Hematology Times

Antihemophilic factor

The European Commission has approved a full-length recombinant factor VIII product for the treatment and prevention of bleeding in hemophilia A patients of all ages.

The product, Kovaltry (formerly BAY 81-8973), will be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The approval of Kovaltry is based on results from the LEOPOLD trials—3 multinational trials of patients with severe hemophilia A.

The trials were supported by Bayer HealthCare AG, the company developing Kovaltry.

LEOPOLD I

LEOPOLD I is an open-label, cross-over, phase 3 study of males, ages 12 to 65, with severe hemophilia A. Sixty-two patients were assigned to either 2- or 3-times-weekly dosing with Kovaltry, based on each patient’s phenotype, prior bleeding history, and other factors.

The median annualized bleeding rate (ABR) was 1.0 for all the patients who received Kovaltry prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD II

LEOPOLD II is a randomized, cross-over, open-label trial conducted in males ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive Kovaltry as a low-dose prophylaxis regimen (n=28) twice per week, high-dose prophylaxis (n=31) 3 times a week, or on-demand treatment (n=21).

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD Kids

LEOPOLD Kids is an open-label, non-randomized, phase 3 study designed to evaluate Kovaltry in children age 12 and younger. The study is divided into 2 parts. Part A enrolled only previously treated children, and part B, which is ongoing, includes only untreated children.

For part A, 51 children received Kovaltry twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days. The median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with at least a reasonable suspected causal relationship to Kovaltry.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

Antihemophilic factor

The European Commission has approved a full-length recombinant factor VIII product for the treatment and prevention of bleeding in hemophilia A patients of all ages.

The product, Kovaltry (formerly BAY 81-8973), will be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The approval of Kovaltry is based on results from the LEOPOLD trials—3 multinational trials of patients with severe hemophilia A.

The trials were supported by Bayer HealthCare AG, the company developing Kovaltry.

LEOPOLD I

LEOPOLD I is an open-label, cross-over, phase 3 study of males, ages 12 to 65, with severe hemophilia A. Sixty-two patients were assigned to either 2- or 3-times-weekly dosing with Kovaltry, based on each patient’s phenotype, prior bleeding history, and other factors.

The median annualized bleeding rate (ABR) was 1.0 for all the patients who received Kovaltry prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD II

LEOPOLD II is a randomized, cross-over, open-label trial conducted in males ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive Kovaltry as a low-dose prophylaxis regimen (n=28) twice per week, high-dose prophylaxis (n=31) 3 times a week, or on-demand treatment (n=21).

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD Kids

LEOPOLD Kids is an open-label, non-randomized, phase 3 study designed to evaluate Kovaltry in children age 12 and younger. The study is divided into 2 parts. Part A enrolled only previously treated children, and part B, which is ongoing, includes only untreated children.

For part A, 51 children received Kovaltry twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days. The median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with at least a reasonable suspected causal relationship to Kovaltry.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

Antihemophilic factor

The European Commission has approved a full-length recombinant factor VIII product for the treatment and prevention of bleeding in hemophilia A patients of all ages.

The product, Kovaltry (formerly BAY 81-8973), will be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The approval of Kovaltry is based on results from the LEOPOLD trials—3 multinational trials of patients with severe hemophilia A.

The trials were supported by Bayer HealthCare AG, the company developing Kovaltry.

LEOPOLD I

LEOPOLD I is an open-label, cross-over, phase 3 study of males, ages 12 to 65, with severe hemophilia A. Sixty-two patients were assigned to either 2- or 3-times-weekly dosing with Kovaltry, based on each patient’s phenotype, prior bleeding history, and other factors.

The median annualized bleeding rate (ABR) was 1.0 for all the patients who received Kovaltry prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD II

LEOPOLD II is a randomized, cross-over, open-label trial conducted in males ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive Kovaltry as a low-dose prophylaxis regimen (n=28) twice per week, high-dose prophylaxis (n=31) 3 times a week, or on-demand treatment (n=21).

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

LEOPOLD Kids

LEOPOLD Kids is an open-label, non-randomized, phase 3 study designed to evaluate Kovaltry in children age 12 and younger. The study is divided into 2 parts. Part A enrolled only previously treated children, and part B, which is ongoing, includes only untreated children.

For part A, 51 children received Kovaltry twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days. The median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with at least a reasonable suspected causal relationship to Kovaltry.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

Prescription medications

Photo courtesy of the CDC

The European Commission has approved use of the antiplatelet agent ticagrelor (Brilique) at a 60 mg dose to treat patients beyond the first year after a heart attack who are at high risk of developing a further atherothrombotic event.

The treatment may be used as continuation therapy after an initial 1-year treatment with 90 mg ticagrelor plus aspirin or after a year of other dual antiplatelet therapy.

This approval is applicable to all 28 European Union (EU) member countries plus Iceland, Norway, and Liechtenstein.

Ticagrelor at a 90 mg dose is already approved in the EU for the prevention of atherothrombotic events in adults with acute coronary syndrome (ACS). In the management of ACS, the recommended maintenance dose of ticagrelor is 90 mg twice daily during the first year after an ACS event.

Now, after the first year, patients with a history of heart attack can continue to be treated with ticagrelor at 60 mg twice daily, which should be taken with a daily maintenance dose of aspirin at 75 mg to 150 mg.

Trial results

The latest EU approval of ticagrelor was based on results from the PEGASUS TIMI-54 study. This trial, which involved more than 21,000 patients, was presented at the American College of Cardiology Congress in March 2015 and simultaneously published in NEJM.

Investigators compared ticagrelor (at 60 mg or 90 mg) plus low-dose aspirin to placebo plus low-dose aspirin in patients who had experienced a heart attack 1 to 3 years prior to study enrollment.

The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke.

The investigators found that patients in either ticagrelor arm were significantly less likely to achieve this endpoint than placebo-treated patients.

At 3 years, the proportion of patients meeting the primary endpoint was 7.85% in the 90 mg group, 7.77% in the 60 mg group, and 9.04% in the placebo group (P=0.008 for 90 mg vs placebo and P=0.004 for 60 mg vs placebo).

Patients receiving ticagrelor also had a significantly higher incidence of major bleeding and dyspnea. The rate of TIMI major bleeding was 2.60% in the 90 mg group, 2.30% in the 60 mg group, and 1.06% in the placebo group (P<0.001 for each ticagrelor dose vs placebo).

The rate of dyspnea was 18.93% in the 90 mg group, 15.84% in 60 mg group, and 6.38% in the placebo group (P<0.001 for both comparisons). The rate of dyspnea leading to treatment discontinuation was 6.5%, 4.55%, and 0.79%, respectively (P<0.001 for both comparisons).

Ticagrelor has been approved in more than 100 countries. The drug is under development by AstraZeneca.

Prescription medications

Photo courtesy of the CDC

The European Commission has approved use of the antiplatelet agent ticagrelor (Brilique) at a 60 mg dose to treat patients beyond the first year after a heart attack who are at high risk of developing a further atherothrombotic event.

The treatment may be used as continuation therapy after an initial 1-year treatment with 90 mg ticagrelor plus aspirin or after a year of other dual antiplatelet therapy.

