Hematology Times

PHILADELPHIA—Results of a large study support the recommendation that patients with platelet consumptive disorders only receive platelet transfusions if they exhibit severe or life-threatening bleeding that is refractory to other therapies.

The research indicated that platelet transfusions may increase the risk of arterial thrombosis and mortality among hospitalized patients with thrombotic thrombocytopenic purpura (TTP) and those with heparin-induced thrombocytopenia (HIT).

Platelet transfusions were also associated with a greater risk of acute myocardial infarction in TTP patients.

However, transfused patients with immune thrombocytopenia (ITP) did not have an increased risk of such complications.

The study did not establish a causal link between transfusions and complications, as it was retrospective and the researchers did not know the exact timing of events.

However, the complications and the transfusions did occur during the same hospital admission, noted Ruchika Goel, MD, of Johns Hopkins University in Baltimore, Maryland. She presented these findings at the AABB Annual Meeting 2014 (abstract S41-030G).

Dr Goel and her colleagues conducted this study to assess current platelet transfusion practices in the US in hospitalized patients with TTP, HIT, and ITP. The team wanted to explore any associations between transfusions and bleeding, venous and arterial thrombotic events, acute myocardial infarction, stroke, and in-hospital mortality in these patients.

“Currently, very little data are available on the risks and benefits associated with platelet transfusions in various platelet consumptive or disruptive disorders,” Dr Goel said. “Thus, evidence-based platelet transfusion guidelines in these disorders are either non-existent or they’re based on consensus statements, with not much supportive data.”

With this in mind, the researchers analyzed data from the Nationwide Inpatient Sample, a stratified probability sample of 20% of all discharges at community hospitals in the US, which covers more than 1100 hospitals across 47 states. The team looked at 5 years of data spanning the period from 2007 through 2011.

They included patients in whom TTP and ITP were the primary admitting diagnoses and patients in whom HIT was 1 of the top 3 diagnoses. Hospitalizations in which patients had a prior history of thrombosis were excluded, as were hospitalizations with any thrombosis/thromboembolism listed as the primary admitting diagnosis (implying that it was already present at admission).

So the analysis included 10,624 patients with TTP, 6332 with HIT, and 79,980 with ITP. The median ages were 47.4, 61.8, and 47.5, respectively. And platelet transfusions were given to 10.1%, 7.1%, and 25.8% of patients, respectively.

When the researchers adjusted their analysis for age and gender, they discovered a significantly increased risk of bleeding among all transfused patients. The odds ratios (ORs) were 2.3 for TTP, 5.5 for HIT, and 5.1 for ITP patients.

“The odds of platelet transfusion were significantly higher in patients who had bleeding, thus implying that . . . that was the indication for the transfusion—an actual bleeding complication,” Dr Goel said.

The results also showed that none of the transfused patients had a significantly increased risk of venous thrombosis or stroke. The ORs for venous thrombosis were 1.1 for TTP, 0.8 for HIT, and 1.3 for ITP patients. And the ORs for stroke were 1.6, 0.5, and 1.3, respectively.

However, both TTP patients and HIT patients had a significantly increased risk of arterial thrombosis. The ORs were 5.8 for TTP, 3.4 for HIT, and 0.3 for ITP patients.

TTP patients also had a significantly increased risk of acute myocardial infarction. The ORs were 2.0 for TTP, 1.9 for HIT, and 1.3 for ITP patients.

And patients with TTP and HIT had a significantly increased risk of in-hospital mortality. The ORs were 2.0 for TTP, 5.2 for HIT, and 1.1 for ITP patients.

Dr Goel noted that this study had several limitations. The temporality of events was not reported, there was no information on platelet thresholds for transfusion or disease severity and the effect on outcomes, and accuracy was limited by the precision of discharge coding.

Therefore, further studies are needed to assess whether platelet transfusions are directly responsible for complications or if they serve as a surrogate marker for the severity of illness.

“We propose that, until such studies or trials are indeed available, which are very hard [to conduct in] these rare disorders, platelets should continue to be considered relatively contraindicated and used only for severe or life-threatening bleeding which is refractory to other therapies,” Dr Goel concluded.

PHILADELPHIA—Results of a large study support the recommendation that patients with platelet consumptive disorders only receive platelet transfusions if they exhibit severe or life-threatening bleeding that is refractory to other therapies.

