration.

Julie A. Wolfson, MD, of University of Alabama at Birmingham, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers conducted this study to investigate why AYAs with ALL have not experienced the same improvement in survival rates as pediatric patients with ALL.

“Patients diagnosed between the ages of 15 and 39 simply have not seen the same improvement as those in other age groups,” Dr. Wolfson said. “In this study, we examined factors related to health care delivery and treatment to increase our understanding of why they experience poorer outcomes.”

The researchers retrospectively studied ALL patients diagnosed between ages 1 and 39 and treated at a single center between 1990 and 2010.

Ninety-one patients were children (ages 1 to 14), and 93 were AYAs (ages 15 to 39).

The researchers assessed variables including demographics, insurance status, participation in clinical trials, duration of treatment, and whether the patients had been treated with pediatric-inspired or adult-inspired regimens. Using Kaplan-Meier survival analysis, the researchers calculated the risk of relapse.

Results

As previous research indicated, children with ALL had superior relapse-free survival compared to AYAs.

The 5-year relapse-free survival rate was 74% in children, 29% in younger AYAs (ages 15 to 21), and 32% in older AYAs (ages 22-39). The difference between children and AYAs was statistically significant (P<0.0001), but the difference between younger and older AYAs was not (P=0.6).

Forty-eight percent of AYAs relapsed while on therapy, compared with 17% of children (P<0.001).

In a multivariable analysis adjusted for clinical prognosticators, health care delivery, and treatment, the risk of on-therapy relapse was more than 10 times higher among AYAs than children (hazard ratio [HR], 10.5; P=0.004).

Among AYAs, the strongest predictors of on-therapy relapse were race and enrollment in clinical trials.

Non-white patients were more than twice as likely to relapse as white patients (HR, 2.2; P=0.05), and patients who were not enrolled in clinical trials were more than twice as likely to relapse as trial participants (HR, 2.6, P=0.04).

Dr. Wolfson said this finding adds to evidence suggesting AYA patients should be encouraged to participate in clinical trials.

“It is possible that patients sometimes benefit from being enrolled on a clinical trial not only because the therapy itself is providing a benefit, but also because it is a protocolized, regulated approach that requires patients to stay on course and not take breaks,” she said.

After the completion of therapy, 47% of AYAs suffered a relapse, compared to 13% of children (P<0.0001).

In a multivariable analysis, the risk of relapse after therapy was more than seven times higher among AYAs than children (HR, 7.7; P<0.001).

Among AYAs who relapsed after therapy, the most significant factor associated with relapse was the duration of treatment.

For each additional month of consolidation therapy, there was a 20% lower risk of relapse (HR, 0.8; P=0.03). And for each additional month of maintenance, there was a 30% lower risk of relapse (HR, 0.7; P<0.001).

Dr. Wolfson noted that a range of factors may affect the duration of treatment. For example, the AYA population is more likely to be uninsured or underinsured, which can make them more likely to stop treatment or miss appointments.

Finally, Dr. Wolfson acknowledged that this study had limitations, primarily its single-institution approach and its limited sample size.

This study was funded by the National Institutes of Health, the St. Baldrick’s Scholar Career Development Award, and the Concern Foundation. The authors declared no conflicts of interest.

Photo by Rhoda Baer

New research suggests race, clinical trial participation, and treatment duration may influence the risk of relapse in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

The study showed that AYAs with ALL were significantly more likely to relapse than pediatric ALL patients.

Among AYAs, the risk of on-therapy relapse was higher for non-white patients and those who did not participate in clinical trials. The risk of relapse after therapy was higher for AYAs with a shorter treatment duration.

Julie A. Wolfson, MD, of University of Alabama at Birmingham, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers conducted this study to investigate why AYAs with ALL have not experienced the same improvement in survival rates as pediatric patients with ALL.

“Patients diagnosed between the ages of 15 and 39 simply have not seen the same improvement as those in other age groups,” Dr. Wolfson said. “In this study, we examined factors related to health care delivery and treatment to increase our understanding of why they experience poorer outcomes.”