This approval is applicable to all 28 European Union (EU) member countries plus Iceland, Norway, and Liechtenstein.

Ticagrelor at a 90 mg dose is already approved in the EU for the prevention of atherothrombotic events in adults with acute coronary syndrome (ACS). In the management of ACS, the recommended maintenance dose of ticagrelor is 90 mg twice daily during the first year after an ACS event.

Now, after the first year, patients with a history of heart attack can continue to be treated with ticagrelor at 60 mg twice daily, which should be taken with a daily maintenance dose of aspirin at 75 mg to 150 mg.

Trial results

The latest EU approval of ticagrelor was based on results from the PEGASUS TIMI-54 study. This trial, which involved more than 21,000 patients, was presented at the American College of Cardiology Congress in March 2015 and simultaneously published in NEJM.

Investigators compared ticagrelor (at 60 mg or 90 mg) plus low-dose aspirin to placebo plus low-dose aspirin in patients who had experienced a heart attack 1 to 3 years prior to study enrollment.

The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke.

The investigators found that patients in either ticagrelor arm were significantly less likely to achieve this endpoint than placebo-treated patients.

At 3 years, the proportion of patients meeting the primary endpoint was 7.85% in the 90 mg group, 7.77% in the 60 mg group, and 9.04% in the placebo group (P=0.008 for 90 mg vs placebo and P=0.004 for 60 mg vs placebo).

Patients receiving ticagrelor also had a significantly higher incidence of major bleeding and dyspnea. The rate of TIMI major bleeding was 2.60% in the 90 mg group, 2.30% in the 60 mg group, and 1.06% in the placebo group (P<0.001 for each ticagrelor dose vs placebo).

The rate of dyspnea was 18.93% in the 90 mg group, 15.84% in 60 mg group, and 6.38% in the placebo group (P<0.001 for both comparisons). The rate of dyspnea leading to treatment discontinuation was 6.5%, 4.55%, and 0.79%, respectively (P<0.001 for both comparisons).

Ticagrelor has been approved in more than 100 countries. The drug is under development by AstraZeneca.

Prescription medications

Photo courtesy of the CDC

The European Commission has approved use of the antiplatelet agent ticagrelor (Brilique) at a 60 mg dose to treat patients beyond the first year after a heart attack who are at high risk of developing a further atherothrombotic event.

The treatment may be used as continuation therapy after an initial 1-year treatment with 90 mg ticagrelor plus aspirin or after a year of other dual antiplatelet therapy.

This approval is applicable to all 28 European Union (EU) member countries plus Iceland, Norway, and Liechtenstein.

Ticagrelor at a 90 mg dose is already approved in the EU for the prevention of atherothrombotic events in adults with acute coronary syndrome (ACS). In the management of ACS, the recommended maintenance dose of ticagrelor is 90 mg twice daily during the first year after an ACS event.

Now, after the first year, patients with a history of heart attack can continue to be treated with ticagrelor at 60 mg twice daily, which should be taken with a daily maintenance dose of aspirin at 75 mg to 150 mg.

Trial results

The latest EU approval of ticagrelor was based on results from the PEGASUS TIMI-54 study. This trial, which involved more than 21,000 patients, was presented at the American College of Cardiology Congress in March 2015 and simultaneously published in NEJM.

Investigators compared ticagrelor (at 60 mg or 90 mg) plus low-dose aspirin to placebo plus low-dose aspirin in patients who had experienced a heart attack 1 to 3 years prior to study enrollment.

The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke.

The investigators found that patients in either ticagrelor arm were significantly less likely to achieve this endpoint than placebo-treated patients.

At 3 years, the proportion of patients meeting the primary endpoint was 7.85% in the 90 mg group, 7.77% in the 60 mg group, and 9.04% in the placebo group (P=0.008 for 90 mg vs placebo and P=0.004 for 60 mg vs placebo).

Patients receiving ticagrelor also had a significantly higher incidence of major bleeding and dyspnea. The rate of TIMI major bleeding was 2.60% in the 90 mg group, 2.30% in the 60 mg group, and 1.06% in the placebo group (P<0.001 for each ticagrelor dose vs placebo).

The rate of dyspnea was 18.93% in the 90 mg group, 15.84% in 60 mg group, and 6.38% in the placebo group (P<0.001 for both comparisons). The rate of dyspnea leading to treatment discontinuation was 6.5%, 4.55%, and 0.79%, respectively (P<0.001 for both comparisons).

Ticagrelor has been approved in more than 100 countries. The drug is under development by AstraZeneca.

Andreas Strasser, PhD

Photo by Cameron Wells,

Walter and Eliza Hall

Institute of Medical Research

Research published in Cell Reports helps explain how the anticancer agent Nutlin3a fights lymphoma and other hematologic malignancies.

Nutlin3a is known to activate the tumor suppressor p53, but it hasn’t been clear exactly which p53 target genes are essential for the drug’s therapeutic activity.

The new research revealed that PUMA-mediated apoptosis—not p21-mediated cell-cycle arrest or senescence—is responsible for Nutlin3a’s therapeutic activity in lymphoid malignancies.

“By understanding how nutlins are killing cancer cells, we can begin to formulate their best possible use, including choosing the best partner drugs to combine the nutlins with,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

With this study, Dr Strasser and his colleagues first found that Nutlin3a activates p53 target gene expression and causes cell-cycle arrest and apoptosis in non-transformed mouse lymphoid cells in vitro.

The team then showed that Nutlin3a-mediated killing of these cells requires PUMA but not p21. In vivo, loss of PUMA protected non-transformed mouse lymphoid cells against Nutlin3a-induced killing. Loss of p21 did not provide the same protection.

Next, the researchers found that malignant Eµ-Myc lymphoma cells were much more sensitive to Nutlin3a than were non-transformed lymphoid cells. In vitro experiments with Eµ-Myc lymphoma cells showed that Nutlin3a promotes p53 accumulation and downstream effector pathway activation.

As in previous experiments, PUMA (not p21) proved critical for Nutlin3a-induced killing of Eµ-Myc lymphoma cells in vitro. And loss of PUMA (but not p21) impaired the regression of Eµ-Myc lymphomas induced by Nutlin3a in vivo.

Finally, the researchers found that PUMA contributed to Nutlin3a-induced apoptosis in myeloid leukemia, multiple myeloma, and Burkitt lymphoma cell lines.

The team noted that, because PUMA, a pro-apoptotic BH3-only protein, is critical for the therapeutic impact of Nutlin3a, it may be possible to boost the drug’s efficacy by combining it with BH3 mimetic drugs such as navitoclax or venetoclax.

Andreas Strasser, PhD

Photo by Cameron Wells,

Walter and Eliza Hall

Institute of Medical Research

Research published in Cell Reports helps explain how the anticancer agent Nutlin3a fights lymphoma and other hematologic malignancies.

Nutlin3a is known to activate the tumor suppressor p53, but it hasn’t been clear exactly which p53 target genes are essential for the drug’s therapeutic activity.

The new research revealed that PUMA-mediated apoptosis—not p21-mediated cell-cycle arrest or senescence—is responsible for Nutlin3a’s therapeutic activity in lymphoid malignancies.

