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American Society of Hematology (ASH): ASH 2016
Microsensor perfectly distinguished coagulopathy patients from controls
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in less than 15 minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating the results with both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity using dielectric spectroscopy, Evi X. Stavrou, MD, said at the annual meeting of the American Society of Hematology. The development points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
Existing point-of-care coagulation assays have several shortcomings, Dr. Stavrou, of Case Western Reserve University, Cleveland, said during a press briefing at the conference. They are relatively insensitive, fail to measure platelet activity, or are only approved for specific subgroups of patients, such as those on warfarin, she specified.
To develop an alternative, Dr. Stavrou and her associates added a parallel-plate capacitive sensing structure to an inexpensive, disposable microfluidic biochip designed to test 9 microliters (less than one drop) of blood. They built the microsensor from biocompatible and chemically inert materials to minimize the chances of artificial contact activation.
To test the device, the researchers used calcium dichloride to induce coagulation in whole blood samples from 11 controls with normal aPTT and PT values. Time curves of output from the microsensor showed that coagulation consistently peaked within 4.5 to 6 minutes.
Next, the investigators tested blood from 12 patients with coagulopathies, including hemophilia A, hemophilia B, acquired von Willebrand factor defect, and congenital hypodysfibrinogenemia. These samples all yielded abnormal curves, with prolonged times to peak that ranged between 7 and 15 minutes – significantly exceeding those of healthy controls (P = .0002).
By plotting rates of true positives against rates of true negatives, the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Finally, the researchers used the microsensor to measure coagulation activity in normal blood samples that they treated with prostaglandin E2 to inhibit platelet aggregation. Normalized permittivity (an electrical measure) was significantly lower than in untreated control samples (P = .03), but time to peak values were the same in both groups. This finding confirms that the chip can identify abnormal platelet function, Dr. Stavrou said. “ClotChip is sensitive to the complete hemostasis process, exhibits better sensitivity and specificity than conventional coagulation assays, and discriminates between coagulation and platelet defects,” she concluded.
The investigators are recruiting volunteers for an expanded round of testing for the device, and are working to optimize construction to further enhance its sensitivity.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in less than 15 minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating the results with both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity using dielectric spectroscopy, Evi X. Stavrou, MD, said at the annual meeting of the American Society of Hematology. The development points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
Existing point-of-care coagulation assays have several shortcomings, Dr. Stavrou, of Case Western Reserve University, Cleveland, said during a press briefing at the conference. They are relatively insensitive, fail to measure platelet activity, or are only approved for specific subgroups of patients, such as those on warfarin, she specified.
To develop an alternative, Dr. Stavrou and her associates added a parallel-plate capacitive sensing structure to an inexpensive, disposable microfluidic biochip designed to test 9 microliters (less than one drop) of blood. They built the microsensor from biocompatible and chemically inert materials to minimize the chances of artificial contact activation.
To test the device, the researchers used calcium dichloride to induce coagulation in whole blood samples from 11 controls with normal aPTT and PT values. Time curves of output from the microsensor showed that coagulation consistently peaked within 4.5 to 6 minutes.
Next, the investigators tested blood from 12 patients with coagulopathies, including hemophilia A, hemophilia B, acquired von Willebrand factor defect, and congenital hypodysfibrinogenemia. These samples all yielded abnormal curves, with prolonged times to peak that ranged between 7 and 15 minutes – significantly exceeding those of healthy controls (P = .0002).
By plotting rates of true positives against rates of true negatives, the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Finally, the researchers used the microsensor to measure coagulation activity in normal blood samples that they treated with prostaglandin E2 to inhibit platelet aggregation. Normalized permittivity (an electrical measure) was significantly lower than in untreated control samples (P = .03), but time to peak values were the same in both groups. This finding confirms that the chip can identify abnormal platelet function, Dr. Stavrou said. “ClotChip is sensitive to the complete hemostasis process, exhibits better sensitivity and specificity than conventional coagulation assays, and discriminates between coagulation and platelet defects,” she concluded.
The investigators are recruiting volunteers for an expanded round of testing for the device, and are working to optimize construction to further enhance its sensitivity.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in less than 15 minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating the results with both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity using dielectric spectroscopy, Evi X. Stavrou, MD, said at the annual meeting of the American Society of Hematology. The development points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
Existing point-of-care coagulation assays have several shortcomings, Dr. Stavrou, of Case Western Reserve University, Cleveland, said during a press briefing at the conference. They are relatively insensitive, fail to measure platelet activity, or are only approved for specific subgroups of patients, such as those on warfarin, she specified.
To develop an alternative, Dr. Stavrou and her associates added a parallel-plate capacitive sensing structure to an inexpensive, disposable microfluidic biochip designed to test 9 microliters (less than one drop) of blood. They built the microsensor from biocompatible and chemically inert materials to minimize the chances of artificial contact activation.