The researchers retrospectively studied ALL patients diagnosed between ages 1 and 39 and treated at a single center between 1990 and 2010.

Ninety-one patients were children (ages 1 to 14), and 93 were AYAs (ages 15 to 39).

The researchers assessed variables including demographics, insurance status, participation in clinical trials, duration of treatment, and whether the patients had been treated with pediatric-inspired or adult-inspired regimens. Using Kaplan-Meier survival analysis, the researchers calculated the risk of relapse.

Results

As previous research indicated, children with ALL had superior relapse-free survival compared to AYAs.

The 5-year relapse-free survival rate was 74% in children, 29% in younger AYAs (ages 15 to 21), and 32% in older AYAs (ages 22-39). The difference between children and AYAs was statistically significant (P<0.0001), but the difference between younger and older AYAs was not (P=0.6).

Forty-eight percent of AYAs relapsed while on therapy, compared with 17% of children (P<0.001).

In a multivariable analysis adjusted for clinical prognosticators, health care delivery, and treatment, the risk of on-therapy relapse was more than 10 times higher among AYAs than children (hazard ratio [HR], 10.5; P=0.004).

Among AYAs, the strongest predictors of on-therapy relapse were race and enrollment in clinical trials.

Non-white patients were more than twice as likely to relapse as white patients (HR, 2.2; P=0.05), and patients who were not enrolled in clinical trials were more than twice as likely to relapse as trial participants (HR, 2.6, P=0.04).

Dr. Wolfson said this finding adds to evidence suggesting AYA patients should be encouraged to participate in clinical trials.

“It is possible that patients sometimes benefit from being enrolled on a clinical trial not only because the therapy itself is providing a benefit, but also because it is a protocolized, regulated approach that requires patients to stay on course and not take breaks,” she said.

After the completion of therapy, 47% of AYAs suffered a relapse, compared to 13% of children (P<0.0001).

In a multivariable analysis, the risk of relapse after therapy was more than seven times higher among AYAs than children (HR, 7.7; P<0.001).

Among AYAs who relapsed after therapy, the most significant factor associated with relapse was the duration of treatment.

For each additional month of consolidation therapy, there was a 20% lower risk of relapse (HR, 0.8; P=0.03). And for each additional month of maintenance, there was a 30% lower risk of relapse (HR, 0.7; P<0.001).

Dr. Wolfson noted that a range of factors may affect the duration of treatment. For example, the AYA population is more likely to be uninsured or underinsured, which can make them more likely to stop treatment or miss appointments.

Finally, Dr. Wolfson acknowledged that this study had limitations, primarily its single-institution approach and its limited sample size.

This study was funded by the National Institutes of Health, the St. Baldrick’s Scholar Career Development Award, and the Concern Foundation. The authors declared no conflicts of interest.

Photo by Rhoda Baer

New research suggests race, clinical trial participation, and treatment duration may influence the risk of relapse in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

The study showed that AYAs with ALL were significantly more likely to relapse than pediatric ALL patients.

Among AYAs, the risk of on-therapy relapse was higher for non-white patients and those who did not participate in clinical trials. The risk of relapse after therapy was higher for AYAs with a shorter treatment duration.

Julie A. Wolfson, MD, of University of Alabama at Birmingham, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

The researchers conducted this study to investigate why AYAs with ALL have not experienced the same improvement in survival rates as pediatric patients with ALL.

“Patients diagnosed between the ages of 15 and 39 simply have not seen the same improvement as those in other age groups,” Dr. Wolfson said. “In this study, we examined factors related to health care delivery and treatment to increase our understanding of why they experience poorer outcomes.”

The researchers retrospectively studied ALL patients diagnosed between ages 1 and 39 and treated at a single center between 1990 and 2010.

Ninety-one patients were children (ages 1 to 14), and 93 were AYAs (ages 15 to 39).

The researchers assessed variables including demographics, insurance status, participation in clinical trials, duration of treatment, and whether the patients had been treated with pediatric-inspired or adult-inspired regimens. Using Kaplan-Meier survival analysis, the researchers calculated the risk of relapse.

Results

As previous research indicated, children with ALL had superior relapse-free survival compared to AYAs.

