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FDA grants fast track designation to CX-01 for AML
The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.
The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
CX-01 research
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances in February.
The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.
They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).
Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.
At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.
The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.
Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.
The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.
About fast track, orphan designations
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.
The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
CX-01 research
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances in February.
The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.
They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).
Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.
At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.
The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.
Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.
The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.
About fast track, orphan designations
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).
CX-01 also has orphan drug designation from the FDA.
CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.
CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.
The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.
CX-01 research
Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.
This study builds upon results of a pilot study, which were published in Blood Advances in February.
The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.
They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).
Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.
At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.
The median disease-free survival was 14.8 months, and the median overall survival was not reached.
There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.
Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.
The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.
About fast track, orphan designations
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
EC approves CAR T-cell therapy for ALL, DLBCL
The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.
Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
JULIET trial
Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.
At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.
Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
JULIET trial
Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.
At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Commission (EC) has granted approval for tisagenlecleucel (Kymriah®), a chimeric antigen receptor (CAR) T-cell therapy targeting CD19.
Tisagenlecleucel (formerly CTL019) is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
The EC’s approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
JULIET trial
Updated results from JULIET were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached.
At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least one AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
FDA approves new use for ibrutinib in WM
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
The US Food and Drug Administration (FDA) has approved ibrutinib (Imbruvica®) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).
This is the ninth FDA approval for ibrutinib and the second approval for the drug in WM.
The latest approval was supported by the phase 3 iNNOVATE trial, in which researchers compared ibrutinib plus rituximab to rituximab alone in patients with previously untreated or relapsed/refractory WM.
Results from iNNOVATE were presented at the 2018 ASCO Annual Meeting (abstract 8003) and simultaneously published in NEJM.
The trial enrolled 150 patients. They received rituximab at 375 mg/m2 with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.
Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.
The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.
The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).
The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.
Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm. Serious AEs occurred in 43% and 33%, respectively.
There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.
Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).
AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).
About ibrutinib
Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA-approved to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic graft-versus-host disease (cGVHD), and WM.
In November 2013, ibrutinib was approved to treat adults with MCL who have received at least one prior therapy.
In February 2014, ibrutinib was approved to treat adults with CLL who have received at least one prior therapy. In July 2014, ibrutinib received approval for adult CLL patients with 17p deletion, and, in March 2016, ibrutinib was approved as a frontline CLL treatment.
Ibrutinib was approved for use as a single agent in adults with WM in January 2015.
In May 2016, ibrutinib was approved in combination with bendamustine and rituximab for adults with previously treated CLL/SLL.
In January 2017, ibrutinib was approved for adults with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, ibrutinib was approved to treat adults with cGVHD that did not respond to one or more lines of systemic therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
Rivaroxaban doesn’t reduce risk of fatal VTE
MUNICH—Extended thromboprophylaxis with rivaroxaban does not significantly reduce the risk of fatal venous thromboembolism (VTE) in patients hospitalized for medical illness, according to new research.
In the MARINER trial, the combined rate of symptomatic VTE and VTE-related death was similar in patients who received placebo and those who received rivaroxaban for 45 days after hospital discharge.
Rates of VTE-related death were similar between the treatment groups, but the rate of nonfatal VTE was lower with rivaroxaban.
The researchers therefore concluded that some medically ill patients may benefit from extended thromboprophylaxis with rivaroxaban, although more research is needed.
Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital in New York, New York, presented these results at ESC Congress 2018.
The research was also published in NEJM. The study was funded by Janssen Research and Development.
The MARINER trial included 12,019 medically ill patients who had an increased risk of VTE and had been hospitalized for 3 to 10 days.
The patients were randomized to receive rivaroxaban (n=6007) at 10 mg daily (7.5 mg in patients with renal impairment) or daily placebo (n=6012) for 45 days after hospital discharge. In all, 11,962 patients (99.5%) received at least one dose of assigned treatment.
Results
The study’s primary endpoint was a composite of symptomatic VTE and VTE-related death. This endpoint was met in 0.83% (n=50) of patients in the rivaroxaban arm and 1.10% (n=66) of patients in the placebo arm (hazard ratio [HR]=0.76; P=0.136).
The incidence of VTE-related death was 0.72% (n=43) in the rivaroxaban arm and 0.77% (n=46) in the placebo arm (HR=0.93, P=0.751).
The incidence of symptomatic VTE was 0.18% (n=11) in the rivaroxaban arm and 0.42% (n=25) in the placebo arm (HR=0.44, P=0.023).
“We were able to reduce instances of non-fatal blood clots and pulmonary embolism by more than half, which shows that the use of direct oral anticoagulants . . . after the hospitalization of medically ill patients could help prevent clots from forming,” Dr. Spyropoulos said.
He and his colleagues also examined an exploratory secondary composite endpoint of symptomatic VTE and all-cause mortality and found that 1.30% (n=78) of patients in the rivaroxaban arm experienced an event, compared to 1.78% (n=107) of patients in the placebo arm (HR=0.73, P=0.033).
The study’s principal safety outcome was major bleeding. It occurred in 0.28% (n=17) of patients in the rivaroxaban arm and 0.15% (n=9) of those in the placebo arm (HR=1.88, P=0.124).
The difference in risk of major bleeding with rivaroxaban compared to placebo was 0.28 percentage points, and the difference in risk of symptomatic VTE with rivaroxaban vs placebo was -0.24 percentage points.
This suggests the number of patients needed to prevent one symptomatic VTE event is 430, and the number needed to cause one major bleed is 856.
Dr. Spyropoulos therefore concluded that thromboprophylaxis, when used in appropriate medically ill patients, might reduce the population health burden of symptomatic VTE with little serious bleeding.
“Our next course of research is to further identify and refine a post-discharge treatment program which would maximize the net clinical benefit across a defined spectrum of medically ill patients,” he said.
MUNICH—Extended thromboprophylaxis with rivaroxaban does not significantly reduce the risk of fatal venous thromboembolism (VTE) in patients hospitalized for medical illness, according to new research.
In the MARINER trial, the combined rate of symptomatic VTE and VTE-related death was similar in patients who received placebo and those who received rivaroxaban for 45 days after hospital discharge.
Rates of VTE-related death were similar between the treatment groups, but the rate of nonfatal VTE was lower with rivaroxaban.
The researchers therefore concluded that some medically ill patients may benefit from extended thromboprophylaxis with rivaroxaban, although more research is needed.
Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital in New York, New York, presented these results at ESC Congress 2018.
The research was also published in NEJM. The study was funded by Janssen Research and Development.
The MARINER trial included 12,019 medically ill patients who had an increased risk of VTE and had been hospitalized for 3 to 10 days.
The patients were randomized to receive rivaroxaban (n=6007) at 10 mg daily (7.5 mg in patients with renal impairment) or daily placebo (n=6012) for 45 days after hospital discharge. In all, 11,962 patients (99.5%) received at least one dose of assigned treatment.