To test the device, the researchers used calcium dichloride to induce coagulation in whole blood samples from 11 controls with normal aPTT and PT values. Time curves of output from the microsensor showed that coagulation consistently peaked within 4.5 to 6 minutes.
Next, the investigators tested blood from 12 patients with coagulopathies, including hemophilia A, hemophilia B, acquired von Willebrand factor defect, and congenital hypodysfibrinogenemia. These samples all yielded abnormal curves, with prolonged times to peak that ranged between 7 and 15 minutes – significantly exceeding those of healthy controls (P = .0002).
By plotting rates of true positives against rates of true negatives, the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Finally, the researchers used the microsensor to measure coagulation activity in normal blood samples that they treated with prostaglandin E2 to inhibit platelet aggregation. Normalized permittivity (an electrical measure) was significantly lower than in untreated control samples (P = .03), but time to peak values were the same in both groups. This finding confirms that the chip can identify abnormal platelet function, Dr. Stavrou said. “ClotChip is sensitive to the complete hemostasis process, exhibits better sensitivity and specificity than conventional coagulation assays, and discriminates between coagulation and platelet defects,” she concluded.
The investigators are recruiting volunteers for an expanded round of testing for the device, and are working to optimize construction to further enhance its sensitivity.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
AT ASH 2016
Key clinical point: A prototype point-of-care microsensor perfectly distinguished patients with various coagulopathies from healthy controls.
Major finding: The area under the receiver operating characteristic curve was 100%, compared with 78% for aPTT and 59% for PT.
Data source: Oral and poster sessions at ASH 2016.
Disclosures: None of the investigators had relevant financial disclosures.
VIDEO: Combination venetoclax-LDAC therapy boosts overall survival in AML
SAN DIEGO – Combination therapy with the BCL-2 inhibitor venetoclax and low-dose cytarabine (LDAC) achieved a 61% overall response rate in older patients with treatment-naive acute myeloid leukemia, Andrew Wei, MBBS, PhD, reported at the annual meeting of the American Society of Hematology.
That is about three times higher than historically reported response rates for this deadly blood cancer, said Dr. Wei of Alfred Hospital in Melbourne, Australia. He discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The multicenter phase II study evaluated 28-cycles of venetoclax (600 mg, given orally) and LDAC (20 mg/m2 subcutaneously) in 53 treatment-naive AML patients aged 65 years and older, who were ineligible for intensive chemotherapy but had adequate liver and kidney function and an ECOG performance status between 0 and 2.
A total of 21% of patients had a complete remission, 33% had complete remission with incomplete marrow recovery, and 70% reached one of these endpoints during cycles 1 and 2. Common adverse events included vomiting, diarrhea, hypokalemia, and febrile neutropenia. Grade 3-4 adverse events included febrile neutropenia, hypokalemia, hypophosphatemia, and hypertension.
Researchers are planning larger randomized trials of venetoclax/LDAC combination therapy in AML, Dr. Wei said. Larger sample sizes will yield more data on how to best target this regimen based on prognostic indicators, such as gene mutations, he added.
Abbvie is the maker of venetoclax and sponsored the study. Dr. Wei disclosed a consulting relationship with Abbvie and ties to Novartis, Celgene, and several other pharmaceutical companies.
SAN DIEGO – Combination therapy with the BCL-2 inhibitor venetoclax and low-dose cytarabine (LDAC) achieved a 61% overall response rate in older patients with treatment-naive acute myeloid leukemia, Andrew Wei, MBBS, PhD, reported at the annual meeting of the American Society of Hematology.
That is about three times higher than historically reported response rates for this deadly blood cancer, said Dr. Wei of Alfred Hospital in Melbourne, Australia. He discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The multicenter phase II study evaluated 28-cycles of venetoclax (600 mg, given orally) and LDAC (20 mg/m2 subcutaneously) in 53 treatment-naive AML patients aged 65 years and older, who were ineligible for intensive chemotherapy but had adequate liver and kidney function and an ECOG performance status between 0 and 2.
A total of 21% of patients had a complete remission, 33% had complete remission with incomplete marrow recovery, and 70% reached one of these endpoints during cycles 1 and 2. Common adverse events included vomiting, diarrhea, hypokalemia, and febrile neutropenia. Grade 3-4 adverse events included febrile neutropenia, hypokalemia, hypophosphatemia, and hypertension.
Researchers are planning larger randomized trials of venetoclax/LDAC combination therapy in AML, Dr. Wei said. Larger sample sizes will yield more data on how to best target this regimen based on prognostic indicators, such as gene mutations, he added.
Abbvie is the maker of venetoclax and sponsored the study. Dr. Wei disclosed a consulting relationship with Abbvie and ties to Novartis, Celgene, and several other pharmaceutical companies.
SAN DIEGO – Combination therapy with the BCL-2 inhibitor venetoclax and low-dose cytarabine (LDAC) achieved a 61% overall response rate in older patients with treatment-naive acute myeloid leukemia, Andrew Wei, MBBS, PhD, reported at the annual meeting of the American Society of Hematology.