The 5-year relapse-free survival rate was 74% in children, 29% in younger AYAs (ages 15 to 21), and 32% in older AYAs (ages 22-39). The difference between children and AYAs was statistically significant (P<0.0001), but the difference between younger and older AYAs was not (P=0.6).

Forty-eight percent of AYAs relapsed while on therapy, compared with 17% of children (P<0.001).

In a multivariable analysis adjusted for clinical prognosticators, health care delivery, and treatment, the risk of on-therapy relapse was more than 10 times higher among AYAs than children (hazard ratio [HR], 10.5; P=0.004).

Among AYAs, the strongest predictors of on-therapy relapse were race and enrollment in clinical trials.

Non-white patients were more than twice as likely to relapse as white patients (HR, 2.2; P=0.05), and patients who were not enrolled in clinical trials were more than twice as likely to relapse as trial participants (HR, 2.6, P=0.04).

Dr. Wolfson said this finding adds to evidence suggesting AYA patients should be encouraged to participate in clinical trials.

“It is possible that patients sometimes benefit from being enrolled on a clinical trial not only because the therapy itself is providing a benefit, but also because it is a protocolized, regulated approach that requires patients to stay on course and not take breaks,” she said.

After the completion of therapy, 47% of AYAs suffered a relapse, compared to 13% of children (P<0.0001).

In a multivariable analysis, the risk of relapse after therapy was more than seven times higher among AYAs than children (HR, 7.7; P<0.001).

Among AYAs who relapsed after therapy, the most significant factor associated with relapse was the duration of treatment.

For each additional month of consolidation therapy, there was a 20% lower risk of relapse (HR, 0.8; P=0.03). And for each additional month of maintenance, there was a 30% lower risk of relapse (HR, 0.7; P<0.001).

Dr. Wolfson noted that a range of factors may affect the duration of treatment. For example, the AYA population is more likely to be uninsured or underinsured, which can make them more likely to stop treatment or miss appointments.

Finally, Dr. Wolfson acknowledged that this study had limitations, primarily its single-institution approach and its limited sample size.

This study was funded by the National Institutes of Health, the St. Baldrick’s Scholar Career Development Award, and the Concern Foundation. The authors declared no conflicts of interest.

Photo courtesy of Amgen

The Japanese Ministry of Health, Labour and Welfare has approved blinatumomab (Blincyto®) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab is the first and only bispecific T-cell engager immunotherapy construct approved globally.

The drug’s approval in Japan is based on data from the phase 3 TOWER study and the phase 1b/2 Horai study.

The TOWER trial (NCT02013167) enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of four protocol-defined standard of care (SOC) chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Blinatumomab demonstrated an improvement in median overall survival over SOC. The median overall survival was 7.7 months with blinatumomab and 4.0 months with SOC (hazard ratio for death=0.71; P=0.012).

Grade 3 or higher adverse events (AEs) of interest, according to the researchers, were:

• Infection (34% with blinatumomab and 52% with chemotherapy)
• Neutropenia (38% and 58%, respectively)
• Elevated liver enzymes (13% and 15%, respectively)
• Neurologic events (9% and 8%, respectively)
• Cytokine release syndrome (5% and 0%, respectively)
• Infusion reactions (3% and 1%, respectively)
• Lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the SOC arm.

These results were published in The New England Journal of Medicine last year.

Horai

For this single-arm trial (NCT02412306), researchers evaluated blinatumomab in 35 Japanese adult and pediatric patients with relapsed or refractory B-ALL. An extension of this study is ongoing.

Efficacy data from Horai are not available.

According to Amgen, the major AEs occurring in adults on this trial were cytokine release syndrome (46.2%), pyrexia (46.2%), decrease in white blood cell count (38.5%), and decrease in platelet count (34.6%).

Major AEs in pediatric patients were elevated liver enzymes (66.7%), pyrexia (66.7%), cytokine release syndrome (55.6%), and abdominal pain (44.4%).

Photo courtesy of Amgen

The Japanese Ministry of Health, Labour and Welfare has approved blinatumomab (Blincyto®) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab is the first and only bispecific T-cell engager immunotherapy construct approved globally.

