Hematology Times

Photo from Shire

The European Commission (EC) has granted marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The EC approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials—one in a surgical setting and one in a non-surgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.

Phase 1 trial

This trial (NCT00816660, 070701) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII)—referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII to plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

The safety analysis included 32 patients who received rVWF-rFVIII. There were no thrombotic events, serious adverse events, or new cases of inhibitors to VWF or FVIII in these patients.

The pharmacokinetic analysis included 19 patients. The researchers said the pharmacokinetics of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar with rVWF-rFVIII and pdVWF-pdFVIII.

FVIII levels were higher after infusion with rVWF-rFVIII than with pdVWF-pdFVIII, even after 72 hours. The researchers said this suggests that rVWF alone “could maintain sufficient FVIII activity to treat a bleeding episode once the initial FVIII level has reached a therapeutic threshold.”

These results were published in Blood in 2013.

Phase 3: Non-surgical

This study (NCT01410227, 071001) included 49 patients with VWD who received vonicog alfa with or without rFVIII.

All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).

Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.

There were 8 adverse events considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious events—chest discomfort and increased heart rate—but these were resolved.

There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.

These results were published in Blood in 2015.

Phase 3: Surgical setting

This trial (NCT02283268, 071101) enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).

Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.

Within an hour of surgery, patients received a dose of vonicog alfa, with or without rFVIII, depending on the target FVIII:C levels at the 3-hour assessment.

Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.

Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.

Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.

One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.

One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.

These results were presented at the WFH 2018 World Congress.

Photo from Shire

The European Commission (EC) has granted marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The EC approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials—one in a surgical setting and one in a non-surgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.

Phase 1 trial

This trial (NCT00816660, 070701) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII)—referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII to plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

The safety analysis included 32 patients who received rVWF-rFVIII. There were no thrombotic events, serious adverse events, or new cases of inhibitors to VWF or FVIII in these patients.

The pharmacokinetic analysis included 19 patients. The researchers said the pharmacokinetics of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar with rVWF-rFVIII and pdVWF-pdFVIII.

FVIII levels were higher after infusion with rVWF-rFVIII than with pdVWF-pdFVIII, even after 72 hours. The researchers said this suggests that rVWF alone “could maintain sufficient FVIII activity to treat a bleeding episode once the initial FVIII level has reached a therapeutic threshold.”

These results were published in Blood in 2013.

Phase 3: Non-surgical

This study (NCT01410227, 071001) included 49 patients with VWD who received vonicog alfa with or without rFVIII.

All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).

Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.

There were 8 adverse events considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious events—chest discomfort and increased heart rate—but these were resolved.

There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.

These results were published in Blood in 2015.

Phase 3: Surgical setting

This trial (NCT02283268, 071101) enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).

Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.

Within an hour of surgery, patients received a dose of vonicog alfa, with or without rFVIII, depending on the target FVIII:C levels at the 3-hour assessment.

Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.

Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.

Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.

One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.

One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.

These results were presented at the WFH 2018 World Congress.

Photo from Shire

The European Commission (EC) has granted marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The EC approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials—one in a surgical setting and one in a non-surgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.

Phase 1 trial

This trial (NCT00816660, 070701) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII)—referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII to plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

The safety analysis included 32 patients who received rVWF-rFVIII. There were no thrombotic events, serious adverse events, or new cases of inhibitors to VWF or FVIII in these patients.

The pharmacokinetic analysis included 19 patients. The researchers said the pharmacokinetics of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar with rVWF-rFVIII and pdVWF-pdFVIII.

FVIII levels were higher after infusion with rVWF-rFVIII than with pdVWF-pdFVIII, even after 72 hours. The researchers said this suggests that rVWF alone “could maintain sufficient FVIII activity to treat a bleeding episode once the initial FVIII level has reached a therapeutic threshold.”

These results were published in Blood in 2013.

Phase 3: Non-surgical

This study (NCT01410227, 071001) included 49 patients with VWD who received vonicog alfa with or without rFVIII.

All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).

Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.

There were 8 adverse events considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious events—chest discomfort and increased heart rate—but these were resolved.

There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.

These results were published in Blood in 2015.

Phase 3: Surgical setting

This trial (NCT02283268, 071101) enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).

Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.

Within an hour of surgery, patients received a dose of vonicog alfa, with or without rFVIII, depending on the target FVIII:C levels at the 3-hour assessment.

Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.

Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.

Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.

One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.

One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.

These results were presented at the WFH 2018 World Congress.

Children’s Research Hospital

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

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

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

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

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

With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.

New classifications

The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

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

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

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

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

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

Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

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

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:

• ZNF384r acute leukemia (either B-ALL or MPAL)
• WT1-mutant T/myeloid MPAL
• Ph-like B/myeloid MPAL.

Evolution of MPAL

The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.

The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.

“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.

“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.

Children’s Research Hospital

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

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

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

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

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

With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.