The research indicated that platelet transfusions may increase the risk of arterial thrombosis and mortality among hospitalized patients with thrombotic thrombocytopenic purpura (TTP) and those with heparin-induced thrombocytopenia (HIT).

Platelet transfusions were also associated with a greater risk of acute myocardial infarction in TTP patients.

However, transfused patients with immune thrombocytopenia (ITP) did not have an increased risk of such complications.

The study did not establish a causal link between transfusions and complications, as it was retrospective and the researchers did not know the exact timing of events.

However, the complications and the transfusions did occur during the same hospital admission, noted Ruchika Goel, MD, of Johns Hopkins University in Baltimore, Maryland. She presented these findings at the AABB Annual Meeting 2014 (abstract S41-030G).

Dr Goel and her colleagues conducted this study to assess current platelet transfusion practices in the US in hospitalized patients with TTP, HIT, and ITP. The team wanted to explore any associations between transfusions and bleeding, venous and arterial thrombotic events, acute myocardial infarction, stroke, and in-hospital mortality in these patients.

“Currently, very little data are available on the risks and benefits associated with platelet transfusions in various platelet consumptive or disruptive disorders,” Dr Goel said. “Thus, evidence-based platelet transfusion guidelines in these disorders are either non-existent or they’re based on consensus statements, with not much supportive data.”

With this in mind, the researchers analyzed data from the Nationwide Inpatient Sample, a stratified probability sample of 20% of all discharges at community hospitals in the US, which covers more than 1100 hospitals across 47 states. The team looked at 5 years of data spanning the period from 2007 through 2011.

They included patients in whom TTP and ITP were the primary admitting diagnoses and patients in whom HIT was 1 of the top 3 diagnoses. Hospitalizations in which patients had a prior history of thrombosis were excluded, as were hospitalizations with any thrombosis/thromboembolism listed as the primary admitting diagnosis (implying that it was already present at admission).

So the analysis included 10,624 patients with TTP, 6332 with HIT, and 79,980 with ITP. The median ages were 47.4, 61.8, and 47.5, respectively. And platelet transfusions were given to 10.1%, 7.1%, and 25.8% of patients, respectively.

When the researchers adjusted their analysis for age and gender, they discovered a significantly increased risk of bleeding among all transfused patients. The odds ratios (ORs) were 2.3 for TTP, 5.5 for HIT, and 5.1 for ITP patients.

“The odds of platelet transfusion were significantly higher in patients who had bleeding, thus implying that . . . that was the indication for the transfusion—an actual bleeding complication,” Dr Goel said.

The results also showed that none of the transfused patients had a significantly increased risk of venous thrombosis or stroke. The ORs for venous thrombosis were 1.1 for TTP, 0.8 for HIT, and 1.3 for ITP patients. And the ORs for stroke were 1.6, 0.5, and 1.3, respectively.

However, both TTP patients and HIT patients had a significantly increased risk of arterial thrombosis. The ORs were 5.8 for TTP, 3.4 for HIT, and 0.3 for ITP patients.

TTP patients also had a significantly increased risk of acute myocardial infarction. The ORs were 2.0 for TTP, 1.9 for HIT, and 1.3 for ITP patients.

And patients with TTP and HIT had a significantly increased risk of in-hospital mortality. The ORs were 2.0 for TTP, 5.2 for HIT, and 1.1 for ITP patients.

Dr Goel noted that this study had several limitations. The temporality of events was not reported, there was no information on platelet thresholds for transfusion or disease severity and the effect on outcomes, and accuracy was limited by the precision of discharge coding.

Therefore, further studies are needed to assess whether platelet transfusions are directly responsible for complications or if they serve as a surrogate marker for the severity of illness.

“We propose that, until such studies or trials are indeed available, which are very hard [to conduct in] these rare disorders, platelets should continue to be considered relatively contraindicated and used only for severe or life-threatening bleeding which is refractory to other therapies,” Dr Goel concluded.

PHILADELPHIA—Results of a large study support the recommendation that patients with platelet consumptive disorders only receive platelet transfusions if they exhibit severe or life-threatening bleeding that is refractory to other therapies.

The research indicated that platelet transfusions may increase the risk of arterial thrombosis and mortality among hospitalized patients with thrombotic thrombocytopenic purpura (TTP) and those with heparin-induced thrombocytopenia (HIT).

