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Jennifer Smith is the editor of Oncology Practice, part of MDedge Hematology/Oncology. She was previously the editor of Hematology Times, an editor at Principal Investigators Association, and a reporter at The Oneida Daily Dispatch. She has a BS in journalism.
Model inspired by Netflix, Amazon may help guide MDS treatment
NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.
The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.
Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.
Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.
The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).
The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:
- DNMT3A and SF3B1
- EZH2 and NK
- ASXL1, TET2, and NK
- STAG2, IDH1/2, and NK
- TP53, del(5q), and CK
- BCOR/BCORL1 and NK
- JAK2, TET2, and NK
- U2AF1, +/– ETV6, and NK
However, only the following two combinations could predict response to lenalidomide:
- DDX41 and NK
- MECOM and KDM6A/B
These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.
Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.
“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.
Dr. Madanat and his colleagues reported having no relevant conflicts of interest.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.
The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.
Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.
Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.
The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).
The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:
- DNMT3A and SF3B1
- EZH2 and NK
- ASXL1, TET2, and NK
- STAG2, IDH1/2, and NK
- TP53, del(5q), and CK
- BCOR/BCORL1 and NK
- JAK2, TET2, and NK
- U2AF1, +/– ETV6, and NK
However, only the following two combinations could predict response to lenalidomide:
- DDX41 and NK
- MECOM and KDM6A/B
These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.
Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.
“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.
Dr. Madanat and his colleagues reported having no relevant conflicts of interest.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. — A model that mimics the recommender system used by Netflix and Amazon can help predict outcomes of lenalidomide treatment in patients with non–deletion 5q (non-del[5q]) myelodysplastic syndromes (MDS), according to new research.
The model was used to identify genomic biomarkers that were associated with resistance or response to lenalidomide. Researchers found these associations in 39% of patients with non-del(5q) MDS, and the model predicted response or resistance with 82% accuracy.
Yazan Madanat, MD, of the Cleveland Clinic, and his colleagues presented these findings at the Acute Leukemia Forum of Hemedicus.
Dr. Madanat explained that his group’s model is similar to the recommender system used by Netflix and Amazon, which makes suggestions for new products based on customers’ past behavior. Dr. Madanat and his colleagues used their model to show that patients with certain molecular or cytogenetic abnormalities are likely to respond or not respond to lenalidomide.
The researchers began by looking at 139 patients who had received at least two cycles of lenalidomide treatment. There were 118 patients with MDS, and 108 who had received lenalidomide monotherapy. However, the team focused on the 100 patients who had non-del(5q) MDS, 58 of whom had normal karyotype (NK) and 19 of whom had complex karyotype (CK).
The model revealed several combinations of genomic/cytogenetic abnormalities that could predict resistance to lenalidomide, including the following:
- DNMT3A and SF3B1
- EZH2 and NK
- ASXL1, TET2, and NK
- STAG2, IDH1/2, and NK
- TP53, del(5q), and CK
- BCOR/BCORL1 and NK
- JAK2, TET2, and NK
- U2AF1, +/– ETV6, and NK
However, only the following two combinations could predict response to lenalidomide:
- DDX41 and NK
- MECOM and KDM6A/B
These combinations could be applied to 39% of the patients with non-del(5q) MDS, and the model predicted response or resistance to lenalidomide with 82% accuracy.
Although the biomarkers were found in only a subset of patients, Dr. Madanat said these findings may help physicians tailor therapy for MDS patients, given the high level of accuracy the researchers observed.
“It’s really important to validate the results in a prospective manner and to ensure that we’re able to apply them clinically and potentially change the way we’re treating our patients,” he added.
Dr. Madanat and his colleagues reported having no relevant conflicts of interest.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
Researchers to be honored at ASPHO
Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.
Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.
Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.
Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.
Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.
Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.
Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.
Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.
Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.
Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.
Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.
Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.
Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.
Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.
Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.
Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.
Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.
Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.
Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.
Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.
Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.
Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.
Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.
Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.
Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
Sorafenib plus GCLAM held safe in AML, MDS phase-1 study
NEWPORT BEACH, CALIF. – A five-drug regimen was deemed safe in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and it appeared to be effective regardless of patients’ FLT3 status.
Researchers tested this regimen – sorafenib plus granulocyte colony–stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone (GCLAM) – in a phase 1 trial.
Kelsey-Leigh Garcia, a clinical research coordinator at Seattle Cancer Care Alliance, and her colleagues presented the results at the Acute Leukemia Forum of Hemedicus.
“The background for doing this study was our institutional results of GCLAM [Leukemia. 2018 Nov;32(11):2352-62] that showed a higher minimal residual disease–negative complete response rate than 7+3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] and an international study by Röllig that showed the addition of sorafenib to 7+3 increased event-free survival versus [7+3 and] placebo [Lancet Oncol. 2015 Dec;16(16):1691-9],” Ms. Garcia said.