That is about three times higher than historically reported response rates for this deadly blood cancer, said Dr. Wei of Alfred Hospital in Melbourne, Australia. He discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The multicenter phase II study evaluated 28-cycles of venetoclax (600 mg, given orally) and LDAC (20 mg/m2 subcutaneously) in 53 treatment-naive AML patients aged 65 years and older, who were ineligible for intensive chemotherapy but had adequate liver and kidney function and an ECOG performance status between 0 and 2.
A total of 21% of patients had a complete remission, 33% had complete remission with incomplete marrow recovery, and 70% reached one of these endpoints during cycles 1 and 2. Common adverse events included vomiting, diarrhea, hypokalemia, and febrile neutropenia. Grade 3-4 adverse events included febrile neutropenia, hypokalemia, hypophosphatemia, and hypertension.
Researchers are planning larger randomized trials of venetoclax/LDAC combination therapy in AML, Dr. Wei said. Larger sample sizes will yield more data on how to best target this regimen based on prognostic indicators, such as gene mutations, he added.
Abbvie is the maker of venetoclax and sponsored the study. Dr. Wei disclosed a consulting relationship with Abbvie and ties to Novartis, Celgene, and several other pharmaceutical companies.
AT ASH 2016
Key clinical point: Combination therapy with venetoclax and low-dose cytarabine (LDAC) achieved a high overall response rate in patients with AML.
Major finding: In all, 61% of patients achieved an overall response. Grade 3-4 adverse events included febrile neutropenia, hypokalemia, hypophosphatemia, and hypertension.
Data source: A multicenter phase II study of venetoclax (600 mg) and LDAC (20 mg/m2) in 53 treatment-naive AML patients aged 65 years and older, who were ineligible for intensive chemotherapy but had adequate liver and kidney function and an ECOG performance status of 0-2.
Disclosures: Abbvie is the maker of venetoclax and sponsored the study. Dr. Wei disclosed a consulting relationship with Abbvie and ties to Novartis, Celgene, and several other pharmaceutical companies.
VIDEO: CPX-351 may allow more high-risk AML patients to have allogeneic transplants
SAN DIEGO – Induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed more older patients with newly diagnosed secondary AML to bridge successfully to transplant than did standard 7+3 cytarabine and daunorubicin, based on data reported by Jeffrey E. Lancet, MD, at the annual meeting of the American Society of Hematology.
The data come from a subgroup analysis of a phase III study in 60- to 75-year-old patients with secondary AML. Initial survival data from that randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
Dr. Lancet of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., credited the better results to the higher level of complete responses and complete responses with incomplete platelet or neutrophil recovery with the liposomal formulation.
In a video interview, Dr. Lancet discussed how better disease control allowed more patients to be transplanted and next steps for expanded study in this patient population as well as in younger patients with AML.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mdales@frontlinemedcom.com
On Twitter @maryjodales
SAN DIEGO – Induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed more older patients with newly diagnosed secondary AML to bridge successfully to transplant than did standard 7+3 cytarabine and daunorubicin, based on data reported by Jeffrey E. Lancet, MD, at the annual meeting of the American Society of Hematology.
The data come from a subgroup analysis of a phase III study in 60- to 75-year-old patients with secondary AML. Initial survival data from that randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
Dr. Lancet of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., credited the better results to the higher level of complete responses and complete responses with incomplete platelet or neutrophil recovery with the liposomal formulation.
In a video interview, Dr. Lancet discussed how better disease control allowed more patients to be transplanted and next steps for expanded study in this patient population as well as in younger patients with AML.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mdales@frontlinemedcom.com
On Twitter @maryjodales
SAN DIEGO – Induction therapy with the investigational drug CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin, allowed more older patients with newly diagnosed secondary AML to bridge successfully to transplant than did standard 7+3 cytarabine and daunorubicin, based on data reported by Jeffrey E. Lancet, MD, at the annual meeting of the American Society of Hematology.
The data come from a subgroup analysis of a phase III study in 60- to 75-year-old patients with secondary AML. Initial survival data from that randomized open-label study, reported last June at the annual meeting of the American Society of Clinical Oncology, indicated CPX-351 significantly improved overall survival, event-free survival, and treatment response without an increase in 60-day mortality or in the frequency and severity of adverse events, compared with the standard 7+3 regimen of cytarabine and daunorubicin.
Dr. Lancet of the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla., credited the better results to the higher level of complete responses and complete responses with incomplete platelet or neutrophil recovery with the liposomal formulation.
In a video interview, Dr. Lancet discussed how better disease control allowed more patients to be transplanted and next steps for expanded study in this patient population as well as in younger patients with AML.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mdales@frontlinemedcom.com
On Twitter @maryjodales
AT ASH 2016
VIDEO: Half-dose TKI safe, cost-effective in CML in stable remission
SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,
In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.
Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,
In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.
Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,
In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.
Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
VIDEO: Venetoclax shows early good results in multiple myeloma
SAN DIEGO – Venetoclax has shown preliminary good results as an investigational monotherapy in patients with relapsed/refractory multiple myeloma, based on phase I data reported at the annual meeting of the American Society of Hematology.
Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minn., reported that venetoclax monotherapy had anti-myeloma activity in a dose-finding study among patients treated with a median of five previous therapies. As would be expected, the best responses to the small-molecule BCL-2 inhibitor were seen primarily in patients with t(11;14) chromosomal aberrations and high BCL-2, low BCL-XL and low MCL-1 expression levels.
In a video interview, Dr. Kumar discussed the results of this early-stage research as well as ongoing studies that are beginning to examine venetoclax in combination regimens for multiple myeloma.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Venetoclax is approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion who have received at least one prior treatment. Dr. Kumar receives research funding from Abbvie, the maker of venetoclax (Venclexta), and is a consultant to and receives research funding from several other drug companies.
mdales@frontlinemedcom.com
On Twitter @maryjodales
SAN DIEGO – Venetoclax has shown preliminary good results as an investigational monotherapy in patients with relapsed/refractory multiple myeloma, based on phase I data reported at the annual meeting of the American Society of Hematology.
Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minn., reported that venetoclax monotherapy had anti-myeloma activity in a dose-finding study among patients treated with a median of five previous therapies. As would be expected, the best responses to the small-molecule BCL-2 inhibitor were seen primarily in patients with t(11;14) chromosomal aberrations and high BCL-2, low BCL-XL and low MCL-1 expression levels.
In a video interview, Dr. Kumar discussed the results of this early-stage research as well as ongoing studies that are beginning to examine venetoclax in combination regimens for multiple myeloma.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Venetoclax is approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion who have received at least one prior treatment. Dr. Kumar receives research funding from Abbvie, the maker of venetoclax (Venclexta), and is a consultant to and receives research funding from several other drug companies.
mdales@frontlinemedcom.com
On Twitter @maryjodales
SAN DIEGO – Venetoclax has shown preliminary good results as an investigational monotherapy in patients with relapsed/refractory multiple myeloma, based on phase I data reported at the annual meeting of the American Society of Hematology.
Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minn., reported that venetoclax monotherapy had anti-myeloma activity in a dose-finding study among patients treated with a median of five previous therapies. As would be expected, the best responses to the small-molecule BCL-2 inhibitor were seen primarily in patients with t(11;14) chromosomal aberrations and high BCL-2, low BCL-XL and low MCL-1 expression levels.
In a video interview, Dr. Kumar discussed the results of this early-stage research as well as ongoing studies that are beginning to examine venetoclax in combination regimens for multiple myeloma.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Venetoclax is approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion who have received at least one prior treatment. Dr. Kumar receives research funding from Abbvie, the maker of venetoclax (Venclexta), and is a consultant to and receives research funding from several other drug companies.
mdales@frontlinemedcom.com
On Twitter @maryjodales
AT ASH 2016
VIDEO: 33A + ‘7 + 3’ equals good remission numbers in untreated AML
SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.
Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“In 1973, 43 years ago, the first paper was published on what we still continue to use as the initial therapy for a very aggressive cancer, acute myeloid leukemia,” he said at a briefing at the American Society of Hematology annual meeting.
“Nothing has been shown yet to be superior to that, despite four decades of clinical research,” he added.
Recent studies have suggested that depth of postinduction remissions, specifically being minimal residual disease (MRD)-negative, is associated with improved survival, he noted.
Vadastuximab talirine (33A, for short) is an antibody-drug conjugate targeted to CD33, which is expressed in approximately 90% of AML cells. The drug is designed to deliver a cytotoxic agent to myeloid leukemia cells.
As reported previously, 33A, in combination with a hypomethylating agent (decitabine or azacitidine) in 49 evaluable patients, was associated with a composite CR/CRi rate of 71%; the rates of CR/CRi were similar regardless of the partner agent used.
The overall response rate in that study was 76%, with responses seen among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.
Rapid complete remissions
In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.
The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.
Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.
The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.
As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.
All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.
Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.
Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.
The death rate was 2%.
“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”
33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.
A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.
Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.
SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.
Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“In 1973, 43 years ago, the first paper was published on what we still continue to use as the initial therapy for a very aggressive cancer, acute myeloid leukemia,” he said at a briefing at the American Society of Hematology annual meeting.
“Nothing has been shown yet to be superior to that, despite four decades of clinical research,” he added.
Recent studies have suggested that depth of postinduction remissions, specifically being minimal residual disease (MRD)-negative, is associated with improved survival, he noted.
Vadastuximab talirine (33A, for short) is an antibody-drug conjugate targeted to CD33, which is expressed in approximately 90% of AML cells. The drug is designed to deliver a cytotoxic agent to myeloid leukemia cells.
As reported previously, 33A, in combination with a hypomethylating agent (decitabine or azacitidine) in 49 evaluable patients, was associated with a composite CR/CRi rate of 71%; the rates of CR/CRi were similar regardless of the partner agent used.