Platelet transfusions were also associated with a greater risk of acute myocardial infarction in TTP patients.

However, transfused patients with immune thrombocytopenia (ITP) did not have an increased risk of such complications.

The study did not establish a causal link between transfusions and complications, as it was retrospective and the researchers did not know the exact timing of events.

However, the complications and the transfusions did occur during the same hospital admission, noted Ruchika Goel, MD, of Johns Hopkins University in Baltimore, Maryland. She presented these findings at the AABB Annual Meeting 2014 (abstract S41-030G).

Dr Goel and her colleagues conducted this study to assess current platelet transfusion practices in the US in hospitalized patients with TTP, HIT, and ITP. The team wanted to explore any associations between transfusions and bleeding, venous and arterial thrombotic events, acute myocardial infarction, stroke, and in-hospital mortality in these patients.

“Currently, very little data are available on the risks and benefits associated with platelet transfusions in various platelet consumptive or disruptive disorders,” Dr Goel said. “Thus, evidence-based platelet transfusion guidelines in these disorders are either non-existent or they’re based on consensus statements, with not much supportive data.”

With this in mind, the researchers analyzed data from the Nationwide Inpatient Sample, a stratified probability sample of 20% of all discharges at community hospitals in the US, which covers more than 1100 hospitals across 47 states. The team looked at 5 years of data spanning the period from 2007 through 2011.

They included patients in whom TTP and ITP were the primary admitting diagnoses and patients in whom HIT was 1 of the top 3 diagnoses. Hospitalizations in which patients had a prior history of thrombosis were excluded, as were hospitalizations with any thrombosis/thromboembolism listed as the primary admitting diagnosis (implying that it was already present at admission).

So the analysis included 10,624 patients with TTP, 6332 with HIT, and 79,980 with ITP. The median ages were 47.4, 61.8, and 47.5, respectively. And platelet transfusions were given to 10.1%, 7.1%, and 25.8% of patients, respectively.

When the researchers adjusted their analysis for age and gender, they discovered a significantly increased risk of bleeding among all transfused patients. The odds ratios (ORs) were 2.3 for TTP, 5.5 for HIT, and 5.1 for ITP patients.

“The odds of platelet transfusion were significantly higher in patients who had bleeding, thus implying that . . . that was the indication for the transfusion—an actual bleeding complication,” Dr Goel said.

The results also showed that none of the transfused patients had a significantly increased risk of venous thrombosis or stroke. The ORs for venous thrombosis were 1.1 for TTP, 0.8 for HIT, and 1.3 for ITP patients. And the ORs for stroke were 1.6, 0.5, and 1.3, respectively.

However, both TTP patients and HIT patients had a significantly increased risk of arterial thrombosis. The ORs were 5.8 for TTP, 3.4 for HIT, and 0.3 for ITP patients.

TTP patients also had a significantly increased risk of acute myocardial infarction. The ORs were 2.0 for TTP, 1.9 for HIT, and 1.3 for ITP patients.

And patients with TTP and HIT had a significantly increased risk of in-hospital mortality. The ORs were 2.0 for TTP, 5.2 for HIT, and 1.1 for ITP patients.

Dr Goel noted that this study had several limitations. The temporality of events was not reported, there was no information on platelet thresholds for transfusion or disease severity and the effect on outcomes, and accuracy was limited by the precision of discharge coding.

Therefore, further studies are needed to assess whether platelet transfusions are directly responsible for complications or if they serve as a surrogate marker for the severity of illness.

“We propose that, until such studies or trials are indeed available, which are very hard [to conduct in] these rare disorders, platelets should continue to be considered relatively contraindicated and used only for severe or life-threatening bleeding which is refractory to other therapies,” Dr Goel concluded.

Leukemia cells targeted by

CD22ΔE12-siRNA nanoparticle

Credit: Fatih Uckun

Researchers have identified a molecular target for RNA interference (RNAi) therapy, and they believe that, by targeting this molecular lesion, they may be able to eliminate drug resistance in B-lineage acute lymphoblastic leukemia (ALL).

“We knew that we could kill chemotherapy-resistant leukemia cells if we only knew what made them so resistant,” said study author Fatih Uckun, MD, PhD, of the Children’s Hospital Los Angeles in California.

“Once we determined the mechanism, the next step was obvious—to rationally design a drug that would take out that specific target.”