“By understanding how nutlins are killing cancer cells, we can begin to formulate their best possible use, including choosing the best partner drugs to combine the nutlins with,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

With this study, Dr Strasser and his colleagues first found that Nutlin3a activates p53 target gene expression and causes cell-cycle arrest and apoptosis in non-transformed mouse lymphoid cells in vitro.

The team then showed that Nutlin3a-mediated killing of these cells requires PUMA but not p21. In vivo, loss of PUMA protected non-transformed mouse lymphoid cells against Nutlin3a-induced killing. Loss of p21 did not provide the same protection.

Next, the researchers found that malignant Eµ-Myc lymphoma cells were much more sensitive to Nutlin3a than were non-transformed lymphoid cells. In vitro experiments with Eµ-Myc lymphoma cells showed that Nutlin3a promotes p53 accumulation and downstream effector pathway activation.

As in previous experiments, PUMA (not p21) proved critical for Nutlin3a-induced killing of Eµ-Myc lymphoma cells in vitro. And loss of PUMA (but not p21) impaired the regression of Eµ-Myc lymphomas induced by Nutlin3a in vivo.

Finally, the researchers found that PUMA contributed to Nutlin3a-induced apoptosis in myeloid leukemia, multiple myeloma, and Burkitt lymphoma cell lines.

The team noted that, because PUMA, a pro-apoptotic BH3-only protein, is critical for the therapeutic impact of Nutlin3a, it may be possible to boost the drug’s efficacy by combining it with BH3 mimetic drugs such as navitoclax or venetoclax.

Andreas Strasser, PhD

Photo by Cameron Wells,

Walter and Eliza Hall

Institute of Medical Research

Research published in Cell Reports helps explain how the anticancer agent Nutlin3a fights lymphoma and other hematologic malignancies.

Nutlin3a is known to activate the tumor suppressor p53, but it hasn’t been clear exactly which p53 target genes are essential for the drug’s therapeutic activity.

The new research revealed that PUMA-mediated apoptosis—not p21-mediated cell-cycle arrest or senescence—is responsible for Nutlin3a’s therapeutic activity in lymphoid malignancies.

“By understanding how nutlins are killing cancer cells, we can begin to formulate their best possible use, including choosing the best partner drugs to combine the nutlins with,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

With this study, Dr Strasser and his colleagues first found that Nutlin3a activates p53 target gene expression and causes cell-cycle arrest and apoptosis in non-transformed mouse lymphoid cells in vitro.

The team then showed that Nutlin3a-mediated killing of these cells requires PUMA but not p21. In vivo, loss of PUMA protected non-transformed mouse lymphoid cells against Nutlin3a-induced killing. Loss of p21 did not provide the same protection.

Next, the researchers found that malignant Eµ-Myc lymphoma cells were much more sensitive to Nutlin3a than were non-transformed lymphoid cells. In vitro experiments with Eµ-Myc lymphoma cells showed that Nutlin3a promotes p53 accumulation and downstream effector pathway activation.

As in previous experiments, PUMA (not p21) proved critical for Nutlin3a-induced killing of Eµ-Myc lymphoma cells in vitro. And loss of PUMA (but not p21) impaired the regression of Eµ-Myc lymphomas induced by Nutlin3a in vivo.

Finally, the researchers found that PUMA contributed to Nutlin3a-induced apoptosis in myeloid leukemia, multiple myeloma, and Burkitt lymphoma cell lines.

The team noted that, because PUMA, a pro-apoptotic BH3-only protein, is critical for the therapeutic impact of Nutlin3a, it may be possible to boost the drug’s efficacy by combining it with BH3 mimetic drugs such as navitoclax or venetoclax.

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

HSCT preparation

Photo by Chad McNeeley

HONOLULU—Despite disappointing results in a phase 3 trial, investigators believe the oral nucleotide analog brincidofovir may still be viable as cytomegalovirus (CMV) prophylaxis in patients undergoing hematopoietic stem cell transplant (HSCT).

As reported last December, brincidofovir did not meet the primary endpoint of the phase 3 SUPPRESS trial, which was to prevent clinically significant CMV infection at week 24 after HSCT.

However, trial investigators said the drug did prevent CMV through week 14, which was the end of the treatment period.

The team believes they have an explanation for these findings, which were presented at the 2016 BMT Tandem Meetings (abstract 5). The trial was supported by Chimerix, the company developing brincidofovir.

The SUPPRESS trial included 452 subjects at high risk for CMV who were randomized to receive brincidofovir or placebo twice weekly for up to 14 weeks following allogeneic HSCT. They were then followed for 10 weeks after treatment.

Baseline characteristics were similar between the treatment arms, although there were more males in the placebo arm than the brincidofovir arm—66% and 54%, respectively. The median age was 56 in the brincidofovir arm and 54 in the placebo arm (overall range, 18-77).

Key results

The primary endpoint was assessed at week 24. At that time, the proportion of patients with clinically significant CMV infection was similar in the brincidofovir and placebo arms—51% and 52%, respectively.

However, the investigators did note that brincidofovir exhibited an antiviral effect during the trial. At the end of the on-treatment period at week 14, patients who received brincidofovir had fewer clinically significant CMV infections than patients in the placebo group—24% and 38%, respectively (P=0.002).

The investigators said the failure to meet the primary endpoint at week 24 appears to be associated with CMV events in the post-treatment period among subjects on the brincidofovir arm, driven by higher use of corticosteroids and other immunosuppressive therapies for the treatment of presumptive graft-versus-host disease (GVHD).

Diarrhea can be a symptom of GVHD in the gut and is also a known side effect of brincidofovir that can be managed by a temporary dose interruption, as described in the safety monitoring and management plan (SMMP) developed during the phase 2 trial of the drug (then known as CMX001).

In the SUPPRESS trial, diarrhea in brincidofovir-treated patients was more frequent and often presumed to be gut GVHD. So patients were treated with corticosteroids rather than undergoing temporary treatment interruption according to the SMMP. Among patients who were managed according to the SMMP, the investigators observed significantly fewer CMV infections (P=0.03) and lower mortality (P<0.001).

There was an 8-fold increase in the use of corticosteroids through week 14 in the brincidofovir arm compared to the placebo arm. The median cumulative dose of prednisone-equivalent corticosteroids was 26 mg/kg and 3 mg/kg, respectively.

The use of corticosteroids and other immunosuppressive therapies for the treatment of GVHD is known to increase the risk of infections, including CMV infections that occur when patients discontinue antiviral therapy.

Among patients who either underwent T-cell depletion or received alemtuzumab/ATG to decrease the risk of GVHD, those who were randomized to receive brincidofovir showed a lower incidence of CMV when compared to placebo, at a rate consistent with what was observed in the phase 2 study.

Additional endpoints

Brincidofovir did not prevent infection with non-CMV DNA viruses, such as BK virus.

And there was no significant difference between the treatment arms with regard to all-cause mortality. The rate was 15.5% in the brincidofovir arm and 10.1% in the placebo arm (P=0.12).

The investigators said the numerical differences in mortality appear to be driven by higher use of corticosteroids and other immunosuppressive therapies in the subjects who received brincidofovir.

The rate of treatment-emergent adverse events (AEs) was 100% in the brincidofovir arm and 98% in the placebo arm. The rate of grade 3 or higher AEs was 67% and 38%, respectively. The rate of serious AEs was 57% and 38%, respectively.