New classifications

The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

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

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

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

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

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

Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

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

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:

• ZNF384r acute leukemia (either B-ALL or MPAL)
• WT1-mutant T/myeloid MPAL
• Ph-like B/myeloid MPAL.

Evolution of MPAL

The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.

The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.

“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.

“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.

Children’s Research Hospital

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

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

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

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

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

With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.

New classifications

The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

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

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

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

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

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

Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

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

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:

• ZNF384r acute leukemia (either B-ALL or MPAL)
• WT1-mutant T/myeloid MPAL
• Ph-like B/myeloid MPAL.

Evolution of MPAL

The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.

The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.

“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.

“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.

Photo by Rhoda Baer

The American Association for Cancer Research (AACR) has released its annual Cancer Progress Report, detailing recent advances in the fight against cancer and calling on elected officials to address the challenges that remain.

The AACR Cancer Progress Report 2018 lists the 22 new approvals for cancer treatments that have occurred during the last 12 months, including 12 therapies approved to treat hematologic malignancies.

However, the report also notes that cancer continues to pose immense public health challenges in the United States.

The estimated number of new cancer cases for 2018 is 1,735,350, and the estimated number of cancer deaths is 609,640.

The number of new cancer cases is predicted to increase to 2,387,304 in 2035. This is due, in large part, to the rising number of people age 65 and older, according to the report.

With this in mind, the AACR is calling on elected officials to:

Maintain “robust, sustained, and predictable growth” of the National Institutes of Health (NIH) budget, increasing it at least $2 billion in fiscal year (FY) 2019, for a total funding level of at least $39.1 billion.

Make sure the $711 million in funding provided through the 21st Century Cures Act for targeted initiatives—including the National Cancer Moonshot—“is fully appropriated in FY 2019 and is supplemental to the healthy increase for the NIH’s base budget.”

Raise the Food and Drug Administration’s base budget in FY 2019 to $3.1 billion—a $308 million increase above its FY 2018 level—to secure support for regulatory science and speed the development of medical products that are safe and effective.

Provide the Centers for Disease Control and Prevention’s Cancer Prevention and Control Programs with total funding of at least $517 million. This would include funding for “comprehensive cancer control, cancer registries, and screening and awareness programs for specific cancers.”

Photo by Rhoda Baer

The American Association for Cancer Research (AACR) has released its annual Cancer Progress Report, detailing recent advances in the fight against cancer and calling on elected officials to address the challenges that remain.

The AACR Cancer Progress Report 2018 lists the 22 new approvals for cancer treatments that have occurred during the last 12 months, including 12 therapies approved to treat hematologic malignancies.

However, the report also notes that cancer continues to pose immense public health challenges in the United States.

The estimated number of new cancer cases for 2018 is 1,735,350, and the estimated number of cancer deaths is 609,640.

The number of new cancer cases is predicted to increase to 2,387,304 in 2035. This is due, in large part, to the rising number of people age 65 and older, according to the report.

With this in mind, the AACR is calling on elected officials to:

Maintain “robust, sustained, and predictable growth” of the National Institutes of Health (NIH) budget, increasing it at least $2 billion in fiscal year (FY) 2019, for a total funding level of at least $39.1 billion.

Make sure the $711 million in funding provided through the 21st Century Cures Act for targeted initiatives—including the National Cancer Moonshot—“is fully appropriated in FY 2019 and is supplemental to the healthy increase for the NIH’s base budget.”

Raise the Food and Drug Administration’s base budget in FY 2019 to $3.1 billion—a $308 million increase above its FY 2018 level—to secure support for regulatory science and speed the development of medical products that are safe and effective.

Provide the Centers for Disease Control and Prevention’s Cancer Prevention and Control Programs with total funding of at least $517 million. This would include funding for “comprehensive cancer control, cancer registries, and screening and awareness programs for specific cancers.”

Photo by Rhoda Baer

The American Association for Cancer Research (AACR) has released its annual Cancer Progress Report, detailing recent advances in the fight against cancer and calling on elected officials to address the challenges that remain.

The AACR Cancer Progress Report 2018 lists the 22 new approvals for cancer treatments that have occurred during the last 12 months, including 12 therapies approved to treat hematologic malignancies.

However, the report also notes that cancer continues to pose immense public health challenges in the United States.

The estimated number of new cancer cases for 2018 is 1,735,350, and the estimated number of cancer deaths is 609,640.

The number of new cancer cases is predicted to increase to 2,387,304 in 2035. This is due, in large part, to the rising number of people age 65 and older, according to the report.

With this in mind, the AACR is calling on elected officials to:

Maintain “robust, sustained, and predictable growth” of the National Institutes of Health (NIH) budget, increasing it at least $2 billion in fiscal year (FY) 2019, for a total funding level of at least $39.1 billion.

Make sure the $711 million in funding provided through the 21st Century Cures Act for targeted initiatives—including the National Cancer Moonshot—“is fully appropriated in FY 2019 and is supplemental to the healthy increase for the NIH’s base budget.”