“GCLAM is the standard backbone at our institution, and we wanted to ask the question, ‘If we add sorafenib, can this improve upon the results of GCLAM?’ ” said Anna Halpern, MD, a hematologist-oncologist at the University of Washington, Seattle and principal investigator of the phase 1 trial.
The trial (NCT02728050) included 47 patients, 39 with AML and 8 with MDS. Patients were aged 60 years or younger and had a median age of 48. They had a median treatment-related mortality score of 1.76 (range, 0.19-12.26). A total of 11 patients (23%) had FLT3-ITD, and 4 (9%) had FLT3-TKD.
Treatment and toxicity
For induction, patients received G-CSF at 5 mcg/kg on days 0-5, cladribine at 5 mg/m2 on days 1-5, and cytarabine at 2 g/m2 on days 1-5. Mitoxantrone was given at 10 mg/m2, 12 mg/m2, 15 mg/m2, or 18 mg/m2 on days 1-3. Sorafenib was given at 200 mg twice daily, 400 mg in the morning and 200 mg in the afternoon, or 400 mg b.i.d. on days 10-19.
For consolidation, patients could receive up to four cycles of G-CSF, cladribine, and cytarabine plus sorafenib on days 8-27. Patients who did not proceed to transplant could receive 12 months of sorafenib as maintenance therapy.
There were four dose-limiting toxicities.
- Grade 4 intracranial hemorrhage with mitoxantrone at 12 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 prolonged count recovery with mitoxantrone at 15 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 sepsis, Sweet syndrome, and Bell’s palsy with mitoxantrone at 18 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 3 cardiomyopathy and acute pericarditis with mitoxantrone at 18 mg/m2 and sorafenib at 400 mg b.i.d.
However, these toxicities did not define the maximum-tolerated dose. Therefore, the recommended phase 2 dose of mitoxantrone is 18 mg/m2, and the recommended phase 2 dose of sorafenib is 400 mg b.i.d.
There were no grade 5 treatment-related adverse events. Grade 3 events included febrile neutropenia (90%), maculopapular rash (20%), infections (10%), hand-foot syndrome (2%), and diarrhea (1%). Grade 4 events included sepsis, intracranial hemorrhage, and oral mucositis (all 1%).
Response and survival
Among the 46 evaluable patients, 83% achieved a complete response, 78% had a minimal residual disease–negative complete response, and 4% had a minimal residual disease–negative complete response with incomplete count recovery. A morphological leukemia-free state was achieved by 4% of patients, and 8% had resistant disease.
Fifty-nine percent of patients went on to transplant. The median overall survival had not been reached at a median follow-up of 10 months.
The researchers compared outcomes in this trial with outcomes in a cohort of patients who had received GCLAM alone, and there were no significant differences in overall survival or event-free survival.
“The trial wasn’t powered, necessarily, for efficacy, but we compared these results to our historical cohort of medically matched and age-matched patients treated with GCLAM alone and, so far, found no differences in survival between the two groups,” Dr. Halpern said.
She noted, however, that follow-up was short in the sorafenib trial, and it included patients treated with all dose levels of sorafenib and mitoxantrone.
A phase 2 study of sorafenib plus GCLAM in newly diagnosed AML or high-risk MDS is now underway.
Dr. Halpern and Ms. Garcia reported that they had no conflicts of interest. The phase 1 trial was sponsored by the University of Washington in collaboration with the National Cancer Institute, and funding was provided by Bayer.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – A five-drug regimen was deemed safe in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and it appeared to be effective regardless of patients’ FLT3 status.
Researchers tested this regimen – sorafenib plus granulocyte colony–stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone (GCLAM) – in a phase 1 trial.
Kelsey-Leigh Garcia, a clinical research coordinator at Seattle Cancer Care Alliance, and her colleagues presented the results at the Acute Leukemia Forum of Hemedicus.
“The background for doing this study was our institutional results of GCLAM [Leukemia. 2018 Nov;32(11):2352-62] that showed a higher minimal residual disease–negative complete response rate than 7+3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] and an international study by Röllig that showed the addition of sorafenib to 7+3 increased event-free survival versus [7+3 and] placebo [Lancet Oncol. 2015 Dec;16(16):1691-9],” Ms. Garcia said.
“GCLAM is the standard backbone at our institution, and we wanted to ask the question, ‘If we add sorafenib, can this improve upon the results of GCLAM?’ ” said Anna Halpern, MD, a hematologist-oncologist at the University of Washington, Seattle and principal investigator of the phase 1 trial.
The trial (NCT02728050) included 47 patients, 39 with AML and 8 with MDS. Patients were aged 60 years or younger and had a median age of 48. They had a median treatment-related mortality score of 1.76 (range, 0.19-12.26). A total of 11 patients (23%) had FLT3-ITD, and 4 (9%) had FLT3-TKD.