The rate of AEs leading to treatment discontinuation was 26% and 7%, respectively. And the rate of AEs leading to treatment change or interruption was 45% and 15%, respectively.

The most common AEs in the brincidofovir arm were diarrhea (61%), acute GVHD (57%), abdominal pain (34%), nausea (31%), vomiting (24%), peripheral edema (17%), hyperglycemia (16%), hypokalemia (16%), hypomagnesemia (13%), and ALT elevation (11%). There was no evidence of bone marrow toxicity, kidney toxicity, or viral resistance to brincidofovir.

Brincidofovir development

Chimerix said it will discuss the SUPPRESS data in full with the US Food and Drug Administration and other regulators, including the benefit-to-risk profile in specific subpopulations, as well as the current adenovirus and smallpox data, to determine next steps for the brincidofovir clinical programs.

The development of an intravenous (IV) formulation of brincidofovir is progressing toward clinical testing and has the potential to avoid the gastrointestinal side effects of orally administered brincidofovir.

Preclinical studies of IV brincidofovir have shown a lower risk of gastrointestinal effects based on maintained body weight during dosing and no evidence of injury in preliminary review of the gastrointestinal tract.

If human studies continue to support these findings, IV dosing during the first few weeks after transplant when patients are recovering from conditioning chemotherapy could be explored, with oral brincidofovir therapy available as patients are discharged home.

As there is no preventive therapy approved for CMV in HSCT recipients, Chimerix said it is committed to moving brincidofovir forward in this indication. Plans for brincidofovir in HSCT recipients will be the subject of further discussions with regulators.

 

 

Person on a scale

 

A new analysis indicates that having a higher body weight and taller stature during adolescence may increase the risk of developing non-Hodgkin lymphoma (NHL).

Global rates of NHL have been on the rise in recent years, and research suggests that rising rates of obesity may be contributing to this trend.

With this in mind, investigators examined whether adolescent weight and height might be associated with the risk of developing NHL later in life.

They reported their results in Cancer.

The study included 2,352,988 subjects, ages 16 to 19, who were examined between 1967 and 2011. Their information was linked to the Israel National Cancer Registry, which included 4021 cases of NHL from 1967 through 2012.

The data showed that being overweight or obese in adolescence was associated with an increased risk of NHL later in life. When compared to adolescents of normal weight, the hazard ratio (HR) was 1.25 for subjects who were overweight or obese. The HR for underweight individuals was 0.98.

Being overweight or obese in adolescence was a significant predictor for marginal zone lymphoma (HR=1.70), primary cutaneous lymphoma (PCL, HR=1.44), and diffuse large B-cell lymphoma (DLBCL, HR=1.31). Excess weight was a borderline predictor for follicular lymphoma (HR=1.28).

“It is important to be aware that overweight and obesity are not risk factors only for diabetes and cardiovascular disease but also for lymphomas,” said study author Merav Leiba, MD, of the Sheba Medical Center in Israel.

Dr Leiba and her colleagues also observed an increased risk of NHL corresponding with increases in subjects’ height. When compared with the mid-range height category, shorter individuals had an HR of 1.25, and the tallest individuals had an HR of 1.28.

The strongest associations between taller height and NHL were observed for primary cutaneous lymphoma and diffuse large B-cell lymphoma. The HRs for the tallest group, compared to the shortest group, were 3.19 for PCL and 2.21 for DLBCL.

The investigators said additional research is needed to help explain the links between height, weight, and NHL.

 

 

Person on a scale

 

A new analysis indicates that having a higher body weight and taller stature during adolescence may increase the risk of developing non-Hodgkin lymphoma (NHL).

Global rates of NHL have been on the rise in recent years, and research suggests that rising rates of obesity may be contributing to this trend.

With this in mind, investigators examined whether adolescent weight and height might be associated with the risk of developing NHL later in life.

They reported their results in Cancer.

The study included 2,352,988 subjects, ages 16 to 19, who were examined between 1967 and 2011. Their information was linked to the Israel National Cancer Registry, which included 4021 cases of NHL from 1967 through 2012.

The data showed that being overweight or obese in adolescence was associated with an increased risk of NHL later in life. When compared to adolescents of normal weight, the hazard ratio (HR) was 1.25 for subjects who were overweight or obese. The HR for underweight individuals was 0.98.

Being overweight or obese in adolescence was a significant predictor for marginal zone lymphoma (HR=1.70), primary cutaneous lymphoma (PCL, HR=1.44), and diffuse large B-cell lymphoma (DLBCL, HR=1.31). Excess weight was a borderline predictor for follicular lymphoma (HR=1.28).

“It is important to be aware that overweight and obesity are not risk factors only for diabetes and cardiovascular disease but also for lymphomas,” said study author Merav Leiba, MD, of the Sheba Medical Center in Israel.

Dr Leiba and her colleagues also observed an increased risk of NHL corresponding with increases in subjects’ height. When compared with the mid-range height category, shorter individuals had an HR of 1.25, and the tallest individuals had an HR of 1.28.

The strongest associations between taller height and NHL were observed for primary cutaneous lymphoma and diffuse large B-cell lymphoma. The HRs for the tallest group, compared to the shortest group, were 3.19 for PCL and 2.21 for DLBCL.

The investigators said additional research is needed to help explain the links between height, weight, and NHL.

 

 

Person on a scale

 

A new analysis indicates that having a higher body weight and taller stature during adolescence may increase the risk of developing non-Hodgkin lymphoma (NHL).

Global rates of NHL have been on the rise in recent years, and research suggests that rising rates of obesity may be contributing to this trend.

With this in mind, investigators examined whether adolescent weight and height might be associated with the risk of developing NHL later in life.

They reported their results in Cancer.

The study included 2,352,988 subjects, ages 16 to 19, who were examined between 1967 and 2011. Their information was linked to the Israel National Cancer Registry, which included 4021 cases of NHL from 1967 through 2012.

The data showed that being overweight or obese in adolescence was associated with an increased risk of NHL later in life. When compared to adolescents of normal weight, the hazard ratio (HR) was 1.25 for subjects who were overweight or obese. The HR for underweight individuals was 0.98.

Being overweight or obese in adolescence was a significant predictor for marginal zone lymphoma (HR=1.70), primary cutaneous lymphoma (PCL, HR=1.44), and diffuse large B-cell lymphoma (DLBCL, HR=1.31). Excess weight was a borderline predictor for follicular lymphoma (HR=1.28).

“It is important to be aware that overweight and obesity are not risk factors only for diabetes and cardiovascular disease but also for lymphomas,” said study author Merav Leiba, MD, of the Sheba Medical Center in Israel.

Dr Leiba and her colleagues also observed an increased risk of NHL corresponding with increases in subjects’ height. When compared with the mid-range height category, shorter individuals had an HR of 1.25, and the tallest individuals had an HR of 1.28.

The strongest associations between taller height and NHL were observed for primary cutaneous lymphoma and diffuse large B-cell lymphoma. The HRs for the tallest group, compared to the shortest group, were 3.19 for PCL and 2.21 for DLBCL.