Results
The study’s primary endpoint was a composite of symptomatic VTE and VTE-related death. This endpoint was met in 0.83% (n=50) of patients in the rivaroxaban arm and 1.10% (n=66) of patients in the placebo arm (hazard ratio [HR]=0.76; P=0.136).
The incidence of VTE-related death was 0.72% (n=43) in the rivaroxaban arm and 0.77% (n=46) in the placebo arm (HR=0.93, P=0.751).
The incidence of symptomatic VTE was 0.18% (n=11) in the rivaroxaban arm and 0.42% (n=25) in the placebo arm (HR=0.44, P=0.023).
“We were able to reduce instances of non-fatal blood clots and pulmonary embolism by more than half, which shows that the use of direct oral anticoagulants . . . after the hospitalization of medically ill patients could help prevent clots from forming,” Dr. Spyropoulos said.
He and his colleagues also examined an exploratory secondary composite endpoint of symptomatic VTE and all-cause mortality and found that 1.30% (n=78) of patients in the rivaroxaban arm experienced an event, compared to 1.78% (n=107) of patients in the placebo arm (HR=0.73, P=0.033).
The study’s principal safety outcome was major bleeding. It occurred in 0.28% (n=17) of patients in the rivaroxaban arm and 0.15% (n=9) of those in the placebo arm (HR=1.88, P=0.124).
The difference in risk of major bleeding with rivaroxaban compared to placebo was 0.28 percentage points, and the difference in risk of symptomatic VTE with rivaroxaban vs placebo was -0.24 percentage points.
This suggests the number of patients needed to prevent one symptomatic VTE event is 430, and the number needed to cause one major bleed is 856.
Dr. Spyropoulos therefore concluded that thromboprophylaxis, when used in appropriate medically ill patients, might reduce the population health burden of symptomatic VTE with little serious bleeding.
“Our next course of research is to further identify and refine a post-discharge treatment program which would maximize the net clinical benefit across a defined spectrum of medically ill patients,” he said.
MUNICH—Extended thromboprophylaxis with rivaroxaban does not significantly reduce the risk of fatal venous thromboembolism (VTE) in patients hospitalized for medical illness, according to new research.
In the MARINER trial, the combined rate of symptomatic VTE and VTE-related death was similar in patients who received placebo and those who received rivaroxaban for 45 days after hospital discharge.
Rates of VTE-related death were similar between the treatment groups, but the rate of nonfatal VTE was lower with rivaroxaban.
The researchers therefore concluded that some medically ill patients may benefit from extended thromboprophylaxis with rivaroxaban, although more research is needed.
Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital in New York, New York, presented these results at ESC Congress 2018.
The research was also published in NEJM. The study was funded by Janssen Research and Development.
The MARINER trial included 12,019 medically ill patients who had an increased risk of VTE and had been hospitalized for 3 to 10 days.
The patients were randomized to receive rivaroxaban (n=6007) at 10 mg daily (7.5 mg in patients with renal impairment) or daily placebo (n=6012) for 45 days after hospital discharge. In all, 11,962 patients (99.5%) received at least one dose of assigned treatment.
Results
The study’s primary endpoint was a composite of symptomatic VTE and VTE-related death. This endpoint was met in 0.83% (n=50) of patients in the rivaroxaban arm and 1.10% (n=66) of patients in the placebo arm (hazard ratio [HR]=0.76; P=0.136).
The incidence of VTE-related death was 0.72% (n=43) in the rivaroxaban arm and 0.77% (n=46) in the placebo arm (HR=0.93, P=0.751).
The incidence of symptomatic VTE was 0.18% (n=11) in the rivaroxaban arm and 0.42% (n=25) in the placebo arm (HR=0.44, P=0.023).
“We were able to reduce instances of non-fatal blood clots and pulmonary embolism by more than half, which shows that the use of direct oral anticoagulants . . . after the hospitalization of medically ill patients could help prevent clots from forming,” Dr. Spyropoulos said.
He and his colleagues also examined an exploratory secondary composite endpoint of symptomatic VTE and all-cause mortality and found that 1.30% (n=78) of patients in the rivaroxaban arm experienced an event, compared to 1.78% (n=107) of patients in the placebo arm (HR=0.73, P=0.033).
The study’s principal safety outcome was major bleeding. It occurred in 0.28% (n=17) of patients in the rivaroxaban arm and 0.15% (n=9) of those in the placebo arm (HR=1.88, P=0.124).
The difference in risk of major bleeding with rivaroxaban compared to placebo was 0.28 percentage points, and the difference in risk of symptomatic VTE with rivaroxaban vs placebo was -0.24 percentage points.
This suggests the number of patients needed to prevent one symptomatic VTE event is 430, and the number needed to cause one major bleed is 856.
Dr. Spyropoulos therefore concluded that thromboprophylaxis, when used in appropriate medically ill patients, might reduce the population health burden of symptomatic VTE with little serious bleeding.
“Our next course of research is to further identify and refine a post-discharge treatment program which would maximize the net clinical benefit across a defined spectrum of medically ill patients,” he said.
Regimen appears effective in elderly, unfit MDS/AML
A low-intensity regimen could be an effective treatment option for elderly or unfit patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to researchers.
The regimen—cladribine plus low-dose cytarabine alternating with decitabine—produced a response rate of 68%.
The median disease-free survival (DFS) was 10.8 months, and the median overall survival (OS) was 13.8 months.
The regimen was considered well tolerated, although all patients experienced myelosuppression, and three-quarters developed infections that may have been treatment-related.
Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in The Lancet Haematology.
This phase 2 trial enrolled 118 patients with previously untreated AML or high-risk MDS. Seventeen percent of patients had therapy-related AML, 25% had secondary AML (prior MDS or myeloproliferative neoplasm [MPN]), and 15% had treated secondary AML (received treatment for MDS/MPN).
Forty-one percent of patients had an adverse risk karyotype, and 27% had a complex karyotype. Patients had a range of mutations, but the most common were in RAS, TP53, DNMT3a, NPM1, and FLT3-ITD.
Most patients (n=116) were age 60 or older, with a median age of 69. However, there were 2 patients younger than age 60. Both had “extensive” exposure to anthracycline, and one had a prior myocardial infarction.
Treatment
Patients received cladribine plus low-dose cytarabine for two cycles, alternating with decitabine for two cycles, for up to 18 cycles (28 days each).
For cycle 1, patients received cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 5 and cytarabine at 20 mg (given subcutaneously) twice daily on days 1 to 10.
Patients who achieved remission went on to receive consolidation with cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 3 and cytarabine at 20 mg twice daily on days 1 to 10, alternating with decitabine at 20 mg/m² (intravenously) on days 1 to 5.
Efficacy
The objective response rate was 68%, the rate of complete response was 58%, and the rate of complete response with incomplete count recovery was 9%.