The drug’s approval in Japan is based on data from the phase 3 TOWER study and the phase 1b/2 Horai study.

The TOWER trial (NCT02013167) enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of four protocol-defined standard of care (SOC) chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Blinatumomab demonstrated an improvement in median overall survival over SOC. The median overall survival was 7.7 months with blinatumomab and 4.0 months with SOC (hazard ratio for death=0.71; P=0.012).

Grade 3 or higher adverse events (AEs) of interest, according to the researchers, were:

• Infection (34% with blinatumomab and 52% with chemotherapy)
• Neutropenia (38% and 58%, respectively)
• Elevated liver enzymes (13% and 15%, respectively)
• Neurologic events (9% and 8%, respectively)
• Cytokine release syndrome (5% and 0%, respectively)
• Infusion reactions (3% and 1%, respectively)
• Lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the SOC arm.

These results were published in The New England Journal of Medicine last year.

Horai

For this single-arm trial (NCT02412306), researchers evaluated blinatumomab in 35 Japanese adult and pediatric patients with relapsed or refractory B-ALL. An extension of this study is ongoing.

Efficacy data from Horai are not available.

According to Amgen, the major AEs occurring in adults on this trial were cytokine release syndrome (46.2%), pyrexia (46.2%), decrease in white blood cell count (38.5%), and decrease in platelet count (34.6%).

Major AEs in pediatric patients were elevated liver enzymes (66.7%), pyrexia (66.7%), cytokine release syndrome (55.6%), and abdominal pain (44.4%).

Photo courtesy of Amgen

The Japanese Ministry of Health, Labour and Welfare has approved blinatumomab (Blincyto®) for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab is the first and only bispecific T-cell engager immunotherapy construct approved globally.

The drug’s approval in Japan is based on data from the phase 3 TOWER study and the phase 1b/2 Horai study.

The TOWER trial (NCT02013167) enrolled 405 patients with Ph-negative, relapsed/refractory B-ALL, 376 of whom ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of four protocol-defined standard of care (SOC) chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine arabinoside, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine arabinoside-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Blinatumomab demonstrated an improvement in median overall survival over SOC. The median overall survival was 7.7 months with blinatumomab and 4.0 months with SOC (hazard ratio for death=0.71; P=0.012).

Grade 3 or higher adverse events (AEs) of interest, according to the researchers, were:

• Infection (34% with blinatumomab and 52% with chemotherapy)
• Neutropenia (38% and 58%, respectively)
• Elevated liver enzymes (13% and 15%, respectively)
• Neurologic events (9% and 8%, respectively)
• Cytokine release syndrome (5% and 0%, respectively)
• Infusion reactions (3% and 1%, respectively)
• Lymphopenia (2% and 4%, respectively).

Fatal AEs occurred in 19% of patients in the blinatumomab arm and 17% of those in the SOC arm.

These results were published in The New England Journal of Medicine last year.

Horai

For this single-arm trial (NCT02412306), researchers evaluated blinatumomab in 35 Japanese adult and pediatric patients with relapsed or refractory B-ALL. An extension of this study is ongoing.

Efficacy data from Horai are not available.

According to Amgen, the major AEs occurring in adults on this trial were cytokine release syndrome (46.2%), pyrexia (46.2%), decrease in white blood cell count (38.5%), and decrease in platelet count (34.6%).

Major AEs in pediatric patients were elevated liver enzymes (66.7%), pyrexia (66.7%), cytokine release syndrome (55.6%), and abdominal pain (44.4%).

The Food and Drug Administration has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL. In addition, OBI-3424 significantly reduced leukemia bone marrow infiltration in four of six evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

[email protected]

The Food and Drug Administration has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL. In addition, OBI-3424 significantly reduced leukemia bone marrow infiltration in four of six evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

[email protected]

The Food and Drug Administration has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL. In addition, OBI-3424 significantly reduced leukemia bone marrow infiltration in four of six evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

[email protected]

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Cancer Research Center

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL.