Treatment and toxicity
For induction, patients received G-CSF at 5 mcg/kg on days 0-5, cladribine at 5 mg/m2 on days 1-5, and cytarabine at 2 g/m2 on days 1-5. Mitoxantrone was given at 10 mg/m2, 12 mg/m2, 15 mg/m2, or 18 mg/m2 on days 1-3. Sorafenib was given at 200 mg twice daily, 400 mg in the morning and 200 mg in the afternoon, or 400 mg b.i.d. on days 10-19.
For consolidation, patients could receive up to four cycles of G-CSF, cladribine, and cytarabine plus sorafenib on days 8-27. Patients who did not proceed to transplant could receive 12 months of sorafenib as maintenance therapy.
There were four dose-limiting toxicities.
- Grade 4 intracranial hemorrhage with mitoxantrone at 12 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 prolonged count recovery with mitoxantrone at 15 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 sepsis, Sweet syndrome, and Bell’s palsy with mitoxantrone at 18 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 3 cardiomyopathy and acute pericarditis with mitoxantrone at 18 mg/m2 and sorafenib at 400 mg b.i.d.
However, these toxicities did not define the maximum-tolerated dose. Therefore, the recommended phase 2 dose of mitoxantrone is 18 mg/m2, and the recommended phase 2 dose of sorafenib is 400 mg b.i.d.
There were no grade 5 treatment-related adverse events. Grade 3 events included febrile neutropenia (90%), maculopapular rash (20%), infections (10%), hand-foot syndrome (2%), and diarrhea (1%). Grade 4 events included sepsis, intracranial hemorrhage, and oral mucositis (all 1%).
Response and survival
Among the 46 evaluable patients, 83% achieved a complete response, 78% had a minimal residual disease–negative complete response, and 4% had a minimal residual disease–negative complete response with incomplete count recovery. A morphological leukemia-free state was achieved by 4% of patients, and 8% had resistant disease.
Fifty-nine percent of patients went on to transplant. The median overall survival had not been reached at a median follow-up of 10 months.
The researchers compared outcomes in this trial with outcomes in a cohort of patients who had received GCLAM alone, and there were no significant differences in overall survival or event-free survival.
“The trial wasn’t powered, necessarily, for efficacy, but we compared these results to our historical cohort of medically matched and age-matched patients treated with GCLAM alone and, so far, found no differences in survival between the two groups,” Dr. Halpern said.
She noted, however, that follow-up was short in the sorafenib trial, and it included patients treated with all dose levels of sorafenib and mitoxantrone.
A phase 2 study of sorafenib plus GCLAM in newly diagnosed AML or high-risk MDS is now underway.
Dr. Halpern and Ms. Garcia reported that they had no conflicts of interest. The phase 1 trial was sponsored by the University of Washington in collaboration with the National Cancer Institute, and funding was provided by Bayer.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – A five-drug regimen was deemed safe in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and it appeared to be effective regardless of patients’ FLT3 status.
Researchers tested this regimen – sorafenib plus granulocyte colony–stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone (GCLAM) – in a phase 1 trial.
Kelsey-Leigh Garcia, a clinical research coordinator at Seattle Cancer Care Alliance, and her colleagues presented the results at the Acute Leukemia Forum of Hemedicus.
“The background for doing this study was our institutional results of GCLAM [Leukemia. 2018 Nov;32(11):2352-62] that showed a higher minimal residual disease–negative complete response rate than 7+3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] and an international study by Röllig that showed the addition of sorafenib to 7+3 increased event-free survival versus [7+3 and] placebo [Lancet Oncol. 2015 Dec;16(16):1691-9],” Ms. Garcia said.
“GCLAM is the standard backbone at our institution, and we wanted to ask the question, ‘If we add sorafenib, can this improve upon the results of GCLAM?’ ” said Anna Halpern, MD, a hematologist-oncologist at the University of Washington, Seattle and principal investigator of the phase 1 trial.
The trial (NCT02728050) included 47 patients, 39 with AML and 8 with MDS. Patients were aged 60 years or younger and had a median age of 48. They had a median treatment-related mortality score of 1.76 (range, 0.19-12.26). A total of 11 patients (23%) had FLT3-ITD, and 4 (9%) had FLT3-TKD.
Treatment and toxicity
For induction, patients received G-CSF at 5 mcg/kg on days 0-5, cladribine at 5 mg/m2 on days 1-5, and cytarabine at 2 g/m2 on days 1-5. Mitoxantrone was given at 10 mg/m2, 12 mg/m2, 15 mg/m2, or 18 mg/m2 on days 1-3. Sorafenib was given at 200 mg twice daily, 400 mg in the morning and 200 mg in the afternoon, or 400 mg b.i.d. on days 10-19.
For consolidation, patients could receive up to four cycles of G-CSF, cladribine, and cytarabine plus sorafenib on days 8-27. Patients who did not proceed to transplant could receive 12 months of sorafenib as maintenance therapy.