The overall response rate in that study was 76%, with responses seen among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.
Rapid complete remissions
In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.
The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.
Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.
The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.
As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.
All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.
Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.
Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.
The death rate was 2%.
“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”
33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.
A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.
Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.
SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.
Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.
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“In 1973, 43 years ago, the first paper was published on what we still continue to use as the initial therapy for a very aggressive cancer, acute myeloid leukemia,” he said at a briefing at the American Society of Hematology annual meeting.
“Nothing has been shown yet to be superior to that, despite four decades of clinical research,” he added.
Recent studies have suggested that depth of postinduction remissions, specifically being minimal residual disease (MRD)-negative, is associated with improved survival, he noted.
Vadastuximab talirine (33A, for short) is an antibody-drug conjugate targeted to CD33, which is expressed in approximately 90% of AML cells. The drug is designed to deliver a cytotoxic agent to myeloid leukemia cells.
As reported previously, 33A, in combination with a hypomethylating agent (decitabine or azacitidine) in 49 evaluable patients, was associated with a composite CR/CRi rate of 71%; the rates of CR/CRi were similar regardless of the partner agent used.
The overall response rate in that study was 76%, with responses seen among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.
Rapid complete remissions
In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.
The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.
Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.
The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.
As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.
All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.
Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.
Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.
The death rate was 2%.
“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”
33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.
A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.
Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.
AT ASH 2016
Key clinical point: Deep remissions following induction therapy with AML are associated with better survival outcomes.
Major finding: Adding the antibody drug conjugate vadastuximab talirine (33A) to 7+3 induction therapy induced complete or near-complete remissions 76% of patients with newly diagnosed acute myeloid leukemia.
Data source: Phase Ib study in 42 patients with previously untreated primary or secondary AML.
Disclosures: Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.
Halving the TKI dose safe, cost effective in CML patients with stable remissions
SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.
In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.
“What we wanted to explore in the Destiny study is cutting the dose of tyrosine kinase inhibitor therapy in CML by half, followed by stopping therapy not just in patients with undetectable disease but also with stable low levels of disease,” Dr. Copland said during a briefing at the meeting.
“We hypothesized that more patients would be able to reduce therapy safely, and a proportion of these would be able to go on to stop therapy; also, that the patients on half-dose therapy would have reduced amount of side effects compared to those on full-dose therapy,” she added.
Several recent studies, including the EURO-SKI trial, have shown that it is safe to stop TKI therapy in those patients who are optimally responding and have undetectable levels of the BCR-ABL transcript.
Rendezvous with Destiny
In Destiny, the investigators enrolled patients with “good, but not perfect” molecular responses: MR3 or better, defined as a minimum of 3 consecutive tests each with greater than 10,000 ABL control transcripts following a minimum of 3 years on a TKI at standard prescribed doses. The median overall duration of TKI therapy was 7 years.
Participants on imatinib had their daily doses reduced to 200 mg, those on nilotinib had their doses cut back to 200 mg twice daily, and those on dasatinib had their quotidian doses halved to 50 mg.
After 12 months of half-dose therapy, molecular recurrence, defined as a loss of MR3 on two consecutive samples, was detected in 9 of 49 patients (18.4%) with MR3 but not MR4 remissions, compared with 3 of 125 patients (2.4%) with MR4 or better remissions (P less than .001).
The median time to relapse was 4.4 months among MR3/not 4 patients vs. 8.7 months for MR4 or better patients.
The probability of molecular recurrence on dose reduction was unrelated to either age, sex, performance status, type of TKI, or the duration of TKI therapy (median 7 years overall).
No patients experienced either progression to advanced phase disease or loss of cytogenetic response. During the course of follow-up, one patient died, and there were 15 serious adverse events, but these were determined to be unrelated to either CML or TKI treatment.
All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.
As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.
The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).
EURO-SKI Update
Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.
The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.
As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.
“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.
The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.
EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.
SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.
In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.
“What we wanted to explore in the Destiny study is cutting the dose of tyrosine kinase inhibitor therapy in CML by half, followed by stopping therapy not just in patients with undetectable disease but also with stable low levels of disease,” Dr. Copland said during a briefing at the meeting.
“We hypothesized that more patients would be able to reduce therapy safely, and a proportion of these would be able to go on to stop therapy; also, that the patients on half-dose therapy would have reduced amount of side effects compared to those on full-dose therapy,” she added.
Several recent studies, including the EURO-SKI trial, have shown that it is safe to stop TKI therapy in those patients who are optimally responding and have undetectable levels of the BCR-ABL transcript.
Rendezvous with Destiny
In Destiny, the investigators enrolled patients with “good, but not perfect” molecular responses: MR3 or better, defined as a minimum of 3 consecutive tests each with greater than 10,000 ABL control transcripts following a minimum of 3 years on a TKI at standard prescribed doses. The median overall duration of TKI therapy was 7 years.
Participants on imatinib had their daily doses reduced to 200 mg, those on nilotinib had their doses cut back to 200 mg twice daily, and those on dasatinib had their quotidian doses halved to 50 mg.