The median DFS was 10.8 months, and the median OS was 13.8 months. The 1-year OS rate was 64%, and the 2-year OS rate was 28%.
Outcomes were better in patients with a diploid karyotype than in those with adverse karyotypes or TP53 mutation. Among patients with a diploid karyotype (n=38), the response rate was 84%, and the median OS was 19.9 months.
Among patients with adverse karyotypes (n=48), the response rate was 50%, and the median OS was 10.5 months. In patients with TP53 mutation (n=20), the response rate was 40%, and the median OS was 8.9 months.
Of all responders (n=80), 23% went on to allogeneic stem cell transplant. There was no significant difference in OS between patients who received a transplant and those who did not. The median OS was 16.4 months and 15.9 months, respectively (P=0.18).
Safety
The researchers said this regimen was generally well tolerated, but all patients experienced myelosuppression.
The most common non-hematologic adverse events (AEs) considered at least possibly related to treatment included infection (n=88), elevated total bilirubin (n=26), rash (n=13), nausea (n=13), diarrhea (n=9), ALT/AST elevation (n=7), elevated creatinine (n=7), mucositis (n=7), and constipation (n=6).
Overall, grade 3/4 non-hematologic AEs tended to occur in few patients. The exception was infections. There were 77 grade 3 infections, and two grade 4 infections.
There were 9 grade 5 infections but no other fatal AEs considered at least possibly related to treatment.
One patient (1%) died within the first 4 weeks of treatment, and 8 (7%) died within the first 8 weeks. None of these patients had responded.
“Our findings suggest that the combination of cladribine and low-dose cytarabine alternating with decitabine is a highly active and well tolerated regimen for older patients with AML,” the researchers wrote.
The team also called for a phase 3 trial comparing this regimen to hypomethylating agents.
This study was sponsored by MD Anderson and supported, in part, by the National Institutes of Health.
A low-intensity regimen could be an effective treatment option for elderly or unfit patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to researchers.
The regimen—cladribine plus low-dose cytarabine alternating with decitabine—produced a response rate of 68%.
The median disease-free survival (DFS) was 10.8 months, and the median overall survival (OS) was 13.8 months.
The regimen was considered well tolerated, although all patients experienced myelosuppression, and three-quarters developed infections that may have been treatment-related.
Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in The Lancet Haematology.
This phase 2 trial enrolled 118 patients with previously untreated AML or high-risk MDS. Seventeen percent of patients had therapy-related AML, 25% had secondary AML (prior MDS or myeloproliferative neoplasm [MPN]), and 15% had treated secondary AML (received treatment for MDS/MPN).
Forty-one percent of patients had an adverse risk karyotype, and 27% had a complex karyotype. Patients had a range of mutations, but the most common were in RAS, TP53, DNMT3a, NPM1, and FLT3-ITD.
Most patients (n=116) were age 60 or older, with a median age of 69. However, there were 2 patients younger than age 60. Both had “extensive” exposure to anthracycline, and one had a prior myocardial infarction.
Treatment
Patients received cladribine plus low-dose cytarabine for two cycles, alternating with decitabine for two cycles, for up to 18 cycles (28 days each).
For cycle 1, patients received cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 5 and cytarabine at 20 mg (given subcutaneously) twice daily on days 1 to 10.
Patients who achieved remission went on to receive consolidation with cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 3 and cytarabine at 20 mg twice daily on days 1 to 10, alternating with decitabine at 20 mg/m² (intravenously) on days 1 to 5.
Efficacy
The objective response rate was 68%, the rate of complete response was 58%, and the rate of complete response with incomplete count recovery was 9%.
The median DFS was 10.8 months, and the median OS was 13.8 months. The 1-year OS rate was 64%, and the 2-year OS rate was 28%.
Outcomes were better in patients with a diploid karyotype than in those with adverse karyotypes or TP53 mutation. Among patients with a diploid karyotype (n=38), the response rate was 84%, and the median OS was 19.9 months.
Among patients with adverse karyotypes (n=48), the response rate was 50%, and the median OS was 10.5 months. In patients with TP53 mutation (n=20), the response rate was 40%, and the median OS was 8.9 months.
Of all responders (n=80), 23% went on to allogeneic stem cell transplant. There was no significant difference in OS between patients who received a transplant and those who did not. The median OS was 16.4 months and 15.9 months, respectively (P=0.18).
Safety
The researchers said this regimen was generally well tolerated, but all patients experienced myelosuppression.
The most common non-hematologic adverse events (AEs) considered at least possibly related to treatment included infection (n=88), elevated total bilirubin (n=26), rash (n=13), nausea (n=13), diarrhea (n=9), ALT/AST elevation (n=7), elevated creatinine (n=7), mucositis (n=7), and constipation (n=6).
Overall, grade 3/4 non-hematologic AEs tended to occur in few patients. The exception was infections. There were 77 grade 3 infections, and two grade 4 infections.
There were 9 grade 5 infections but no other fatal AEs considered at least possibly related to treatment.
One patient (1%) died within the first 4 weeks of treatment, and 8 (7%) died within the first 8 weeks. None of these patients had responded.
“Our findings suggest that the combination of cladribine and low-dose cytarabine alternating with decitabine is a highly active and well tolerated regimen for older patients with AML,” the researchers wrote.
The team also called for a phase 3 trial comparing this regimen to hypomethylating agents.
This study was sponsored by MD Anderson and supported, in part, by the National Institutes of Health.
A low-intensity regimen could be an effective treatment option for elderly or unfit patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to researchers.
The regimen—cladribine plus low-dose cytarabine alternating with decitabine—produced a response rate of 68%.
The median disease-free survival (DFS) was 10.8 months, and the median overall survival (OS) was 13.8 months.
The regimen was considered well tolerated, although all patients experienced myelosuppression, and three-quarters developed infections that may have been treatment-related.
Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in The Lancet Haematology.
This phase 2 trial enrolled 118 patients with previously untreated AML or high-risk MDS. Seventeen percent of patients had therapy-related AML, 25% had secondary AML (prior MDS or myeloproliferative neoplasm [MPN]), and 15% had treated secondary AML (received treatment for MDS/MPN).
Forty-one percent of patients had an adverse risk karyotype, and 27% had a complex karyotype. Patients had a range of mutations, but the most common were in RAS, TP53, DNMT3a, NPM1, and FLT3-ITD.
Most patients (n=116) were age 60 or older, with a median age of 69. However, there were 2 patients younger than age 60. Both had “extensive” exposure to anthracycline, and one had a prior myocardial infarction.
Treatment
Patients received cladribine plus low-dose cytarabine for two cycles, alternating with decitabine for two cycles, for up to 18 cycles (28 days each).
For cycle 1, patients received cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 5 and cytarabine at 20 mg (given subcutaneously) twice daily on days 1 to 10.
Patients who achieved remission went on to receive consolidation with cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 3 and cytarabine at 20 mg twice daily on days 1 to 10, alternating with decitabine at 20 mg/m² (intravenously) on days 1 to 5.