The researchers said OBI-3424 significantly reduced leukemia bone marrow infiltration in 4 of 6 evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

Enrollment has begun in a phase 1/2 trial (NCT03592264) of OBI-3424 in patients with hepatocellular carcinoma and castrate-resistant prostate cancer.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Cancer Research Center

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL.

The researchers said OBI-3424 significantly reduced leukemia bone marrow infiltration in 4 of 6 evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

Enrollment has begun in a phase 1/2 trial (NCT03592264) of OBI-3424 in patients with hepatocellular carcinoma and castrate-resistant prostate cancer.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Cancer Research Center

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL.

The researchers said OBI-3424 significantly reduced leukemia bone marrow infiltration in 4 of 6 evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

Enrollment has begun in a phase 1/2 trial (NCT03592264) of OBI-3424 in patients with hepatocellular carcinoma and castrate-resistant prostate cancer.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.

Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.

Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.

This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.

In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.

The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.

“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”

The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.

This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.

In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.

WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.

[email protected]

SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.

An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.

Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.

Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.

This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.

In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.

The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.

“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”

The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.

This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.

In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.

WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.

[email protected]

SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.

An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.

Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.

Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.

This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.

In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.

The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.

“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”

The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.

This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.

In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.

WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.

[email protected]

SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

The cost-effectiveness of tisagenlecleucel (Kymriah) depends on long-term clinical outcomes, which are presently unknown, according to investigators.

Courtesy Stanford University

If the long-term outcomes are more modest than clinical trials suggest, then payers may be unwilling to cover the costly therapy, reported John K. Lin, MD, of the Center for Primary Care and Outcomes Research at Stanford (Calif.) University, and his colleagues. Lowering the price or setting up an outcomes-based pricing structure may be necessary to get insurers to cover the therapy.

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was approved by the Food and Drug Administration in August 2017 for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL). In 2018, the FDA expanded the indication for tisagenlecleucel to include adults with relapsed or refractory large B-cell lymphoma, though outcomes from lymphoma trials are not analyzed in the current study.

At a wholesale acquisition cost of $475,000 per infusion, it is the most expensive existing oncology therapy to date, and can be accompanied by expensive, potentially fatal adverse effects. However, clinical trials suggest that tisagenlecleucel can offer years of relapse-free remission, thereby allowing patients to forgo other expensive therapies such as hematopoietic stem cell transplantation (HSCT).

“Although tisagenlecleucel-induced remission rates are promising, compared with those of established therapies (greater than 80% vs. less than 50%), only short-term follow-up data currently exist,” the investigators wrote in the Journal of Clinical Oncology. “Given the high cost and broad applicability in other malignancies of tisagenlecleucel, a pressing question for policy makers, payers, patients, and clinicians is whether the cost of therapy represents reasonable value.”

The study used a Markov model to assess various long-term clinical outcome rates and cost thresholds of tisagenlecleucel. The lifetime cost of therapy was assessed and compared with costs of existing therapies.

The results showed that a 5-year relapse free survival rate of 40% would make the present cost ($475,000) of tisagenlecleucel economically reasonable. In this scenario, the increased life expectancy would be 12.1 years and would result in an additional 5.07 quality-adjusted life years (QALY) gained at a cost of $61,000 per QALY, compared with blinatumomab.

But if long-term outcomes are less favorable, tisagenlecleucel becomes much less cost effective. A 5-year relapse-free survival rate of 20% would drop increased life expectancy to 3.8 years, resulting in 1.80 QALYs gained and raising the cost to $151,000 per QALY.

“Our results suggest that at tisagenlecleucel’s current price and payment structure, its economic value is uncertain,” the investigators wrote.

They suggested a price drop to $200,000 or $350,000, which would allow the drug to remain cost effective even in a worse-case scenario, in which patients relapse and tisagenlecleucel is a bridge to transplant. Another option is to move to outcomes-based pricing. Making payment conditional on 7 months of remission would make the treatment cost effective, according to the analysis.

“Price reductions of tisagenlecleucel or payment only for longer-term remissions would favorably influence cost-effectiveness, even if long-term clinical outcomes are modest,” the investigators wrote.