There were four dose-limiting toxicities.
- Grade 4 intracranial hemorrhage with mitoxantrone at 12 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 prolonged count recovery with mitoxantrone at 15 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 sepsis, Sweet syndrome, and Bell’s palsy with mitoxantrone at 18 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 3 cardiomyopathy and acute pericarditis with mitoxantrone at 18 mg/m2 and sorafenib at 400 mg b.i.d.
However, these toxicities did not define the maximum-tolerated dose. Therefore, the recommended phase 2 dose of mitoxantrone is 18 mg/m2, and the recommended phase 2 dose of sorafenib is 400 mg b.i.d.
There were no grade 5 treatment-related adverse events. Grade 3 events included febrile neutropenia (90%), maculopapular rash (20%), infections (10%), hand-foot syndrome (2%), and diarrhea (1%). Grade 4 events included sepsis, intracranial hemorrhage, and oral mucositis (all 1%).
Response and survival
Among the 46 evaluable patients, 83% achieved a complete response, 78% had a minimal residual disease–negative complete response, and 4% had a minimal residual disease–negative complete response with incomplete count recovery. A morphological leukemia-free state was achieved by 4% of patients, and 8% had resistant disease.
Fifty-nine percent of patients went on to transplant. The median overall survival had not been reached at a median follow-up of 10 months.
The researchers compared outcomes in this trial with outcomes in a cohort of patients who had received GCLAM alone, and there were no significant differences in overall survival or event-free survival.
“The trial wasn’t powered, necessarily, for efficacy, but we compared these results to our historical cohort of medically matched and age-matched patients treated with GCLAM alone and, so far, found no differences in survival between the two groups,” Dr. Halpern said.
She noted, however, that follow-up was short in the sorafenib trial, and it included patients treated with all dose levels of sorafenib and mitoxantrone.
A phase 2 study of sorafenib plus GCLAM in newly diagnosed AML or high-risk MDS is now underway.
Dr. Halpern and Ms. Garcia reported that they had no conflicts of interest. The phase 1 trial was sponsored by the University of Washington in collaboration with the National Cancer Institute, and funding was provided by Bayer.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
Study highlights lack of data on transgender leukemia patients
NEWPORT BEACH, CALIF. – Researchers have shown they can identify transgender leukemia patients by detecting gender-karyotype mismatches, but some transgender patients may be overlooked with this method.
The researchers’ work also highlights how little we know about transgender patients with leukemia and other cancers.
Alison Alpert, MD, of the University of Rochester (N.Y.) Medical Center, and her colleagues conducted this research and presented their findings in a poster at the Acute Leukemia Forum of Hemedicus.
“There’s almost no data about transgender people with cancer ... in terms of prevalence or anything else,” Dr. Alpert noted. “And because we don’t know which patients with cancer are transgender, we can’t begin to answer any of the other big questions for patients.”
Specifically, it’s unclear what kinds of cancer transgender patients have, if there are health disparities among transgender patients, if it is safe to continue hormone therapy during cancer treatment, and if it is possible to do transition-related surgeries in the context of cancer care.
With this in mind, Dr. Alpert and her colleagues set out to identify transgender patients by detecting gender-karyotype mismatches. The team analyzed data on patients with acute myeloid leukemia (AML) or myelodysplastic syndromes enrolled in five Southwest Oncology Group (SWOG) trials.
Of the 1,748 patients analyzed, six (0.3%) had a gender-karyotype mismatch. Five patients had a 46,XY karyotype and identified as female, and one patient had a 46,XX karyotype and identified as male.
“Some transgender patients have their gender identity accurately reflected in the electronic medical record, [but] some transgender patients probably don’t,” Dr. Alpert noted. “So we identified some, but probably not all, and probably not even most, transgender patients with leukemia in this cohort.”
All six of the transgender patients identified had AML, and all were white. They ranged in age from 18 to 57 years. Four patients had achieved a complete response to therapy, and two had refractory disease.
Four patients, including one who was refractory, were still alive at last follow-up. The remaining two patients, including one who had achieved a complete response, had died.
The transgender patients identified in this analysis represent a very small percentage of the population studied, Dr. Alpert noted. Therefore, the researchers could not draw any conclusions about transgender patients with AML.
“Mostly, what we did was, we pointed out how little information we have,” Dr. Alpert said. “Oncologists don’t routinely collect gender identity information, and this information doesn’t exist in cooperative group databases either.”
“But going forward, what probably really needs to happen is that oncologists need to ask their patients whether they are transgender or not. And then, ideally, consent forms for large cooperative groups like SWOG would include gender identity data, and then we would be able to answer some of our other questions and better counsel our patients.”