Efficacy
The objective response rate was 68%, the rate of complete response was 58%, and the rate of complete response with incomplete count recovery was 9%.
The median DFS was 10.8 months, and the median OS was 13.8 months. The 1-year OS rate was 64%, and the 2-year OS rate was 28%.
Outcomes were better in patients with a diploid karyotype than in those with adverse karyotypes or TP53 mutation. Among patients with a diploid karyotype (n=38), the response rate was 84%, and the median OS was 19.9 months.
Among patients with adverse karyotypes (n=48), the response rate was 50%, and the median OS was 10.5 months. In patients with TP53 mutation (n=20), the response rate was 40%, and the median OS was 8.9 months.
Of all responders (n=80), 23% went on to allogeneic stem cell transplant. There was no significant difference in OS between patients who received a transplant and those who did not. The median OS was 16.4 months and 15.9 months, respectively (P=0.18).
Safety
The researchers said this regimen was generally well tolerated, but all patients experienced myelosuppression.
The most common non-hematologic adverse events (AEs) considered at least possibly related to treatment included infection (n=88), elevated total bilirubin (n=26), rash (n=13), nausea (n=13), diarrhea (n=9), ALT/AST elevation (n=7), elevated creatinine (n=7), mucositis (n=7), and constipation (n=6).
Overall, grade 3/4 non-hematologic AEs tended to occur in few patients. The exception was infections. There were 77 grade 3 infections, and two grade 4 infections.
There were 9 grade 5 infections but no other fatal AEs considered at least possibly related to treatment.
One patient (1%) died within the first 4 weeks of treatment, and 8 (7%) died within the first 8 weeks. None of these patients had responded.
“Our findings suggest that the combination of cladribine and low-dose cytarabine alternating with decitabine is a highly active and well tolerated regimen for older patients with AML,” the researchers wrote.
The team also called for a phase 3 trial comparing this regimen to hypomethylating agents.
This study was sponsored by MD Anderson and supported, in part, by the National Institutes of Health.
Study reveals ‘complete mental health’ among cancer survivors
New research suggests cancer survivors are just as likely as people without a history of cancer to have complete mental health (CMH), which is defined as “optimal functioning” and the “absence of psychopathology.”
In a study of nearly 11,000 Canadians, 77.5% of cancer survivors and 76.8% of people with no cancer history had CMH.
As for patients who were battling cancer at the time of the study, 66.1% had CMH.
Esme Fuller-Thomson, PhD, and Keri West, both of the University of Toronto in Canada, conducted this research and reported the findings in Aging & Mental Health.
“Cancer patients were doing much better than we had expected,” Dr. Fuller-Thomson said. “Two-thirds met our very stringent criteria for complete mental health . . . . The news for cancer survivors was even better, with three-quarters living in complete mental health, which is a prevalence comparable to that of individuals with no cancer history.”
This study included a nationally representative sample of Canadian community dwellers age 50 and older. Subjects had current cancer (n=438), previous cancer (n=1174), or no cancer history (n=9279).
Data were obtained from Statistics Canada’s 2012 Canadian Community Health Survey-Mental Health.
To meet criteria for CMH, subjects had to have all of the following:
- Absence of mental illness, addictions, and suicidal thoughts in the past year
- Almost daily happiness or life satisfaction in the past month
- Psychosocial well-being.
The prevalence of CMH was 77.5% in cancer survivors and 76.8% in subjects who had never had cancer. Both were significantly higher than the 66.1% prevalence of CMH in current cancer patients (P<0.001).
In a multivariable model adjusted for demographics, current cancer patients had 45% lower odds of CMH compared to subjects with no cancer history (odds ratio [OR]=0.55). The odds of CMH were comparable for cancer survivors and those without a history of cancer (OR=0.98).
The researchers also conducted a multivariable analysis in which they adjusted for “all relevant factors,” which included demographics as well as adverse childhood events, socioeconomic status, health variables, lifetime mental illness, etc.
In this analysis, current cancer patients had 37% lower odds of CMH than subjects with no cancer history (OR=0.63). And cancer survivors had comparable odds of CMH as those with no cancer history (OR=1.06).
The researchers identified several factors that were associated with CMH in the population affected by cancer.
“Among those with former or current cancer, the odds of complete mental health were higher for women, white, married, and older respondents, as well as those with higher income and those who did not have disabling pain nor functional limitations,” West said.
“We found that earlier difficulties cast a long shadow. Those who had been physically abused during their childhood and those who had ever had depression or anxiety disorders were less likely to be in complete mental health.”
West and Dr Fuller-Thomson emphasized that these results are only correlational, and it is impossible to determine causality due to the cross-sectional and observational nature of the study.
The pair also said future longitudinal research is needed to improve understanding of what pathways improve resilience and recovery among cancer patients.
New research suggests cancer survivors are just as likely as people without a history of cancer to have complete mental health (CMH), which is defined as “optimal functioning” and the “absence of psychopathology.”
In a study of nearly 11,000 Canadians, 77.5% of cancer survivors and 76.8% of people with no cancer history had CMH.
As for patients who were battling cancer at the time of the study, 66.1% had CMH.
Esme Fuller-Thomson, PhD, and Keri West, both of the University of Toronto in Canada, conducted this research and reported the findings in Aging & Mental Health.
“Cancer patients were doing much better than we had expected,” Dr. Fuller-Thomson said. “Two-thirds met our very stringent criteria for complete mental health . . . . The news for cancer survivors was even better, with three-quarters living in complete mental health, which is a prevalence comparable to that of individuals with no cancer history.”
This study included a nationally representative sample of Canadian community dwellers age 50 and older. Subjects had current cancer (n=438), previous cancer (n=1174), or no cancer history (n=9279).
Data were obtained from Statistics Canada’s 2012 Canadian Community Health Survey-Mental Health.
To meet criteria for CMH, subjects had to have all of the following:
- Absence of mental illness, addictions, and suicidal thoughts in the past year
- Almost daily happiness or life satisfaction in the past month
- Psychosocial well-being.
The prevalence of CMH was 77.5% in cancer survivors and 76.8% in subjects who had never had cancer. Both were significantly higher than the 66.1% prevalence of CMH in current cancer patients (P<0.001).
In a multivariable model adjusted for demographics, current cancer patients had 45% lower odds of CMH compared to subjects with no cancer history (odds ratio [OR]=0.55). The odds of CMH were comparable for cancer survivors and those without a history of cancer (OR=0.98).
The researchers also conducted a multivariable analysis in which they adjusted for “all relevant factors,” which included demographics as well as adverse childhood events, socioeconomic status, health variables, lifetime mental illness, etc.
In this analysis, current cancer patients had 37% lower odds of CMH than subjects with no cancer history (OR=0.63). And cancer survivors had comparable odds of CMH as those with no cancer history (OR=1.06).