The study was funded by a Veterans Affairs Office of Academic Affiliations advanced fellowship in health service and research development, and a National Center for Advancing Translational Science Clinical and Translational Science Award. One of the study coauthors reported consulting and research funding from Novartis.

SOURCE: Lin et al. J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642.

Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.

Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.

“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, PhD, of Statens Serum Institut in Copenhagen. “This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”

She noted that the study could not determine if the associations shown are causal or consequential so further studies will be needed both to confirm the findings and identify the underlying mechanisms.

For this study, Dr. Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1-9 years.

Compared with controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.

Concentrations of interleukin (IL)–8, soluble receptor sIL-6R alpha, transforming growth factor (TGF)–beta 1, monocyte chemotactic protein (MCP)–1, and C-reactive protein (CRP) were significantly lower among the BCP-ALL patients.

On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls.

The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls had IL-6 and IL-17 concentrations that were below the limit of detection.

“We also demonstrated that several previously shown ALL risk factors – namely, birth order, gestational age, and sex – were associated with the neonatal concentrations of inflammatory markers,” Dr. Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”

The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.

Increasing gestational age was associated with significantly lower sIL-6R alpha and TGF-beta 1 concentrations and higher CRP concentrations. And boys had significantly lower sIL-6R alpha and IL-8 concentrations and higher CRP concentrations than girls.

However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact attributable to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.

“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Dr. Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL.”

The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. The investigators reported having no conflicts of interest.

[email protected]

SOURCE: Søegaard SH et al. Cancer Res. 2018;78(18);5458-63.

Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.

Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.

“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, PhD, of Statens Serum Institut in Copenhagen. “This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”

She noted that the study could not determine if the associations shown are causal or consequential so further studies will be needed both to confirm the findings and identify the underlying mechanisms.

For this study, Dr. Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1-9 years.

Compared with controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.

Concentrations of interleukin (IL)–8, soluble receptor sIL-6R alpha, transforming growth factor (TGF)–beta 1, monocyte chemotactic protein (MCP)–1, and C-reactive protein (CRP) were significantly lower among the BCP-ALL patients.

On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls.

The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls had IL-6 and IL-17 concentrations that were below the limit of detection.

“We also demonstrated that several previously shown ALL risk factors – namely, birth order, gestational age, and sex – were associated with the neonatal concentrations of inflammatory markers,” Dr. Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”

The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.

Increasing gestational age was associated with significantly lower sIL-6R alpha and TGF-beta 1 concentrations and higher CRP concentrations. And boys had significantly lower sIL-6R alpha and IL-8 concentrations and higher CRP concentrations than girls.

However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact attributable to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.

“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Dr. Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL.”

The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. The investigators reported having no conflicts of interest.

[email protected]

SOURCE: Søegaard SH et al. Cancer Res. 2018;78(18);5458-63.

Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.

Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.

“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, PhD, of Statens Serum Institut in Copenhagen. “This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”

She noted that the study could not determine if the associations shown are causal or consequential so further studies will be needed both to confirm the findings and identify the underlying mechanisms.

For this study, Dr. Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1-9 years.

Compared with controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.

Concentrations of interleukin (IL)–8, soluble receptor sIL-6R alpha, transforming growth factor (TGF)–beta 1, monocyte chemotactic protein (MCP)–1, and C-reactive protein (CRP) were significantly lower among the BCP-ALL patients.

On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls.

The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls had IL-6 and IL-17 concentrations that were below the limit of detection.

“We also demonstrated that several previously shown ALL risk factors – namely, birth order, gestational age, and sex – were associated with the neonatal concentrations of inflammatory markers,” Dr. Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”

The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.

Increasing gestational age was associated with significantly lower sIL-6R alpha and TGF-beta 1 concentrations and higher CRP concentrations. And boys had significantly lower sIL-6R alpha and IL-8 concentrations and higher CRP concentrations than girls.

However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact attributable to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.

“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Dr. Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL.”

The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. The investigators reported having no conflicts of interest.

[email protected]

SOURCE: Søegaard SH et al. Cancer Res. 2018;78(18);5458-63.