Dr. Alpert and her colleagues are hoping to gain insights regarding transgender patients with lymphoma as well. The researchers are analyzing the lymphoma database at the University of Rochester Medical Center, which includes about 2,200 patients.
The team is attempting to identify transgender lymphoma patients using gender-karyotype mismatch as well as other methods, including assessing patients’ medication and surgical histories, determining whether patients have any aliases, and looking for the word “transgender” in patient charts.
“Given that the country is finally starting to talk about transgender patients, their health disparities, and their needs and experiences, it’s really time that we start collecting this data,” Dr. Alpert said.
“[I]f we are able to start to collect this data, it can help us build relationships with our patients, improve their care and outcomes, and, hopefully, be able to better counsel them about hormones and surgery.”
Dr. Alpert and her colleagues did not disclose any conflicts of interest.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Researchers have shown they can identify transgender leukemia patients by detecting gender-karyotype mismatches, but some transgender patients may be overlooked with this method.
The researchers’ work also highlights how little we know about transgender patients with leukemia and other cancers.
Alison Alpert, MD, of the University of Rochester (N.Y.) Medical Center, and her colleagues conducted this research and presented their findings in a poster at the Acute Leukemia Forum of Hemedicus.
“There’s almost no data about transgender people with cancer ... in terms of prevalence or anything else,” Dr. Alpert noted. “And because we don’t know which patients with cancer are transgender, we can’t begin to answer any of the other big questions for patients.”
Specifically, it’s unclear what kinds of cancer transgender patients have, if there are health disparities among transgender patients, if it is safe to continue hormone therapy during cancer treatment, and if it is possible to do transition-related surgeries in the context of cancer care.
With this in mind, Dr. Alpert and her colleagues set out to identify transgender patients by detecting gender-karyotype mismatches. The team analyzed data on patients with acute myeloid leukemia (AML) or myelodysplastic syndromes enrolled in five Southwest Oncology Group (SWOG) trials.
Of the 1,748 patients analyzed, six (0.3%) had a gender-karyotype mismatch. Five patients had a 46,XY karyotype and identified as female, and one patient had a 46,XX karyotype and identified as male.
“Some transgender patients have their gender identity accurately reflected in the electronic medical record, [but] some transgender patients probably don’t,” Dr. Alpert noted. “So we identified some, but probably not all, and probably not even most, transgender patients with leukemia in this cohort.”
All six of the transgender patients identified had AML, and all were white. They ranged in age from 18 to 57 years. Four patients had achieved a complete response to therapy, and two had refractory disease.
Four patients, including one who was refractory, were still alive at last follow-up. The remaining two patients, including one who had achieved a complete response, had died.
The transgender patients identified in this analysis represent a very small percentage of the population studied, Dr. Alpert noted. Therefore, the researchers could not draw any conclusions about transgender patients with AML.
“Mostly, what we did was, we pointed out how little information we have,” Dr. Alpert said. “Oncologists don’t routinely collect gender identity information, and this information doesn’t exist in cooperative group databases either.”
“But going forward, what probably really needs to happen is that oncologists need to ask their patients whether they are transgender or not. And then, ideally, consent forms for large cooperative groups like SWOG would include gender identity data, and then we would be able to answer some of our other questions and better counsel our patients.”
Dr. Alpert and her colleagues are hoping to gain insights regarding transgender patients with lymphoma as well. The researchers are analyzing the lymphoma database at the University of Rochester Medical Center, which includes about 2,200 patients.
The team is attempting to identify transgender lymphoma patients using gender-karyotype mismatch as well as other methods, including assessing patients’ medication and surgical histories, determining whether patients have any aliases, and looking for the word “transgender” in patient charts.
“Given that the country is finally starting to talk about transgender patients, their health disparities, and their needs and experiences, it’s really time that we start collecting this data,” Dr. Alpert said.
“[I]f we are able to start to collect this data, it can help us build relationships with our patients, improve their care and outcomes, and, hopefully, be able to better counsel them about hormones and surgery.”
Dr. Alpert and her colleagues did not disclose any conflicts of interest.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Researchers have shown they can identify transgender leukemia patients by detecting gender-karyotype mismatches, but some transgender patients may be overlooked with this method.
The researchers’ work also highlights how little we know about transgender patients with leukemia and other cancers.
Alison Alpert, MD, of the University of Rochester (N.Y.) Medical Center, and her colleagues conducted this research and presented their findings in a poster at the Acute Leukemia Forum of Hemedicus.
“There’s almost no data about transgender people with cancer ... in terms of prevalence or anything else,” Dr. Alpert noted. “And because we don’t know which patients with cancer are transgender, we can’t begin to answer any of the other big questions for patients.”
Specifically, it’s unclear what kinds of cancer transgender patients have, if there are health disparities among transgender patients, if it is safe to continue hormone therapy during cancer treatment, and if it is possible to do transition-related surgeries in the context of cancer care.