The investigators said additional research is needed to help explain the links between height, weight, and NHL.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

A study published in the British Journal of Hematology has revealed factors that appear to affect survival in patients with acute myeloid leukemia (AML).

The research showed that death was more likely among AML patients treated at centers not affiliated with the National Cancer Institute (NCI).

Death was also more likely for black patients, older patients, those without health insurance, and those who lived in poorer neighborhoods.

“Our study reveals that survival inequalities persist among vulnerable patients with acute myeloid leukemia, such as the uninsured, those of black race/ethnicity, and adolescents and young adults,” said study author Renata Abrahão, MD, of Cancer Prevention Institute of California.

“This study can serve as a baseline to compare changes in survival that may result from potential improvements in health insurance coverage following the implementation of the Affordable Care Act.”

Dr Abrahão and her colleagues analyzed 3935 AML patients who were 39 or younger between 1988 and 2011. The team used data from the California Cancer Registry, which participates in the Surveillance, Epidemiology and End Results program of the NCI.

The data revealed an increase over time in the 5-year survival rate, from 32.9% in 1988–1995 to 50% in 2004–2011. However, 58% of the patients (n=2272) died during follow-up. The overall median follow-up was 10 years, and the median time to death was 0.9 years.

A multivariate analysis revealed several subgroups of patients with worse survival.

Older patients had a greater risk of death when compared to patients ages 0 to 9. The hazard ratio (HR) was 1.23 for patients ages 10 to 19, 1.34 for patients ages 20 to 29, and 1.55 for patients ages 30 to 39.

Black patients had an increased risk of death as well. When compared with white patients, the HR was 1.27 for black patients, 1.05 for Hispanic patients, and 0.98 for Asian/Pacific Islanders.

Patients living in the neighborhoods with the lowest socioeconomic status had an HR of 1.14. And patients who received their initial care at a hospital not affiliated with the NCI had an HR of 1.18.

Health insurance information was only available for patients diagnosed from 1996 to 2011. Among these patients, the risk of death was higher among uninsured patients (HR=1.34) than among privately insured patients, but there was no difference between privately and publicly insured patients.

Explaining the findings

The researchers said AML diagnosis in older children, adolescents, and young adults may require more intensive treatment than in young children, which may lead to a higher probability of treatment-related complications. And recent studies have shown the biology of pediatric AML differs from adult AML, which may lead to a favorable prognosis in younger patients.

In addition, older children, adolescents, and young adults are less likely to participate in clinical trials and more likely to receive treatment at hospitals not affiliated with the NCI, when compared to younger children.

The researchers said it is not clear what factors accounted for the inferior survival observed among black patients. The team speculated that genetics may contribute to the difference in chemotherapy response or that black patients had less access to chemotherapy and other treatments such as hematopoietic stem cell transplant.

The association between lower socioeconomic status and death suggests a lack of access to treatment. The same can be said for the association between death and a lack of insurance.

“[T]his study showed that survival after AML remains low among young patients and highlights the need for new therapeutic regimens to treat this disease with various subtypes,” Dr Abrahão said.

“We emphasized the importance of linking population-based data with genetic and clinical information contained in the patients’ medical records in order to better understand the causes of survival inequalities.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

A study published in the British Journal of Hematology has revealed factors that appear to affect survival in patients with acute myeloid leukemia (AML).

The research showed that death was more likely among AML patients treated at centers not affiliated with the National Cancer Institute (NCI).

Death was also more likely for black patients, older patients, those without health insurance, and those who lived in poorer neighborhoods.

“Our study reveals that survival inequalities persist among vulnerable patients with acute myeloid leukemia, such as the uninsured, those of black race/ethnicity, and adolescents and young adults,” said study author Renata Abrahão, MD, of Cancer Prevention Institute of California.

“This study can serve as a baseline to compare changes in survival that may result from potential improvements in health insurance coverage following the implementation of the Affordable Care Act.”

Dr Abrahão and her colleagues analyzed 3935 AML patients who were 39 or younger between 1988 and 2011. The team used data from the California Cancer Registry, which participates in the Surveillance, Epidemiology and End Results program of the NCI.

The data revealed an increase over time in the 5-year survival rate, from 32.9% in 1988–1995 to 50% in 2004–2011. However, 58% of the patients (n=2272) died during follow-up. The overall median follow-up was 10 years, and the median time to death was 0.9 years.

A multivariate analysis revealed several subgroups of patients with worse survival.

Older patients had a greater risk of death when compared to patients ages 0 to 9. The hazard ratio (HR) was 1.23 for patients ages 10 to 19, 1.34 for patients ages 20 to 29, and 1.55 for patients ages 30 to 39.

Black patients had an increased risk of death as well. When compared with white patients, the HR was 1.27 for black patients, 1.05 for Hispanic patients, and 0.98 for Asian/Pacific Islanders.

Patients living in the neighborhoods with the lowest socioeconomic status had an HR of 1.14. And patients who received their initial care at a hospital not affiliated with the NCI had an HR of 1.18.

Health insurance information was only available for patients diagnosed from 1996 to 2011. Among these patients, the risk of death was higher among uninsured patients (HR=1.34) than among privately insured patients, but there was no difference between privately and publicly insured patients.

Explaining the findings

The researchers said AML diagnosis in older children, adolescents, and young adults may require more intensive treatment than in young children, which may lead to a higher probability of treatment-related complications. And recent studies have shown the biology of pediatric AML differs from adult AML, which may lead to a favorable prognosis in younger patients.

In addition, older children, adolescents, and young adults are less likely to participate in clinical trials and more likely to receive treatment at hospitals not affiliated with the NCI, when compared to younger children.

The researchers said it is not clear what factors accounted for the inferior survival observed among black patients. The team speculated that genetics may contribute to the difference in chemotherapy response or that black patients had less access to chemotherapy and other treatments such as hematopoietic stem cell transplant.

The association between lower socioeconomic status and death suggests a lack of access to treatment. The same can be said for the association between death and a lack of insurance.

“[T]his study showed that survival after AML remains low among young patients and highlights the need for new therapeutic regimens to treat this disease with various subtypes,” Dr Abrahão said.

“We emphasized the importance of linking population-based data with genetic and clinical information contained in the patients’ medical records in order to better understand the causes of survival inequalities.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

A study published in the British Journal of Hematology has revealed factors that appear to affect survival in patients with acute myeloid leukemia (AML).

The research showed that death was more likely among AML patients treated at centers not affiliated with the National Cancer Institute (NCI).

Death was also more likely for black patients, older patients, those without health insurance, and those who lived in poorer neighborhoods.

“Our study reveals that survival inequalities persist among vulnerable patients with acute myeloid leukemia, such as the uninsured, those of black race/ethnicity, and adolescents and young adults,” said study author Renata Abrahão, MD, of Cancer Prevention Institute of California.

“This study can serve as a baseline to compare changes in survival that may result from potential improvements in health insurance coverage following the implementation of the Affordable Care Act.”

Dr Abrahão and her colleagues analyzed 3935 AML patients who were 39 or younger between 1988 and 2011. The team used data from the California Cancer Registry, which participates in the Surveillance, Epidemiology and End Results program of the NCI.

The data revealed an increase over time in the 5-year survival rate, from 32.9% in 1988–1995 to 50% in 2004–2011. However, 58% of the patients (n=2272) died during follow-up. The overall median follow-up was 10 years, and the median time to death was 0.9 years.