Raise the Food and Drug Administration’s base budget in FY 2019 to $3.1 billion—a $308 million increase above its FY 2018 level—to secure support for regulatory science and speed the development of medical products that are safe and effective.

Provide the Centers for Disease Control and Prevention’s Cancer Prevention and Control Programs with total funding of at least $517 million. This would include funding for “comprehensive cancer control, cancer registries, and screening and awareness programs for specific cancers.”

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta^®) to include data on minimal residual disease (MRD).

The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.

The patients were randomized to receive:

• Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m² on day 1 for the first cycle and at 500 mg/m²  on day 1 for cycles 2 to 6 (n=194)
• Bendamustine at 70 mg/m² on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.

“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta^®) to include data on minimal residual disease (MRD).

The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.

The patients were randomized to receive:

• Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m² on day 1 for the first cycle and at 500 mg/m²  on day 1 for cycles 2 to 6 (n=194)
• Bendamustine at 70 mg/m² on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.

“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.

Photo courtesy of Abbvie

The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta^®) to include data on minimal residual disease (MRD).

The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.

The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.

The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.

The patients were randomized to receive:

• Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m² on day 1 for the first cycle and at 500 mg/m²  on day 1 for cycles 2 to 6 (n=194)
• Bendamustine at 70 mg/m² on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).

Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.

The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.

The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.

Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.

“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.

Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.

Photo by Kevin Patrick Robbins/McMaster University

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naïve LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be druggable.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic re-growth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was re-established at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in 7 patients who were in clinical remission after induction.

The researchers found that chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease—not in the three patients who remained in disease-free remission for at least 5 years.

“These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

Photo by Kevin Patrick Robbins/McMaster University

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naïve LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be druggable.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic re-growth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was re-established at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in 7 patients who were in clinical remission after induction.

The researchers found that chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease—not in the three patients who remained in disease-free remission for at least 5 years.

“These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

Photo by Kevin Patrick Robbins/McMaster University

Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).

These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.

Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.

Allison Boyd, PhD, of McMaster University in Hamilton, Ontario, Canada, and her colleagues reported these findings in Cancer Cell.

The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.

LRCs are “molecularly distinct from therapy-naïve LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be druggable.

One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.

Targeting LRCs

Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.

The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”

Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.

In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.

In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic re-growth and nearly doubled the time to relapse.

Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.

“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”

Predicting relapse

Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.

The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.

“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.

The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was re-established at relapse.

“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.

She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.

The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in 7 patients who were in clinical remission after induction.

The researchers found that chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease—not in the three patients who remained in disease-free remission for at least 5 years.

“These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.

This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.

Lab mouse

The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.

Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.

Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.

Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.

The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.

The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.

The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.

“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.

“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”

Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.

The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.

The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.

Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.

This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.

Lab mouse

The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.

Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.

Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.

Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.

The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.

The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.

The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.

“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.

“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”

Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.

The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.

The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.

Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.

This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.

Lab mouse

The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.

Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.

Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.

Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.

The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.

The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.

The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.

“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.

“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”

Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.

The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.

The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.

Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.

This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.

Antihemophilic factor

CSL Behring has announced that Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) is now available in a 3500 IU vial size.

Idelvion is also available in 250 IU, 500 IU, 1000 IU, and 2000 IU vial sizes.

For some patients requiring high doses of Idelvion, the new 3500 IU vial size will reduce the reconstitution time needed to prepare multiple vials for a similar dose.

Idelvion is a fusion protein linking recombinant coagulation factor IX with recombinant albumin, and it is approved by the U.S. Food and Drug Administration to treat children and adults with hemophilia B.

Idelvion can be used as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Idelvion is approved for up to 14-day dosing in appropriate patients.

For more details on Idelvion, see the prescribing information.

Antihemophilic factor

CSL Behring has announced that Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) is now available in a 3500 IU vial size.

Idelvion is also available in 250 IU, 500 IU, 1000 IU, and 2000 IU vial sizes.

For some patients requiring high doses of Idelvion, the new 3500 IU vial size will reduce the reconstitution time needed to prepare multiple vials for a similar dose.

Idelvion is a fusion protein linking recombinant coagulation factor IX with recombinant albumin, and it is approved by the U.S. Food and Drug Administration to treat children and adults with hemophilia B.

Idelvion can be used as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Idelvion is approved for up to 14-day dosing in appropriate patients.

For more details on Idelvion, see the prescribing information.

Antihemophilic factor

CSL Behring has announced that Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) is now available in a 3500 IU vial size.

Idelvion is also available in 250 IU, 500 IU, 1000 IU, and 2000 IU vial sizes.

For some patients requiring high doses of Idelvion, the new 3500 IU vial size will reduce the reconstitution time needed to prepare multiple vials for a similar dose.

Idelvion is a fusion protein linking recombinant coagulation factor IX with recombinant albumin, and it is approved by the U.S. Food and Drug Administration to treat children and adults with hemophilia B.

Idelvion can be used as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Idelvion is approved for up to 14-day dosing in appropriate patients.

For more details on Idelvion, see the prescribing information.