With this in mind, Dr. Alpert and her colleagues set out to identify transgender patients by detecting gender-karyotype mismatches. The team analyzed data on patients with acute myeloid leukemia (AML) or myelodysplastic syndromes enrolled in five Southwest Oncology Group (SWOG) trials.
Of the 1,748 patients analyzed, six (0.3%) had a gender-karyotype mismatch. Five patients had a 46,XY karyotype and identified as female, and one patient had a 46,XX karyotype and identified as male.
“Some transgender patients have their gender identity accurately reflected in the electronic medical record, [but] some transgender patients probably don’t,” Dr. Alpert noted. “So we identified some, but probably not all, and probably not even most, transgender patients with leukemia in this cohort.”
All six of the transgender patients identified had AML, and all were white. They ranged in age from 18 to 57 years. Four patients had achieved a complete response to therapy, and two had refractory disease.
Four patients, including one who was refractory, were still alive at last follow-up. The remaining two patients, including one who had achieved a complete response, had died.
The transgender patients identified in this analysis represent a very small percentage of the population studied, Dr. Alpert noted. Therefore, the researchers could not draw any conclusions about transgender patients with AML.
“Mostly, what we did was, we pointed out how little information we have,” Dr. Alpert said. “Oncologists don’t routinely collect gender identity information, and this information doesn’t exist in cooperative group databases either.”
“But going forward, what probably really needs to happen is that oncologists need to ask their patients whether they are transgender or not. And then, ideally, consent forms for large cooperative groups like SWOG would include gender identity data, and then we would be able to answer some of our other questions and better counsel our patients.”
Dr. Alpert and her colleagues are hoping to gain insights regarding transgender patients with lymphoma as well. The researchers are analyzing the lymphoma database at the University of Rochester Medical Center, which includes about 2,200 patients.
The team is attempting to identify transgender lymphoma patients using gender-karyotype mismatch as well as other methods, including assessing patients’ medication and surgical histories, determining whether patients have any aliases, and looking for the word “transgender” in patient charts.
“Given that the country is finally starting to talk about transgender patients, their health disparities, and their needs and experiences, it’s really time that we start collecting this data,” Dr. Alpert said.
“[I]f we are able to start to collect this data, it can help us build relationships with our patients, improve their care and outcomes, and, hopefully, be able to better counsel them about hormones and surgery.”
Dr. Alpert and her colleagues did not disclose any conflicts of interest.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
ALF 2019 showcases evolving treatment of AML
NEWPORT BEACH, CALIF. – The evolving treatment of acute myeloid leukemia (AML) was highlighted at the Acute Leukemia Forum of Hemedicus.
In a video interview, Martin Tallman, MD, of Memorial Sloan Kettering Cancer Center in New York, discussed several meeting presentations on the treatment of AML.
In his presentation, Craig Jordan, PhD, of the University of Colorado at Denver, Aurora, explained how the combination of venetoclax and azacitidine appears to target leukemic stem cells in AML.
Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented information on novel agents for AML, including antibody-drug conjugates; bispecific therapies; checkpoint inhibitors; and inhibitors of IDH1/2, MCL1, and MDM2.
Richard Larson, MD, of the University of Chicago, explored the possibility of an individualized approach to postremission therapy in AML.
Frederick Appelbaum, MD, of Fred Hutchinson Cancer Research Center in Seattle, showed that various maintenance therapies given after allogeneic hematopoietic stem cell transplant (HSCT) have not proven beneficial for AML patients.
Richard Jones, MD, of Johns Hopkins Medicine in Baltimore, presented data showing that post-HSCT cyclophosphamide has made haploidentical transplants safer and more effective for AML patients.
And James Ferrara, MD, of the Icahn School of Medicine at Mount Sinai, New York, detailed research showing that biomarkers of graft-versus-host disease can predict nonrelapse mortality after HSCT.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – The evolving treatment of acute myeloid leukemia (AML) was highlighted at the Acute Leukemia Forum of Hemedicus.
In a video interview, Martin Tallman, MD, of Memorial Sloan Kettering Cancer Center in New York, discussed several meeting presentations on the treatment of AML.
In his presentation, Craig Jordan, PhD, of the University of Colorado at Denver, Aurora, explained how the combination of venetoclax and azacitidine appears to target leukemic stem cells in AML.
Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented information on novel agents for AML, including antibody-drug conjugates; bispecific therapies; checkpoint inhibitors; and inhibitors of IDH1/2, MCL1, and MDM2.
Richard Larson, MD, of the University of Chicago, explored the possibility of an individualized approach to postremission therapy in AML.
Frederick Appelbaum, MD, of Fred Hutchinson Cancer Research Center in Seattle, showed that various maintenance therapies given after allogeneic hematopoietic stem cell transplant (HSCT) have not proven beneficial for AML patients.