A multivariate analysis revealed several subgroups of patients with worse survival.

Older patients had a greater risk of death when compared to patients ages 0 to 9. The hazard ratio (HR) was 1.23 for patients ages 10 to 19, 1.34 for patients ages 20 to 29, and 1.55 for patients ages 30 to 39.

Black patients had an increased risk of death as well. When compared with white patients, the HR was 1.27 for black patients, 1.05 for Hispanic patients, and 0.98 for Asian/Pacific Islanders.

Patients living in the neighborhoods with the lowest socioeconomic status had an HR of 1.14. And patients who received their initial care at a hospital not affiliated with the NCI had an HR of 1.18.

Health insurance information was only available for patients diagnosed from 1996 to 2011. Among these patients, the risk of death was higher among uninsured patients (HR=1.34) than among privately insured patients, but there was no difference between privately and publicly insured patients.

Explaining the findings

The researchers said AML diagnosis in older children, adolescents, and young adults may require more intensive treatment than in young children, which may lead to a higher probability of treatment-related complications. And recent studies have shown the biology of pediatric AML differs from adult AML, which may lead to a favorable prognosis in younger patients.

In addition, older children, adolescents, and young adults are less likely to participate in clinical trials and more likely to receive treatment at hospitals not affiliated with the NCI, when compared to younger children.

The researchers said it is not clear what factors accounted for the inferior survival observed among black patients. The team speculated that genetics may contribute to the difference in chemotherapy response or that black patients had less access to chemotherapy and other treatments such as hematopoietic stem cell transplant.

The association between lower socioeconomic status and death suggests a lack of access to treatment. The same can be said for the association between death and a lack of insurance.

“[T]his study showed that survival after AML remains low among young patients and highlights the need for new therapeutic regimens to treat this disease with various subtypes,” Dr Abrahão said.

“We emphasized the importance of linking population-based data with genetic and clinical information contained in the patients’ medical records in order to better understand the causes of survival inequalities.”

Blood smear showing
Plasmodium vivax
Image by Mae Melvin

Researchers say they have determined the structure of the protein PvRBP2a, which is used by the malaria parasite Plasmodium vivax to infect human red blood cells.

This revealed that PvRBP2a is structurally similar to PfRh5, the essential erythrocyte-binding protein in the parasite P falciparum.

The researchers believe these findings could help scientists generate new tools to prevent infection with malaria parasites.

Wai-Hong Tham, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues conducted this research and reported the results in PNAS.

“We have produced the first 3-dimensional, atomic resolution structure of the protein [PvRBP2a] using the Australian Synchrotron in Melbourne,” Dr Tham said.

She and her colleagues found that PvRBP2a consists of 10 α-helices and 1 short β-hairpin. And although PvRBP2a is structurally similar to PfRh5, the 2 proteins have different surface properties.

“The 3-dimensional map showed us that the proteins are folded in the same way—like having similar origami instructions,” Dr Tham said. “The difference is actually in the electrical charge on the surface of the molecules.”

“Now that we have an atomic-resolution map, we hope to identify a common part of the protein that could be used to design a vaccine not only for Plasmodium vivax but potentially for both vivax and falciparum.”

“These two species of malaria are responsible for the majority of malaria infections worldwide, so a vaccine that targets both would be a critical addition to our arsenal.”

Dr Tham said there is growing evidence that developing better treatments or preventive strategies for P vivax malaria is imperative for malaria eradication.

“Not only is P vivax the most widespread species of malaria, it is also more difficult to treat because it can hide in the liver for long periods of time without symptoms,” she said. “In addition, studies show that effective treatment of falciparum malaria tends to be accompanied by a resurgence of P vivax, so it is critical to continue looking for better ways to manage this species.”

Blood smear showing
Plasmodium vivax
Image by Mae Melvin

Researchers say they have determined the structure of the protein PvRBP2a, which is used by the malaria parasite Plasmodium vivax to infect human red blood cells.

This revealed that PvRBP2a is structurally similar to PfRh5, the essential erythrocyte-binding protein in the parasite P falciparum.

The researchers believe these findings could help scientists generate new tools to prevent infection with malaria parasites.

Wai-Hong Tham, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues conducted this research and reported the results in PNAS.

“We have produced the first 3-dimensional, atomic resolution structure of the protein [PvRBP2a] using the Australian Synchrotron in Melbourne,” Dr Tham said.

She and her colleagues found that PvRBP2a consists of 10 α-helices and 1 short β-hairpin. And although PvRBP2a is structurally similar to PfRh5, the 2 proteins have different surface properties.

“The 3-dimensional map showed us that the proteins are folded in the same way—like having similar origami instructions,” Dr Tham said. “The difference is actually in the electrical charge on the surface of the molecules.”

“Now that we have an atomic-resolution map, we hope to identify a common part of the protein that could be used to design a vaccine not only for Plasmodium vivax but potentially for both vivax and falciparum.”

“These two species of malaria are responsible for the majority of malaria infections worldwide, so a vaccine that targets both would be a critical addition to our arsenal.”

Dr Tham said there is growing evidence that developing better treatments or preventive strategies for P vivax malaria is imperative for malaria eradication.

“Not only is P vivax the most widespread species of malaria, it is also more difficult to treat because it can hide in the liver for long periods of time without symptoms,” she said. “In addition, studies show that effective treatment of falciparum malaria tends to be accompanied by a resurgence of P vivax, so it is critical to continue looking for better ways to manage this species.”

Blood smear showing
Plasmodium vivax
Image by Mae Melvin

Researchers say they have determined the structure of the protein PvRBP2a, which is used by the malaria parasite Plasmodium vivax to infect human red blood cells.

This revealed that PvRBP2a is structurally similar to PfRh5, the essential erythrocyte-binding protein in the parasite P falciparum.

The researchers believe these findings could help scientists generate new tools to prevent infection with malaria parasites.

Wai-Hong Tham, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues conducted this research and reported the results in PNAS.

“We have produced the first 3-dimensional, atomic resolution structure of the protein [PvRBP2a] using the Australian Synchrotron in Melbourne,” Dr Tham said.

She and her colleagues found that PvRBP2a consists of 10 α-helices and 1 short β-hairpin. And although PvRBP2a is structurally similar to PfRh5, the 2 proteins have different surface properties.

“The 3-dimensional map showed us that the proteins are folded in the same way—like having similar origami instructions,” Dr Tham said. “The difference is actually in the electrical charge on the surface of the molecules.”

“Now that we have an atomic-resolution map, we hope to identify a common part of the protein that could be used to design a vaccine not only for Plasmodium vivax but potentially for both vivax and falciparum.”

“These two species of malaria are responsible for the majority of malaria infections worldwide, so a vaccine that targets both would be a critical addition to our arsenal.”

Dr Tham said there is growing evidence that developing better treatments or preventive strategies for P vivax malaria is imperative for malaria eradication.

“Not only is P vivax the most widespread species of malaria, it is also more difficult to treat because it can hide in the liver for long periods of time without symptoms,” she said. “In addition, studies show that effective treatment of falciparum malaria tends to be accompanied by a resurgence of P vivax, so it is critical to continue looking for better ways to manage this species.”