The researchers identified several factors that were associated with CMH in the population affected by cancer.
“Among those with former or current cancer, the odds of complete mental health were higher for women, white, married, and older respondents, as well as those with higher income and those who did not have disabling pain nor functional limitations,” West said.
“We found that earlier difficulties cast a long shadow. Those who had been physically abused during their childhood and those who had ever had depression or anxiety disorders were less likely to be in complete mental health.”
West and Dr Fuller-Thomson emphasized that these results are only correlational, and it is impossible to determine causality due to the cross-sectional and observational nature of the study.
The pair also said future longitudinal research is needed to improve understanding of what pathways improve resilience and recovery among cancer patients.
New research suggests cancer survivors are just as likely as people without a history of cancer to have complete mental health (CMH), which is defined as “optimal functioning” and the “absence of psychopathology.”
In a study of nearly 11,000 Canadians, 77.5% of cancer survivors and 76.8% of people with no cancer history had CMH.
As for patients who were battling cancer at the time of the study, 66.1% had CMH.
Esme Fuller-Thomson, PhD, and Keri West, both of the University of Toronto in Canada, conducted this research and reported the findings in Aging & Mental Health.
“Cancer patients were doing much better than we had expected,” Dr. Fuller-Thomson said. “Two-thirds met our very stringent criteria for complete mental health . . . . The news for cancer survivors was even better, with three-quarters living in complete mental health, which is a prevalence comparable to that of individuals with no cancer history.”
This study included a nationally representative sample of Canadian community dwellers age 50 and older. Subjects had current cancer (n=438), previous cancer (n=1174), or no cancer history (n=9279).
Data were obtained from Statistics Canada’s 2012 Canadian Community Health Survey-Mental Health.
To meet criteria for CMH, subjects had to have all of the following:
- Absence of mental illness, addictions, and suicidal thoughts in the past year
- Almost daily happiness or life satisfaction in the past month
- Psychosocial well-being.
The prevalence of CMH was 77.5% in cancer survivors and 76.8% in subjects who had never had cancer. Both were significantly higher than the 66.1% prevalence of CMH in current cancer patients (P<0.001).
In a multivariable model adjusted for demographics, current cancer patients had 45% lower odds of CMH compared to subjects with no cancer history (odds ratio [OR]=0.55). The odds of CMH were comparable for cancer survivors and those without a history of cancer (OR=0.98).
The researchers also conducted a multivariable analysis in which they adjusted for “all relevant factors,” which included demographics as well as adverse childhood events, socioeconomic status, health variables, lifetime mental illness, etc.
In this analysis, current cancer patients had 37% lower odds of CMH than subjects with no cancer history (OR=0.63). And cancer survivors had comparable odds of CMH as those with no cancer history (OR=1.06).
The researchers identified several factors that were associated with CMH in the population affected by cancer.
“Among those with former or current cancer, the odds of complete mental health were higher for women, white, married, and older respondents, as well as those with higher income and those who did not have disabling pain nor functional limitations,” West said.
“We found that earlier difficulties cast a long shadow. Those who had been physically abused during their childhood and those who had ever had depression or anxiety disorders were less likely to be in complete mental health.”
West and Dr Fuller-Thomson emphasized that these results are only correlational, and it is impossible to determine causality due to the cross-sectional and observational nature of the study.
The pair also said future longitudinal research is needed to improve understanding of what pathways improve resilience and recovery among cancer patients.
Drug receives priority review for second MM indication
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for elotuzumab (Empliciti).
With this sBLA, Bristol-Myers Squibb Company is seeking approval for elotuzumab in combination with pomalidomide and low-dose dexamethasone to treat patients with relapsed/refractory multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA expects to make a decision on the sBLA for elotuzumab by December 27, 2018.
Elotuzumab is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received one to three prior therapies.
Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.
Supporting trial
The sBLA for elotuzumab is supported by data from ELOQUENT-3, a randomized, phase 2 study in which researchers evaluated the addition of elotuzumab to pomalidomide and low-dose dexamethasone in patients with relapsed/refractory MM.
Data from this study were presented at the 23rd Congress of the European Hematology Association in June.
The trial randomized 117 MM patients who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor.
The patients were randomized to receive either elotuzumab, pomalidomide, and low-dose dexamethasone (EPd; n=60) or pomalidomide and low-dose dexamethasone (Pd; n=57) in 28-day cycles until disease progression or unacceptable toxicity.
The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).
The median progression-free survival was 10.3 months in the EPd arm and 4.7 months in the Pd arm (hazard ratio=0.54, P=0.0078).
Overall survival data were not mature at last follow-up, but there was a trend favoring EPd over Pd (hazard ratio=0.62).
The researchers said adverse events (AEs) in the EPd arm were consistent with expectations based on previous results with elotuzumab and pomalidomide regimens.
Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).
Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).
Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).
In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure (n=1), and general physical health deterioration (n=1).
In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection (n=1), multiple organ failure and infection (n=1), myocardial infarction (n=1), and plasma cell myeloma (n=1).
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for elotuzumab (Empliciti).
With this sBLA, Bristol-Myers Squibb Company is seeking approval for elotuzumab in combination with pomalidomide and low-dose dexamethasone to treat patients with relapsed/refractory multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA expects to make a decision on the sBLA for elotuzumab by December 27, 2018.
Elotuzumab is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received one to three prior therapies.
Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.
Supporting trial
The sBLA for elotuzumab is supported by data from ELOQUENT-3, a randomized, phase 2 study in which researchers evaluated the addition of elotuzumab to pomalidomide and low-dose dexamethasone in patients with relapsed/refractory MM.
Data from this study were presented at the 23rd Congress of the European Hematology Association in June.
The trial randomized 117 MM patients who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor.
The patients were randomized to receive either elotuzumab, pomalidomide, and low-dose dexamethasone (EPd; n=60) or pomalidomide and low-dose dexamethasone (Pd; n=57) in 28-day cycles until disease progression or unacceptable toxicity.
The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).
The median progression-free survival was 10.3 months in the EPd arm and 4.7 months in the Pd arm (hazard ratio=0.54, P=0.0078).
Overall survival data were not mature at last follow-up, but there was a trend favoring EPd over Pd (hazard ratio=0.62).
The researchers said adverse events (AEs) in the EPd arm were consistent with expectations based on previous results with elotuzumab and pomalidomide regimens.
Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).
Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).
Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).
In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure (n=1), and general physical health deterioration (n=1).
In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection (n=1), multiple organ failure and infection (n=1), myocardial infarction (n=1), and plasma cell myeloma (n=1).
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for elotuzumab (Empliciti).
With this sBLA, Bristol-Myers Squibb Company is seeking approval for elotuzumab in combination with pomalidomide and low-dose dexamethasone to treat patients with relapsed/refractory multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.
The FDA expects to make a decision on the sBLA for elotuzumab by December 27, 2018.
Elotuzumab is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received one to three prior therapies.
Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.
Supporting trial
The sBLA for elotuzumab is supported by data from ELOQUENT-3, a randomized, phase 2 study in which researchers evaluated the addition of elotuzumab to pomalidomide and low-dose dexamethasone in patients with relapsed/refractory MM.
Data from this study were presented at the 23rd Congress of the European Hematology Association in June.
The trial randomized 117 MM patients who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor.
The patients were randomized to receive either elotuzumab, pomalidomide, and low-dose dexamethasone (EPd; n=60) or pomalidomide and low-dose dexamethasone (Pd; n=57) in 28-day cycles until disease progression or unacceptable toxicity.
The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).
The median progression-free survival was 10.3 months in the EPd arm and 4.7 months in the Pd arm (hazard ratio=0.54, P=0.0078).
Overall survival data were not mature at last follow-up, but there was a trend favoring EPd over Pd (hazard ratio=0.62).
The researchers said adverse events (AEs) in the EPd arm were consistent with expectations based on previous results with elotuzumab and pomalidomide regimens.
Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).
Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).
Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).
In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure (n=1), and general physical health deterioration (n=1).
In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection (n=1), multiple organ failure and infection (n=1), myocardial infarction (n=1), and plasma cell myeloma (n=1).
D-dimer and WCP can render VDUs unnecessary
Venous duplex ultrasounds (VDUs) may be over-utilized in patients suspected of having deep vein thrombosis (DVT), according to research published in Annals of Vascular Surgery.
The retrospective study indicated that D-dimer tests and the pretest Wells criteria probability (WCP) score could safely exclude DVT.
The researchers therefore believe that consistent use of D-dimer and WCP could reduce the number of unnecessary immediate VDUs, cut costs, and save time.
“Usually, waiting for a venous ultrasound would be a matter of three, four, five hours,” said study author Albeir Mousa, MD, of West Virginia University in Charleston, West Virginia.
“With the D-dimer test, it’s a few minutes, and you’re done.”
For this study, Dr. Mousa and his colleagues reviewed data on 1670 patients who presented to a high-volume tertiary care center with suspected DVT and were referred for VDU. Their average age was 62.1, and 55.7% were female.
The researchers calculated WCP scores for all 1670 patients and divided them into DVT risk groups accordingly—low- (<1), moderate- (1-2), and high-risk (≥3).
The team also divided patients according to D-dimer values—low (0.1-0.59), moderate (0.60-1.2), and high (≥1.3 mg/L FEU).
Results
The researchers found that D-dimer (with an abnormal threshold of ≥0.60 mg/L FEU) identified all patients with DVT (n=183, 11%).
The sensitivity and negative predictive values of D-dimer were both 100%, while specificity was 14.9% and the positive predictive value was 15.9%.
When the researchers used an age-adjusted D-dimer threshold (age x 0.01), the specificity increased from 14.9% to 21.3%, and the positive predictive value increased from 15.9% to 17%.
There were no DVTs among patients with low D-dimer values, but the rate of DVT significantly increased in the moderate (5.9%) and high groups (20.0%; P=0.007).
The rate of DVT increased with increasing WCP as well. The DVT rate was 6.6% in the low WCP group, 14% in the moderate group, and 29.1% in the high group (P<0.001).
The researchers also noted an increase in the rate of DVT across all levels of WCP as D-dimer levels increased.
Based on these findings, the researchers said there were 762 patients who were sent for unnecessary immediate VDUs. This included 685 patients in the low WCP group (<1) who did not undergo D-dimer testing, 51 patients who had moderate D-dimer values, and 26 who had low D-dimer values.
The researchers calculated the potential savings of using D-dimer instead of VDU in these patients, based on US 2016 dollar estimates.
A VDU cost of $1557 per person would mean a total cost of $1,186,434 for 762 patients. A D-dimer cost of $182 per person would mean a total cost of $138,684. So the total potential savings would be $1,047,750.
Dr. Mousa also noted that D-dimer testing is quicker than VDU and requires fewer resources.
“It’s a very simple sample of blood, which is sent to the lab,” he said. “And, usually in 15 or 20 minutes, you have significant information that can help you take good care of the patients. And you can send patients home quicker, with less demand on the hospital staff and the institution, yet increase patient satisfaction.”
Venous duplex ultrasounds (VDUs) may be over-utilized in patients suspected of having deep vein thrombosis (DVT), according to research published in Annals of Vascular Surgery.
The retrospective study indicated that D-dimer tests and the pretest Wells criteria probability (WCP) score could safely exclude DVT.
The researchers therefore believe that consistent use of D-dimer and WCP could reduce the number of unnecessary immediate VDUs, cut costs, and save time.
“Usually, waiting for a venous ultrasound would be a matter of three, four, five hours,” said study author Albeir Mousa, MD, of West Virginia University in Charleston, West Virginia.
“With the D-dimer test, it’s a few minutes, and you’re done.”
For this study, Dr. Mousa and his colleagues reviewed data on 1670 patients who presented to a high-volume tertiary care center with suspected DVT and were referred for VDU. Their average age was 62.1, and 55.7% were female.
The researchers calculated WCP scores for all 1670 patients and divided them into DVT risk groups accordingly—low- (<1), moderate- (1-2), and high-risk (≥3).
The team also divided patients according to D-dimer values—low (0.1-0.59), moderate (0.60-1.2), and high (≥1.3 mg/L FEU).
Results
The researchers found that D-dimer (with an abnormal threshold of ≥0.60 mg/L FEU) identified all patients with DVT (n=183, 11%).
The sensitivity and negative predictive values of D-dimer were both 100%, while specificity was 14.9% and the positive predictive value was 15.9%.
When the researchers used an age-adjusted D-dimer threshold (age x 0.01), the specificity increased from 14.9% to 21.3%, and the positive predictive value increased from 15.9% to 17%.
There were no DVTs among patients with low D-dimer values, but the rate of DVT significantly increased in the moderate (5.9%) and high groups (20.0%; P=0.007).
The rate of DVT increased with increasing WCP as well. The DVT rate was 6.6% in the low WCP group, 14% in the moderate group, and 29.1% in the high group (P<0.001).
The researchers also noted an increase in the rate of DVT across all levels of WCP as D-dimer levels increased.
Based on these findings, the researchers said there were 762 patients who were sent for unnecessary immediate VDUs. This included 685 patients in the low WCP group (<1) who did not undergo D-dimer testing, 51 patients who had moderate D-dimer values, and 26 who had low D-dimer values.
The researchers calculated the potential savings of using D-dimer instead of VDU in these patients, based on US 2016 dollar estimates.
A VDU cost of $1557 per person would mean a total cost of $1,186,434 for 762 patients. A D-dimer cost of $182 per person would mean a total cost of $138,684. So the total potential savings would be $1,047,750.
Dr. Mousa also noted that D-dimer testing is quicker than VDU and requires fewer resources.