Richard Jones, MD, of Johns Hopkins Medicine in Baltimore, presented data showing that post-HSCT cyclophosphamide has made haploidentical transplants safer and more effective for AML patients.
And James Ferrara, MD, of the Icahn School of Medicine at Mount Sinai, New York, detailed research showing that biomarkers of graft-versus-host disease can predict nonrelapse mortality after HSCT.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – The evolving treatment of acute myeloid leukemia (AML) was highlighted at the Acute Leukemia Forum of Hemedicus.
In a video interview, Martin Tallman, MD, of Memorial Sloan Kettering Cancer Center in New York, discussed several meeting presentations on the treatment of AML.
In his presentation, Craig Jordan, PhD, of the University of Colorado at Denver, Aurora, explained how the combination of venetoclax and azacitidine appears to target leukemic stem cells in AML.
Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented information on novel agents for AML, including antibody-drug conjugates; bispecific therapies; checkpoint inhibitors; and inhibitors of IDH1/2, MCL1, and MDM2.
Richard Larson, MD, of the University of Chicago, explored the possibility of an individualized approach to postremission therapy in AML.
Frederick Appelbaum, MD, of Fred Hutchinson Cancer Research Center in Seattle, showed that various maintenance therapies given after allogeneic hematopoietic stem cell transplant (HSCT) have not proven beneficial for AML patients.
Richard Jones, MD, of Johns Hopkins Medicine in Baltimore, presented data showing that post-HSCT cyclophosphamide has made haploidentical transplants safer and more effective for AML patients.
And James Ferrara, MD, of the Icahn School of Medicine at Mount Sinai, New York, detailed research showing that biomarkers of graft-versus-host disease can predict nonrelapse mortality after HSCT.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
Back to the drawing board for MPN combo
NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).
The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”
However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.
Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.
The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.
Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.
Treatment and safety
For the first cycle, patients received decitabine at 20 mg/m2 per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.
“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.
Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.
Response and survival
Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.
Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.
Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.
The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.
The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.
Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.
“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”
Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).
The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”
However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.
Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.
The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.
Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.
Treatment and safety
For the first cycle, patients received decitabine at 20 mg/m2 per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.
“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.
Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.
Response and survival
Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.
Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.
Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.
The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.
The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.
Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.
“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”
Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).
The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”
However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.
Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.
The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.
Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.
Treatment and safety
For the first cycle, patients received decitabine at 20 mg/m2 per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.
“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.
Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.
Response and survival
Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.
Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.
Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.
The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.
The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.
Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.
“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”
Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
Creating CAR T-cell therapies for T-cell malignancies
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM ALF 2019
SB-525 gene therapy looks viable for hemophilia A
Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.
In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.
In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.
Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.
The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.
Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.
Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.
Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.
Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.
“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.
The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).
“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.
Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.
The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.
Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.
In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.
In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.
Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.
The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.
Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.
Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.
Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.
Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.
“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.
The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).
“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.
Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.
The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.
Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.
In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.
In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.
Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.
The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.
Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.
Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.
Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.
Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.
“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.
The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).
“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.
Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.
The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.
In situ vaccination produced responses in indolent NHL
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
FROM NATURE MEDICINE
New leaders at SGO, AACR
The Society of Gynecologic Oncology (SGO) has a new leader at the helm.
Warner K. Huh, MD, of the University of Alabama at Birmingham, has been named president of the SGO. Dr. Huh began his 1-year term at the end of SGO’s Annual Meeting on Women’s Cancer, which took place in March 2019.
Dr. Huh said he plans to focus his presidency on the changing practice of gynecologic oncology, including surgery and novel therapies, clinical trial mentorship, subspecialty awareness, alternative payment models, and the role of gynecologic oncologists in benign gynecologic surgery.
Another newly installed president is Elaine R. Mardis, PhD, of Nationwide Children’s Hospital in Columbus, Ohio. Dr. Mardis was named president of the American Association for Cancer Research (AACR) for 2019-2020.
She has conducted extensive research on the genomic characterization of various cancers. She was inaugurated as AACR president during the AACR’s annual meeting, which took place March 29-April 3, 2019.
Also at the AACR annual meeting, Antoni Ribas, MD, PhD, of the University of California, Los Angeles, was inducted as president-elect of AACR. Dr. Ribas will assume the presidency in April 2020. He has conducted research focused on malignant melanoma and is said to have been “instrumental” in the development of several drugs used to treat the disease.
In other news, the National Comprehensive Cancer Network (NCCN) named Ronald Walters, MD, chair of its board of directors, and Ruth O’Regan, MD, was named vice chair.
Dr. Walters, of the University of Texas MD Anderson Cancer Center in Houston, conducts research focused on health care reform and cost accounting in health care.
Dr. O’Regan, of the University of Wisconsin Carbone Cancer Center in Madison, conducts research focused on identifying mechanisms of treatment resistance and developing new therapies for breast cancer.