After 12 months of half-dose therapy, molecular recurrence, defined as a loss of MR3 on two consecutive samples, was detected in 9 of 49 patients (18.4%) with MR3 but not MR4 remissions, compared with 3 of 125 patients (2.4%) with MR4 or better remissions (P less than .001).
The median time to relapse was 4.4 months among MR3/not 4 patients vs. 8.7 months for MR4 or better patients.
The probability of molecular recurrence on dose reduction was unrelated to either age, sex, performance status, type of TKI, or the duration of TKI therapy (median 7 years overall).
No patients experienced either progression to advanced phase disease or loss of cytogenetic response. During the course of follow-up, one patient died, and there were 15 serious adverse events, but these were determined to be unrelated to either CML or TKI treatment.
All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.
As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.
The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).
EURO-SKI Update
Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.
The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.
As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.
“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.
The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.
EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.
SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.
In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.
“What we wanted to explore in the Destiny study is cutting the dose of tyrosine kinase inhibitor therapy in CML by half, followed by stopping therapy not just in patients with undetectable disease but also with stable low levels of disease,” Dr. Copland said during a briefing at the meeting.
“We hypothesized that more patients would be able to reduce therapy safely, and a proportion of these would be able to go on to stop therapy; also, that the patients on half-dose therapy would have reduced amount of side effects compared to those on full-dose therapy,” she added.
Several recent studies, including the EURO-SKI trial, have shown that it is safe to stop TKI therapy in those patients who are optimally responding and have undetectable levels of the BCR-ABL transcript.
Rendezvous with Destiny
In Destiny, the investigators enrolled patients with “good, but not perfect” molecular responses: MR3 or better, defined as a minimum of 3 consecutive tests each with greater than 10,000 ABL control transcripts following a minimum of 3 years on a TKI at standard prescribed doses. The median overall duration of TKI therapy was 7 years.
Participants on imatinib had their daily doses reduced to 200 mg, those on nilotinib had their doses cut back to 200 mg twice daily, and those on dasatinib had their quotidian doses halved to 50 mg.
After 12 months of half-dose therapy, molecular recurrence, defined as a loss of MR3 on two consecutive samples, was detected in 9 of 49 patients (18.4%) with MR3 but not MR4 remissions, compared with 3 of 125 patients (2.4%) with MR4 or better remissions (P less than .001).
The median time to relapse was 4.4 months among MR3/not 4 patients vs. 8.7 months for MR4 or better patients.
The probability of molecular recurrence on dose reduction was unrelated to either age, sex, performance status, type of TKI, or the duration of TKI therapy (median 7 years overall).
No patients experienced either progression to advanced phase disease or loss of cytogenetic response. During the course of follow-up, one patient died, and there were 15 serious adverse events, but these were determined to be unrelated to either CML or TKI treatment.
All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.
As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.
The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).
EURO-SKI Update
Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.
The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.
As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.
“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.
The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.
EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.
FROM ASH 2016
Key clinical point: Halving TKI doses in patients with chronic myeloid leukemia in stable remission is safe and cost effective.
Major finding: After halving TKI doses, there were 12 molecular relapses among 174 patients with an MR3 or better molecular response.
Data source: Prospective dose-reduction study in 174 patients with CML in MR3 remission or better.
Disclosures: The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad. EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.
Anti-CD22 CAR T-cells shift ALL into complete remission
SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.
In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.
“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.
Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.
Tough target
As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.
In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.
However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.
CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen
In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.
The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.
The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 105 transduced T-cells per recipient weight in kilograms (DL-1), 1 x 106/kg (DL-2), and 3 x 106/kg (DL-3).
The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.
As noted before, three of the remissions were comparatively durable, with one lasting more than a year.
There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.
In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.
“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.
The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.
SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.
In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.
“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.
Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.
Tough target
As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.
In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.
However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.
CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen
In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.
The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.
The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 105 transduced T-cells per recipient weight in kilograms (DL-1), 1 x 106/kg (DL-2), and 3 x 106/kg (DL-3).
The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.
As noted before, three of the remissions were comparatively durable, with one lasting more than a year.
There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.
In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.
“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.
The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.
SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.
In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.
“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.
Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.
Tough target
As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.
In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.
However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.
CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen
In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.
The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.
The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 105 transduced T-cells per recipient weight in kilograms (DL-1), 1 x 106/kg (DL-2), and 3 x 106/kg (DL-3).
The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.
As noted before, three of the remissions were comparatively durable, with one lasting more than a year.
There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.
In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.
“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.
The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.
FROM ASH 2016
Key clinical point: CAR T-cell therapy with an anti-CD22 antigen induced complete, MRD-negative remissions in children/young adults with acute lymphoblastic leukemia.
Major finding: The complete remission rate among patients treated at the two highest dose levels was 80%.
Data source: Phase 1 dose-finding trial in 16 children/young adults with relapsed/refractory ALL or diffuse large B-cell lymphoma.