“It’s a very simple sample of blood, which is sent to the lab,” he said. “And, usually in 15 or 20 minutes, you have significant information that can help you take good care of the patients. And you can send patients home quicker, with less demand on the hospital staff and the institution, yet increase patient satisfaction.”
Venous duplex ultrasounds (VDUs) may be over-utilized in patients suspected of having deep vein thrombosis (DVT), according to research published in Annals of Vascular Surgery.
The retrospective study indicated that D-dimer tests and the pretest Wells criteria probability (WCP) score could safely exclude DVT.
The researchers therefore believe that consistent use of D-dimer and WCP could reduce the number of unnecessary immediate VDUs, cut costs, and save time.
“Usually, waiting for a venous ultrasound would be a matter of three, four, five hours,” said study author Albeir Mousa, MD, of West Virginia University in Charleston, West Virginia.
“With the D-dimer test, it’s a few minutes, and you’re done.”
For this study, Dr. Mousa and his colleagues reviewed data on 1670 patients who presented to a high-volume tertiary care center with suspected DVT and were referred for VDU. Their average age was 62.1, and 55.7% were female.
The researchers calculated WCP scores for all 1670 patients and divided them into DVT risk groups accordingly—low- (<1), moderate- (1-2), and high-risk (≥3).
The team also divided patients according to D-dimer values—low (0.1-0.59), moderate (0.60-1.2), and high (≥1.3 mg/L FEU).
Results
The researchers found that D-dimer (with an abnormal threshold of ≥0.60 mg/L FEU) identified all patients with DVT (n=183, 11%).
The sensitivity and negative predictive values of D-dimer were both 100%, while specificity was 14.9% and the positive predictive value was 15.9%.
When the researchers used an age-adjusted D-dimer threshold (age x 0.01), the specificity increased from 14.9% to 21.3%, and the positive predictive value increased from 15.9% to 17%.
There were no DVTs among patients with low D-dimer values, but the rate of DVT significantly increased in the moderate (5.9%) and high groups (20.0%; P=0.007).
The rate of DVT increased with increasing WCP as well. The DVT rate was 6.6% in the low WCP group, 14% in the moderate group, and 29.1% in the high group (P<0.001).
The researchers also noted an increase in the rate of DVT across all levels of WCP as D-dimer levels increased.
Based on these findings, the researchers said there were 762 patients who were sent for unnecessary immediate VDUs. This included 685 patients in the low WCP group (<1) who did not undergo D-dimer testing, 51 patients who had moderate D-dimer values, and 26 who had low D-dimer values.
The researchers calculated the potential savings of using D-dimer instead of VDU in these patients, based on US 2016 dollar estimates.
A VDU cost of $1557 per person would mean a total cost of $1,186,434 for 762 patients. A D-dimer cost of $182 per person would mean a total cost of $138,684. So the total potential savings would be $1,047,750.
Dr. Mousa also noted that D-dimer testing is quicker than VDU and requires fewer resources.
“It’s a very simple sample of blood, which is sent to the lab,” he said. “And, usually in 15 or 20 minutes, you have significant information that can help you take good care of the patients. And you can send patients home quicker, with less demand on the hospital staff and the institution, yet increase patient satisfaction.”
Enzymes convert blood from type A to O more efficiently
BOSTON—New research suggests enzymes from the human gut can turn type A blood into type O more efficiently than previously studied enzymes.
Researchers found this new family of enzymes—whose name has not been made public—can remove the A antigens from red blood cells (RBCs), thereby converting type A blood to O.
Stephen Withers, PhD, of the University of British Columbia in Vancouver, Canada, presented details on the enzymes at the 256th National Meeting & Exposition of the American Chemical Society (abstract CARB105).
A metagenomics approach
Dr. Withers said researchers have been studying the use of enzymes to modify blood as far back as 1982. However, it has been difficult to identify efficient, selective enzymes that are also safe and economical.
To assess potential enzyme candidates quickly, Dr. Withers and his colleagues used metagenomics.
“With metagenomics, you take all of the organisms from an environment and extract the sum total DNA of those organisms all mixed up together,” Dr. Withers explained.
Casting such a wide net allowed the researchers to sample the genes of millions of microorganisms without the need for individual cultures. The researchers then used E. coli to select for genes that code for enzymes that can cleave sugar residues.
“This is a way of getting that genetic information out of the environment and into the laboratory setting and then screening for the activity we are interested in,” Dr. Withers said.
Focusing on the gut
Dr. Withers and his colleagues had considered sampling DNA from mosquitoes and leeches, the types of organisms that degrade blood, but the researchers ultimately found successful candidate enzymes in the human gut microbiome.
Glycosylated proteins called mucins line the gut wall, providing sugars that serve as attachment points for gut bacteria while also feeding them as they assist in digestion. Some of the mucin sugars are similar in structure to the antigens on RBCs in type A and B blood.
Dr. Withers and his colleagues studied the enzymes the bacteria use to pluck the sugars off mucin and identified a family of enzymes that could convert type A blood to type O.
The name of this enzyme family has not been released to the public, as the patent for the enzymes has not been submitted.
“By homing in on the bacteria feeding on those sugars, we isolated the enzymes the bacteria use to pluck off the sugar molecules,” Dr. Withers explained. “We then produced quantities of those enzymes through cloning and found that they were capable of performing a similar action on blood antigens.”
The enzymes could convert type A blood to type O by removing N-Acetyl galactosamine from the surface of RBCs.
In fact, the new enzymes were 30 times more effective for converting A to O than the alpha-N-acetylgalactosaminidase from Elizabethkingia meningospeticum that was described in a 2007 Nature Biotechnology paper.
Dr. Withers said he and his colleagues needed to use 30 times less of the new enzymes. This means the new enzymes are more economical, and it is easier to remove all traces of the added enzymes, which would need to be done before transfusion.
Looking ahead
Dr. Withers noted that the new enzymes work in whole blood. So if they prove safe for use in humans, the enzymes could potentially be introduced to whole blood donations and left to make the conversion from A to O. Then, the enzymes could be removed by washing RBCs before transfusion.
Dr. Withers and his colleagues are now working to validate these enzymes and test them on a larger scale for potential clinical testing. He also plans to carry out directed evolution, a protein engineering technique that simulates natural evolution, with the goal of creating the most efficient sugar-removing enzyme.
“I am optimistic that we have a very interesting candidate to adjust donated blood to a common type,” Dr. Withers said. “Of course, it will have to go through lots of clinical trials to make sure that it doesn’t have any adverse consequences, but it is looking very promising.”
The researchers acknowledged support and funding from the Canadian Institutes of Health Research.
BOSTON—New research suggests enzymes from the human gut can turn type A blood into type O more efficiently than previously studied enzymes.
Researchers found this new family of enzymes—whose name has not been made public—can remove the A antigens from red blood cells (RBCs), thereby converting type A blood to O.