Finally, Giulio F. Draetta, MD, PhD, was named chief scientific officer at the University of Texas MD Anderson Cancer Center. This is a new position that “champions innovation, develops strong partnerships, and provides focused leadership on the science and clinical translation of research programs,” according to MD Anderson.
Dr. Draetta conducted “fundamental” research on the eukaryotic cell division cycle and DNA damage-induced checkpoints. He has cofounded and led biotechnology companies and headed drug discovery and development programs that led to two drug approvals, according to MD Anderson.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
The Society of Gynecologic Oncology (SGO) has a new leader at the helm.
Warner K. Huh, MD, of the University of Alabama at Birmingham, has been named president of the SGO. Dr. Huh began his 1-year term at the end of SGO’s Annual Meeting on Women’s Cancer, which took place in March 2019.
Dr. Huh said he plans to focus his presidency on the changing practice of gynecologic oncology, including surgery and novel therapies, clinical trial mentorship, subspecialty awareness, alternative payment models, and the role of gynecologic oncologists in benign gynecologic surgery.
Another newly installed president is Elaine R. Mardis, PhD, of Nationwide Children’s Hospital in Columbus, Ohio. Dr. Mardis was named president of the American Association for Cancer Research (AACR) for 2019-2020.
She has conducted extensive research on the genomic characterization of various cancers. She was inaugurated as AACR president during the AACR’s annual meeting, which took place March 29-April 3, 2019.
Also at the AACR annual meeting, Antoni Ribas, MD, PhD, of the University of California, Los Angeles, was inducted as president-elect of AACR. Dr. Ribas will assume the presidency in April 2020. He has conducted research focused on malignant melanoma and is said to have been “instrumental” in the development of several drugs used to treat the disease.
In other news, the National Comprehensive Cancer Network (NCCN) named Ronald Walters, MD, chair of its board of directors, and Ruth O’Regan, MD, was named vice chair.
Dr. Walters, of the University of Texas MD Anderson Cancer Center in Houston, conducts research focused on health care reform and cost accounting in health care.
Dr. O’Regan, of the University of Wisconsin Carbone Cancer Center in Madison, conducts research focused on identifying mechanisms of treatment resistance and developing new therapies for breast cancer.
Finally, Giulio F. Draetta, MD, PhD, was named chief scientific officer at the University of Texas MD Anderson Cancer Center. This is a new position that “champions innovation, develops strong partnerships, and provides focused leadership on the science and clinical translation of research programs,” according to MD Anderson.
Dr. Draetta conducted “fundamental” research on the eukaryotic cell division cycle and DNA damage-induced checkpoints. He has cofounded and led biotechnology companies and headed drug discovery and development programs that led to two drug approvals, according to MD Anderson.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
The Society of Gynecologic Oncology (SGO) has a new leader at the helm.
Warner K. Huh, MD, of the University of Alabama at Birmingham, has been named president of the SGO. Dr. Huh began his 1-year term at the end of SGO’s Annual Meeting on Women’s Cancer, which took place in March 2019.
Dr. Huh said he plans to focus his presidency on the changing practice of gynecologic oncology, including surgery and novel therapies, clinical trial mentorship, subspecialty awareness, alternative payment models, and the role of gynecologic oncologists in benign gynecologic surgery.
Another newly installed president is Elaine R. Mardis, PhD, of Nationwide Children’s Hospital in Columbus, Ohio. Dr. Mardis was named president of the American Association for Cancer Research (AACR) for 2019-2020.
She has conducted extensive research on the genomic characterization of various cancers. She was inaugurated as AACR president during the AACR’s annual meeting, which took place March 29-April 3, 2019.
Also at the AACR annual meeting, Antoni Ribas, MD, PhD, of the University of California, Los Angeles, was inducted as president-elect of AACR. Dr. Ribas will assume the presidency in April 2020. He has conducted research focused on malignant melanoma and is said to have been “instrumental” in the development of several drugs used to treat the disease.
In other news, the National Comprehensive Cancer Network (NCCN) named Ronald Walters, MD, chair of its board of directors, and Ruth O’Regan, MD, was named vice chair.
Dr. Walters, of the University of Texas MD Anderson Cancer Center in Houston, conducts research focused on health care reform and cost accounting in health care.
Dr. O’Regan, of the University of Wisconsin Carbone Cancer Center in Madison, conducts research focused on identifying mechanisms of treatment resistance and developing new therapies for breast cancer.
Finally, Giulio F. Draetta, MD, PhD, was named chief scientific officer at the University of Texas MD Anderson Cancer Center. This is a new position that “champions innovation, develops strong partnerships, and provides focused leadership on the science and clinical translation of research programs,” according to MD Anderson.
Dr. Draetta conducted “fundamental” research on the eukaryotic cell division cycle and DNA damage-induced checkpoints. He has cofounded and led biotechnology companies and headed drug discovery and development programs that led to two drug approvals, according to MD Anderson.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.