Disclosures The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures views
VIDEO: Anti-CD22 CAR for R/R ALL impresses in early trial
SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.
In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.
In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.
In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
ASH: Hemophilia B gene therapy posts strong update
SAN DIEGO – Patients with hemophilia B who received a single 1-hour infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the 12% steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, said during a press briefing at the annual meeting of the American Society of Hematology. One patient infused himself once with factor IX after developing a suspected ankle bleed 2 days after treatment, Dr. High and her associates reported in the accompanying abstract.
This therapy works at a lower dose than previous factor IX gene transfer products and therefore has not caused the hepatotoxicity that halted their development, according to Dr. High, president and chief scientific officer of Spark Therapeutics, which makes SPK-9001. Two of nine patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels, but the immune response was halted by tapering doses of corticosteroids, and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor, she said.
Because the virus capsid breaks down over time, a transient immune response to it “is not really a safety issue, but is an efficacy issue,” Dr. High emphasized. “If it is not caught in time, and patients are not given steroids promptly, they can lose the donated gene. Therefore, quick recognition is key.” Patients who develop an immune response to the viral capsid show sharp declines in factor IX activity levels, rises in baseline AST and ALT, and mononuclear cell reactivity, she explained during an interview.
The current standard of care for hemophilia B involves the cost and treatment burden of intravenous factor IX injections given one to three times weekly. Previous work evaluated factor IX gene transfer mediated by adeno-associated virus, but long-term factor IX activity levels did not reach the trough levels typically achieved with long-acting factor IX prophylaxis. Simply escalating the vector dose did not work because the viral capsid triggered immune-mediated hepatotoxicity, Dr. High noted.
To develop a more efficient product that works at lower doses, she and her associates created a recombinant vector containing a bioengineered adeno-associated virus capsid and a DNA sequence with a promoter designed to drive hepatic expression of a highly active variant of factor IX. To test the product, researchers in Mississippi, Pennsylvania, and California enrolled men aged 18-52 years with a confirmed diagnosis of hemophilia B (no more than 2 IU/dL or 2% endogenous factor IX) who had received at least 50 days of exposure to factor IX products and averaged at least four bleeding events per year requiring factor IX treatment or prophylaxis. Patients had no measurable inhibitory antibodies but otherwise represented the “general hemophilia B population,” Dr. High said. Five of nine patients had multiple target joints, liver disease associated with hepatitis C virus infection, or both. Each patient received a 1-hour infusion of 5 x 1011 vector genomes per body weight and was followed for 7-52 weeks.
Among seven patients who, by Nov. 30, 2016, had surpassed the 12 weeks needed to reach steady state factor IX expression levels, median steady-state level was 30% (range, 13%-38%), Dr. High reported. “Now we can give one quarter the dose [of adeno-associated virus vector] that was given before, and its driving factor IX expression levels five to eight times higher,” she concluded. Results for the first seven treated patients prompted Food and Drug Administration to give the product orphan drug designation in July 2016. Plans for phase III trials are underway, and researchers also are planning to investigate this approach to gene therapy in hemophilia A, Dr. High said.
Spark Therapeutics Inc. and Pfizer sponsored the study. Dr. High is president and chief scientific officer of Spark. Dr. George had no relevant financial disclosures.
SAN DIEGO – Patients with hemophilia B who received a single 1-hour infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the 12% steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, said during a press briefing at the annual meeting of the American Society of Hematology. One patient infused himself once with factor IX after developing a suspected ankle bleed 2 days after treatment, Dr. High and her associates reported in the accompanying abstract.
This therapy works at a lower dose than previous factor IX gene transfer products and therefore has not caused the hepatotoxicity that halted their development, according to Dr. High, president and chief scientific officer of Spark Therapeutics, which makes SPK-9001. Two of nine patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels, but the immune response was halted by tapering doses of corticosteroids, and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor, she said.
Because the virus capsid breaks down over time, a transient immune response to it “is not really a safety issue, but is an efficacy issue,” Dr. High emphasized. “If it is not caught in time, and patients are not given steroids promptly, they can lose the donated gene. Therefore, quick recognition is key.” Patients who develop an immune response to the viral capsid show sharp declines in factor IX activity levels, rises in baseline AST and ALT, and mononuclear cell reactivity, she explained during an interview.
The current standard of care for hemophilia B involves the cost and treatment burden of intravenous factor IX injections given one to three times weekly. Previous work evaluated factor IX gene transfer mediated by adeno-associated virus, but long-term factor IX activity levels did not reach the trough levels typically achieved with long-acting factor IX prophylaxis. Simply escalating the vector dose did not work because the viral capsid triggered immune-mediated hepatotoxicity, Dr. High noted.