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for midostaurin (PKC412) to treat acute myeloid leukemia (AML).

Midostaurin is a multi-targeted kinase inhibitor being developed for adults with newly diagnosed AML who are FLT3-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.

Breakthrough therapy designation is intended to expedite the development and review of new medicines intended to treat serious or life-threatening conditions. The therapy must demonstrate substantial improvement over an available therapy on at least one clinically significant endpoint.

The designation includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.

Phase 3 trial

The breakthrough designation for midostaurin is primarily based on the results of the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 717 patients with newly diagnosed, FLT3-positive AML who were younger than 60 at enrollment. All of the patients received standard induction and consolidation therapy. Roughly half also received midostaurin (n=360), while the other half received placebo (n=357).

Patients who received midostaurin experienced a significant improvement in overall survival (hazard ratio=0.77, P=0.0074). The median overall survival was 74.4 months in the midostaurin arm and 25.6 months in the placebo arm.

The median event-free survival was 8 months in the midostaurin arm and 3.6 months in the placebo arm (P=0.0032). The 5-year event-free survival was 27.5% for midostaurin and 19.3% for placebo.

There was no significant difference between the treatment arms with regard to most non-hematologic grade 3/4 adverse events. The exception was rash/desquamation, which occurred in 13% of patients in the midostaurin arm and 8% of patients in the placebo arm (P=0.02).

Other grade 3/4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation.

Midostaurin development

Novartis has opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable midostaurin access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.

To help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. which is leading regulatory submissions for a companion diagnostic.

Midostaurin is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for midostaurin (PKC412) to treat acute myeloid leukemia (AML).

Midostaurin is a multi-targeted kinase inhibitor being developed for adults with newly diagnosed AML who are FLT3-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.

Breakthrough therapy designation is intended to expedite the development and review of new medicines intended to treat serious or life-threatening conditions. The therapy must demonstrate substantial improvement over an available therapy on at least one clinically significant endpoint.

The designation includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.

Phase 3 trial

The breakthrough designation for midostaurin is primarily based on the results of the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 717 patients with newly diagnosed, FLT3-positive AML who were younger than 60 at enrollment. All of the patients received standard induction and consolidation therapy. Roughly half also received midostaurin (n=360), while the other half received placebo (n=357).

Patients who received midostaurin experienced a significant improvement in overall survival (hazard ratio=0.77, P=0.0074). The median overall survival was 74.4 months in the midostaurin arm and 25.6 months in the placebo arm.

The median event-free survival was 8 months in the midostaurin arm and 3.6 months in the placebo arm (P=0.0032). The 5-year event-free survival was 27.5% for midostaurin and 19.3% for placebo.

There was no significant difference between the treatment arms with regard to most non-hematologic grade 3/4 adverse events. The exception was rash/desquamation, which occurred in 13% of patients in the midostaurin arm and 8% of patients in the placebo arm (P=0.02).

Other grade 3/4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation.

Midostaurin development

Novartis has opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable midostaurin access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.

To help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. which is leading regulatory submissions for a companion diagnostic.

Midostaurin is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for midostaurin (PKC412) to treat acute myeloid leukemia (AML).

Midostaurin is a multi-targeted kinase inhibitor being developed for adults with newly diagnosed AML who are FLT3-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.

Breakthrough therapy designation is intended to expedite the development and review of new medicines intended to treat serious or life-threatening conditions. The therapy must demonstrate substantial improvement over an available therapy on at least one clinically significant endpoint.

The designation includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.

Phase 3 trial

The breakthrough designation for midostaurin is primarily based on the results of the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 717 patients with newly diagnosed, FLT3-positive AML who were younger than 60 at enrollment. All of the patients received standard induction and consolidation therapy. Roughly half also received midostaurin (n=360), while the other half received placebo (n=357).

Patients who received midostaurin experienced a significant improvement in overall survival (hazard ratio=0.77, P=0.0074). The median overall survival was 74.4 months in the midostaurin arm and 25.6 months in the placebo arm.

The median event-free survival was 8 months in the midostaurin arm and 3.6 months in the placebo arm (P=0.0032). The 5-year event-free survival was 27.5% for midostaurin and 19.3% for placebo.

There was no significant difference between the treatment arms with regard to most non-hematologic grade 3/4 adverse events. The exception was rash/desquamation, which occurred in 13% of patients in the midostaurin arm and 8% of patients in the placebo arm (P=0.02).

Other grade 3/4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation.

Midostaurin development

Novartis has opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable midostaurin access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.

To help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. which is leading regulatory submissions for a companion diagnostic.

Midostaurin is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.

Lab mouse

The gene EZH2 is a driver of, and potential therapeutic target for, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), according to a new study.

A previous study, published in Nature in 2012, suggested that nearly half of ETP-ALLs have inactivating alterations in EZH2.

Loss of EZH2 function can inactivate Polycomb repressive complex 2 (PRC2), but it was not clear how PRC2 loss-of-function mutations would aid leukemia growth.

The new study, published in Cell Reports, provides some insight.

Tobias Neff, MD, of the University of Colorado Denver in Aurora, and his colleagues developed a mouse model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL.

Experiments with this model revealed that inactivation of EZH2 helps accelerate leukemia development and enhances a stem-cell-related transcriptional program.

“We have 2 major features of [ETP-ALL]—stem-like cells and increased growth—and, now, we show an actor implicated in both—namely, EZH2/PRC2,” Dr Neff said.

“How exactly the stem-cell-like gene expression profile contributes to the aggressiveness of ETP-ALL is unknown, but we’ve known that these stem-like cells are associated with poor prognosis in acute leukemia.”

The researchers also found that EZH2 inactivation resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. This led them to wonder whether the JAK/STAT pathway might be important in their ETP-ALL model.

The team tested the JAK1/2 inhibitor ruxolitinib in NRASQ61K cells with EZH2 deletion and observed inhibition of cell growth.

“Ruxolitinib is unlikely to treat the disease by itself, but this model will help us test possible drug combinations that could eventually benefit ETP-ALL patients,” Dr Neff said.

He and his colleagues also plan to test the activity of different drugs against other cell types with inactivated EZH2.

“In addition to our specific finding in this disease, we are excited to now have a model that allows us to explore consequences of EZH2 inactivation that may enrich our understanding of a number of other conditions with a similar set of genetic changes,” Dr Neff said.

He and his colleagues noted that EZH2 is known to be inactivated in myelodysplastic syndromes, myeloproliferative neoplasms, and other hematologic malignancies.

Lab mouse

The gene EZH2 is a driver of, and potential therapeutic target for, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), according to a new study.

A previous study, published in Nature in 2012, suggested that nearly half of ETP-ALLs have inactivating alterations in EZH2.

Loss of EZH2 function can inactivate Polycomb repressive complex 2 (PRC2), but it was not clear how PRC2 loss-of-function mutations would aid leukemia growth.

The new study, published in Cell Reports, provides some insight.

Tobias Neff, MD, of the University of Colorado Denver in Aurora, and his colleagues developed a mouse model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL.

Experiments with this model revealed that inactivation of EZH2 helps accelerate leukemia development and enhances a stem-cell-related transcriptional program.