Stephen Withers, PhD, of the University of British Columbia in Vancouver, Canada, presented details on the enzymes at the 256th National Meeting & Exposition of the American Chemical Society (abstract CARB105).
A metagenomics approach
Dr. Withers said researchers have been studying the use of enzymes to modify blood as far back as 1982. However, it has been difficult to identify efficient, selective enzymes that are also safe and economical.
To assess potential enzyme candidates quickly, Dr. Withers and his colleagues used metagenomics.
“With metagenomics, you take all of the organisms from an environment and extract the sum total DNA of those organisms all mixed up together,” Dr. Withers explained.
Casting such a wide net allowed the researchers to sample the genes of millions of microorganisms without the need for individual cultures. The researchers then used E. coli to select for genes that code for enzymes that can cleave sugar residues.
“This is a way of getting that genetic information out of the environment and into the laboratory setting and then screening for the activity we are interested in,” Dr. Withers said.
Focusing on the gut
Dr. Withers and his colleagues had considered sampling DNA from mosquitoes and leeches, the types of organisms that degrade blood, but the researchers ultimately found successful candidate enzymes in the human gut microbiome.
Glycosylated proteins called mucins line the gut wall, providing sugars that serve as attachment points for gut bacteria while also feeding them as they assist in digestion. Some of the mucin sugars are similar in structure to the antigens on RBCs in type A and B blood.
Dr. Withers and his colleagues studied the enzymes the bacteria use to pluck the sugars off mucin and identified a family of enzymes that could convert type A blood to type O.
The name of this enzyme family has not been released to the public, as the patent for the enzymes has not been submitted.
“By homing in on the bacteria feeding on those sugars, we isolated the enzymes the bacteria use to pluck off the sugar molecules,” Dr. Withers explained. “We then produced quantities of those enzymes through cloning and found that they were capable of performing a similar action on blood antigens.”
The enzymes could convert type A blood to type O by removing N-Acetyl galactosamine from the surface of RBCs.
In fact, the new enzymes were 30 times more effective for converting A to O than the alpha-N-acetylgalactosaminidase from Elizabethkingia meningospeticum that was described in a 2007 Nature Biotechnology paper.
Dr. Withers said he and his colleagues needed to use 30 times less of the new enzymes. This means the new enzymes are more economical, and it is easier to remove all traces of the added enzymes, which would need to be done before transfusion.
Looking ahead
Dr. Withers noted that the new enzymes work in whole blood. So if they prove safe for use in humans, the enzymes could potentially be introduced to whole blood donations and left to make the conversion from A to O. Then, the enzymes could be removed by washing RBCs before transfusion.
Dr. Withers and his colleagues are now working to validate these enzymes and test them on a larger scale for potential clinical testing. He also plans to carry out directed evolution, a protein engineering technique that simulates natural evolution, with the goal of creating the most efficient sugar-removing enzyme.
“I am optimistic that we have a very interesting candidate to adjust donated blood to a common type,” Dr. Withers said. “Of course, it will have to go through lots of clinical trials to make sure that it doesn’t have any adverse consequences, but it is looking very promising.”
The researchers acknowledged support and funding from the Canadian Institutes of Health Research.
BOSTON—New research suggests enzymes from the human gut can turn type A blood into type O more efficiently than previously studied enzymes.
Researchers found this new family of enzymes—whose name has not been made public—can remove the A antigens from red blood cells (RBCs), thereby converting type A blood to O.
Stephen Withers, PhD, of the University of British Columbia in Vancouver, Canada, presented details on the enzymes at the 256th National Meeting & Exposition of the American Chemical Society (abstract CARB105).
A metagenomics approach
Dr. Withers said researchers have been studying the use of enzymes to modify blood as far back as 1982. However, it has been difficult to identify efficient, selective enzymes that are also safe and economical.
To assess potential enzyme candidates quickly, Dr. Withers and his colleagues used metagenomics.
“With metagenomics, you take all of the organisms from an environment and extract the sum total DNA of those organisms all mixed up together,” Dr. Withers explained.
Casting such a wide net allowed the researchers to sample the genes of millions of microorganisms without the need for individual cultures. The researchers then used E. coli to select for genes that code for enzymes that can cleave sugar residues.
“This is a way of getting that genetic information out of the environment and into the laboratory setting and then screening for the activity we are interested in,” Dr. Withers said.
Focusing on the gut
Dr. Withers and his colleagues had considered sampling DNA from mosquitoes and leeches, the types of organisms that degrade blood, but the researchers ultimately found successful candidate enzymes in the human gut microbiome.
Glycosylated proteins called mucins line the gut wall, providing sugars that serve as attachment points for gut bacteria while also feeding them as they assist in digestion. Some of the mucin sugars are similar in structure to the antigens on RBCs in type A and B blood.
Dr. Withers and his colleagues studied the enzymes the bacteria use to pluck the sugars off mucin and identified a family of enzymes that could convert type A blood to type O.
The name of this enzyme family has not been released to the public, as the patent for the enzymes has not been submitted.
“By homing in on the bacteria feeding on those sugars, we isolated the enzymes the bacteria use to pluck off the sugar molecules,” Dr. Withers explained. “We then produced quantities of those enzymes through cloning and found that they were capable of performing a similar action on blood antigens.”
The enzymes could convert type A blood to type O by removing N-Acetyl galactosamine from the surface of RBCs.
In fact, the new enzymes were 30 times more effective for converting A to O than the alpha-N-acetylgalactosaminidase from Elizabethkingia meningospeticum that was described in a 2007 Nature Biotechnology paper.
Dr. Withers said he and his colleagues needed to use 30 times less of the new enzymes. This means the new enzymes are more economical, and it is easier to remove all traces of the added enzymes, which would need to be done before transfusion.
Looking ahead
Dr. Withers noted that the new enzymes work in whole blood. So if they prove safe for use in humans, the enzymes could potentially be introduced to whole blood donations and left to make the conversion from A to O. Then, the enzymes could be removed by washing RBCs before transfusion.
Dr. Withers and his colleagues are now working to validate these enzymes and test them on a larger scale for potential clinical testing. He also plans to carry out directed evolution, a protein engineering technique that simulates natural evolution, with the goal of creating the most efficient sugar-removing enzyme.
“I am optimistic that we have a very interesting candidate to adjust donated blood to a common type,” Dr. Withers said. “Of course, it will have to go through lots of clinical trials to make sure that it doesn’t have any adverse consequences, but it is looking very promising.”
The researchers acknowledged support and funding from the Canadian Institutes of Health Research.
AMP publishes report on DNA variants in CMNs
A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).
The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.
The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.
The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.
“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.
“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”
The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.
However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.
AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.
The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.
“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.
A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).
The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.
The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.
The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.
“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.
“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”
The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.
However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.
AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.
The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.
“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.
A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).
The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.
The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.
The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.
“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.
“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”
The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.
However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.
AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.
The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.
“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.