To develop a more efficient product that works at lower doses, she and her associates created a recombinant vector containing a bioengineered adeno-associated virus capsid and a DNA sequence with a promoter designed to drive hepatic expression of a highly active variant of factor IX. To test the product, researchers in Mississippi, Pennsylvania, and California enrolled men aged 18-52 years with a confirmed diagnosis of hemophilia B (no more than 2 IU/dL or 2% endogenous factor IX) who had received at least 50 days of exposure to factor IX products and averaged at least four bleeding events per year requiring factor IX treatment or prophylaxis. Patients had no measurable inhibitory antibodies but otherwise represented the “general hemophilia B population,” Dr. High said. Five of nine patients had multiple target joints, liver disease associated with hepatitis C virus infection, or both. Each patient received a 1-hour infusion of 5 x 1011 vector genomes per body weight and was followed for 7-52 weeks.
Among seven patients who, by Nov. 30, 2016, had surpassed the 12 weeks needed to reach steady state factor IX expression levels, median steady-state level was 30% (range, 13%-38%), Dr. High reported. “Now we can give one quarter the dose [of adeno-associated virus vector] that was given before, and its driving factor IX expression levels five to eight times higher,” she concluded. Results for the first seven treated patients prompted Food and Drug Administration to give the product orphan drug designation in July 2016. Plans for phase III trials are underway, and researchers also are planning to investigate this approach to gene therapy in hemophilia A, Dr. High said.
Spark Therapeutics Inc. and Pfizer sponsored the study. Dr. High is president and chief scientific officer of Spark. Dr. George had no relevant financial disclosures.
SAN DIEGO – Patients with hemophilia B who received a single 1-hour infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the 12% steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, said during a press briefing at the annual meeting of the American Society of Hematology. One patient infused himself once with factor IX after developing a suspected ankle bleed 2 days after treatment, Dr. High and her associates reported in the accompanying abstract.
This therapy works at a lower dose than previous factor IX gene transfer products and therefore has not caused the hepatotoxicity that halted their development, according to Dr. High, president and chief scientific officer of Spark Therapeutics, which makes SPK-9001. Two of nine patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels, but the immune response was halted by tapering doses of corticosteroids, and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor, she said.
Because the virus capsid breaks down over time, a transient immune response to it “is not really a safety issue, but is an efficacy issue,” Dr. High emphasized. “If it is not caught in time, and patients are not given steroids promptly, they can lose the donated gene. Therefore, quick recognition is key.” Patients who develop an immune response to the viral capsid show sharp declines in factor IX activity levels, rises in baseline AST and ALT, and mononuclear cell reactivity, she explained during an interview.
The current standard of care for hemophilia B involves the cost and treatment burden of intravenous factor IX injections given one to three times weekly. Previous work evaluated factor IX gene transfer mediated by adeno-associated virus, but long-term factor IX activity levels did not reach the trough levels typically achieved with long-acting factor IX prophylaxis. Simply escalating the vector dose did not work because the viral capsid triggered immune-mediated hepatotoxicity, Dr. High noted.
To develop a more efficient product that works at lower doses, she and her associates created a recombinant vector containing a bioengineered adeno-associated virus capsid and a DNA sequence with a promoter designed to drive hepatic expression of a highly active variant of factor IX. To test the product, researchers in Mississippi, Pennsylvania, and California enrolled men aged 18-52 years with a confirmed diagnosis of hemophilia B (no more than 2 IU/dL or 2% endogenous factor IX) who had received at least 50 days of exposure to factor IX products and averaged at least four bleeding events per year requiring factor IX treatment or prophylaxis. Patients had no measurable inhibitory antibodies but otherwise represented the “general hemophilia B population,” Dr. High said. Five of nine patients had multiple target joints, liver disease associated with hepatitis C virus infection, or both. Each patient received a 1-hour infusion of 5 x 1011 vector genomes per body weight and was followed for 7-52 weeks.
Among seven patients who, by Nov. 30, 2016, had surpassed the 12 weeks needed to reach steady state factor IX expression levels, median steady-state level was 30% (range, 13%-38%), Dr. High reported. “Now we can give one quarter the dose [of adeno-associated virus vector] that was given before, and its driving factor IX expression levels five to eight times higher,” she concluded. Results for the first seven treated patients prompted Food and Drug Administration to give the product orphan drug designation in July 2016. Plans for phase III trials are underway, and researchers also are planning to investigate this approach to gene therapy in hemophilia A, Dr. High said.
Spark Therapeutics Inc. and Pfizer sponsored the study. Dr. High is president and chief scientific officer of Spark. Dr. George had no relevant financial disclosures.
AT ASH 2016
Key clinical point: Gene therapy with SPK-9001 continues to post strong results in patients with moderate to severe hemophilia B.
Major finding: As of Nov. 30, median steady-state factor IX levels were 30% (range, 13% to 38%). Two of nine patients developed an immune response to the adeno-associated virus capsid that appears to have been halted with tapering doses of corticosteroids.
Data source: An ongoing phase I/II trial of SPK-9001, dosed at 5 x 1011 vector genomes (vg)/kg body weight.
Disclosures: Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. Dr. George had no relevant financial disclosures.