“We have 2 major features of [ETP-ALL]—stem-like cells and increased growth—and, now, we show an actor implicated in both—namely, EZH2/PRC2,” Dr Neff said.

“How exactly the stem-cell-like gene expression profile contributes to the aggressiveness of ETP-ALL is unknown, but we’ve known that these stem-like cells are associated with poor prognosis in acute leukemia.”

The researchers also found that EZH2 inactivation resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. This led them to wonder whether the JAK/STAT pathway might be important in their ETP-ALL model.

The team tested the JAK1/2 inhibitor ruxolitinib in NRASQ61K cells with EZH2 deletion and observed inhibition of cell growth.

“Ruxolitinib is unlikely to treat the disease by itself, but this model will help us test possible drug combinations that could eventually benefit ETP-ALL patients,” Dr Neff said.

He and his colleagues also plan to test the activity of different drugs against other cell types with inactivated EZH2.

“In addition to our specific finding in this disease, we are excited to now have a model that allows us to explore consequences of EZH2 inactivation that may enrich our understanding of a number of other conditions with a similar set of genetic changes,” Dr Neff said.

He and his colleagues noted that EZH2 is known to be inactivated in myelodysplastic syndromes, myeloproliferative neoplasms, and other hematologic malignancies.

Lab mouse

The gene EZH2 is a driver of, and potential therapeutic target for, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), according to a new study.

A previous study, published in Nature in 2012, suggested that nearly half of ETP-ALLs have inactivating alterations in EZH2.

Loss of EZH2 function can inactivate Polycomb repressive complex 2 (PRC2), but it was not clear how PRC2 loss-of-function mutations would aid leukemia growth.

The new study, published in Cell Reports, provides some insight.

Tobias Neff, MD, of the University of Colorado Denver in Aurora, and his colleagues developed a mouse model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL.

Experiments with this model revealed that inactivation of EZH2 helps accelerate leukemia development and enhances a stem-cell-related transcriptional program.

“We have 2 major features of [ETP-ALL]—stem-like cells and increased growth—and, now, we show an actor implicated in both—namely, EZH2/PRC2,” Dr Neff said.

“How exactly the stem-cell-like gene expression profile contributes to the aggressiveness of ETP-ALL is unknown, but we’ve known that these stem-like cells are associated with poor prognosis in acute leukemia.”

The researchers also found that EZH2 inactivation resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. This led them to wonder whether the JAK/STAT pathway might be important in their ETP-ALL model.

The team tested the JAK1/2 inhibitor ruxolitinib in NRASQ61K cells with EZH2 deletion and observed inhibition of cell growth.

“Ruxolitinib is unlikely to treat the disease by itself, but this model will help us test possible drug combinations that could eventually benefit ETP-ALL patients,” Dr Neff said.

He and his colleagues also plan to test the activity of different drugs against other cell types with inactivated EZH2.

“In addition to our specific finding in this disease, we are excited to now have a model that allows us to explore consequences of EZH2 inactivation that may enrich our understanding of a number of other conditions with a similar set of genetic changes,” Dr Neff said.

He and his colleagues noted that EZH2 is known to be inactivated in myelodysplastic syndromes, myeloproliferative neoplasms, and other hematologic malignancies.

Micrograph showing PV

Image courtesy of AFIP

Health Canada has approved the JAK1/2 inhibitor ruxolitinib (Jakavi) for the control of hematocrit in adult patients with polycythemia vera (PV) that is resistant to or intolerant of a cytoreductive agent.

Ruxolitinib is the first targeted treatment approved to treat PV in Canada.

The approval is based on results of the phase 3 RESPONSE trial, which showed that ruxolitinib could provide hematocrit control without phlebotomy in patients with PV.

For RESPONSE, researchers compared ruxolitinib to best available therapy (BAT) for PV. The trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from weeks 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

The primary endpoint was met by significantly more patients in the ruxolitinib arm than the BAT arm— 20.9% and 0.9%, respectively (P<0.0001).

Sixty percent of patients in the ruxolitinib arm achieved hematocrit control, as did 19.6% of patients in the BAT arm. The percentage of patients who had at least a 35% reduction in spleen volume was 38.2% in the ruxolitinib arm and 0.9% in the BAT arm.

The proportion of patients achieving a complete hematologic remission at week 32 was 23.6% in the ruxolitinib arm and 8.9% in the BAT arm (P=0.0028). The proportion of patients achieving a durable primary response at week 48 was 19.1% in the ruxolitinib arm and 0.9% in the BAT arm (P<0.0001).

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued ruxolitinib due to adverse events.

Micrograph showing PV

Image courtesy of AFIP

Health Canada has approved the JAK1/2 inhibitor ruxolitinib (Jakavi) for the control of hematocrit in adult patients with polycythemia vera (PV) that is resistant to or intolerant of a cytoreductive agent.

Ruxolitinib is the first targeted treatment approved to treat PV in Canada.

The approval is based on results of the phase 3 RESPONSE trial, which showed that ruxolitinib could provide hematocrit control without phlebotomy in patients with PV.

For RESPONSE, researchers compared ruxolitinib to best available therapy (BAT) for PV. The trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from weeks 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

The primary endpoint was met by significantly more patients in the ruxolitinib arm than the BAT arm— 20.9% and 0.9%, respectively (P<0.0001).

Sixty percent of patients in the ruxolitinib arm achieved hematocrit control, as did 19.6% of patients in the BAT arm. The percentage of patients who had at least a 35% reduction in spleen volume was 38.2% in the ruxolitinib arm and 0.9% in the BAT arm.

The proportion of patients achieving a complete hematologic remission at week 32 was 23.6% in the ruxolitinib arm and 8.9% in the BAT arm (P=0.0028). The proportion of patients achieving a durable primary response at week 48 was 19.1% in the ruxolitinib arm and 0.9% in the BAT arm (P<0.0001).

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued ruxolitinib due to adverse events.

Micrograph showing PV

Image courtesy of AFIP

Health Canada has approved the JAK1/2 inhibitor ruxolitinib (Jakavi) for the control of hematocrit in adult patients with polycythemia vera (PV) that is resistant to or intolerant of a cytoreductive agent.

Ruxolitinib is the first targeted treatment approved to treat PV in Canada.

The approval is based on results of the phase 3 RESPONSE trial, which showed that ruxolitinib could provide hematocrit control without phlebotomy in patients with PV.

For RESPONSE, researchers compared ruxolitinib to best available therapy (BAT) for PV. The trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from weeks 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

The primary endpoint was met by significantly more patients in the ruxolitinib arm than the BAT arm— 20.9% and 0.9%, respectively (P<0.0001).

Sixty percent of patients in the ruxolitinib arm achieved hematocrit control, as did 19.6% of patients in the BAT arm. The percentage of patients who had at least a 35% reduction in spleen volume was 38.2% in the ruxolitinib arm and 0.9% in the BAT arm.

The proportion of patients achieving a complete hematologic remission at week 32 was 23.6% in the ruxolitinib arm and 8.9% in the BAT arm (P=0.0028). The proportion of patients achieving a durable primary response at week 48 was 19.1% in the ruxolitinib arm and 0.9% in the BAT arm (P<0.0001).

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued ruxolitinib due to adverse events.