The target is a defective gene that results in the production of abnormal CD22—CD22ΔE12. The researchers found that pediatric and adult B-lineage lymphoid malignancies are characterized by a high incidence of CD22ΔE12.

The group’s experiments revealed a causal link between CD22ΔE12 and the aggressive biology of B-ALL cells. When the researchers knocked down CD22ΔE12 in primary B-ALL cells using small interfering RNA (siRNA), they observed inhibition of clonogenicity.

The team therefore theorized that the siRNA-mediated depletion of CD22ΔE12 might be useful for treating B-ALL.

So they designed a nanoparticle formulation of CD22ΔE12-siRNA in which a polypeptide functions as the delivery system. The particle has a diameter of 100 nanometers.

Experiments showed that the nanoparticle could deliver its siRNA cargo into the cytosol of ALL-1 cells, thereby depleting CD22ΔE12 and inhibiting leukemic cell growth in vitro.

The researchers said that further development of this nanoparticle or other nanoformulation platforms for CD22ΔE12-siRNA could facilitate an effective therapeutic RNAi strategy to treat aggressive or chemotherapy-resistant B-lineage lymphoid malignancies.

“The goal is to translate our recent research discoveries in nanotechnology and biotherapy into effective patient-tailored treatment programs for the most common form of childhood cancer,” Dr Uckun said.

He and his colleagues described this research in EBioMedicine.

Leukemia cells targeted by

CD22ΔE12-siRNA nanoparticle

Credit: Fatih Uckun

Researchers have identified a molecular target for RNA interference (RNAi) therapy, and they believe that, by targeting this molecular lesion, they may be able to eliminate drug resistance in B-lineage acute lymphoblastic leukemia (ALL).

“We knew that we could kill chemotherapy-resistant leukemia cells if we only knew what made them so resistant,” said study author Fatih Uckun, MD, PhD, of the Children’s Hospital Los Angeles in California.

“Once we determined the mechanism, the next step was obvious—to rationally design a drug that would take out that specific target.”

The target is a defective gene that results in the production of abnormal CD22—CD22ΔE12. The researchers found that pediatric and adult B-lineage lymphoid malignancies are characterized by a high incidence of CD22ΔE12.

The group’s experiments revealed a causal link between CD22ΔE12 and the aggressive biology of B-ALL cells. When the researchers knocked down CD22ΔE12 in primary B-ALL cells using small interfering RNA (siRNA), they observed inhibition of clonogenicity.

The team therefore theorized that the siRNA-mediated depletion of CD22ΔE12 might be useful for treating B-ALL.

So they designed a nanoparticle formulation of CD22ΔE12-siRNA in which a polypeptide functions as the delivery system. The particle has a diameter of 100 nanometers.

Experiments showed that the nanoparticle could deliver its siRNA cargo into the cytosol of ALL-1 cells, thereby depleting CD22ΔE12 and inhibiting leukemic cell growth in vitro.

The researchers said that further development of this nanoparticle or other nanoformulation platforms for CD22ΔE12-siRNA could facilitate an effective therapeutic RNAi strategy to treat aggressive or chemotherapy-resistant B-lineage lymphoid malignancies.

“The goal is to translate our recent research discoveries in nanotechnology and biotherapy into effective patient-tailored treatment programs for the most common form of childhood cancer,” Dr Uckun said.

He and his colleagues described this research in EBioMedicine.

Leukemia cells targeted by

CD22ΔE12-siRNA nanoparticle

Credit: Fatih Uckun

Researchers have identified a molecular target for RNA interference (RNAi) therapy, and they believe that, by targeting this molecular lesion, they may be able to eliminate drug resistance in B-lineage acute lymphoblastic leukemia (ALL).

“We knew that we could kill chemotherapy-resistant leukemia cells if we only knew what made them so resistant,” said study author Fatih Uckun, MD, PhD, of the Children’s Hospital Los Angeles in California.

“Once we determined the mechanism, the next step was obvious—to rationally design a drug that would take out that specific target.”

The target is a defective gene that results in the production of abnormal CD22—CD22ΔE12. The researchers found that pediatric and adult B-lineage lymphoid malignancies are characterized by a high incidence of CD22ΔE12.

The group’s experiments revealed a causal link between CD22ΔE12 and the aggressive biology of B-ALL cells. When the researchers knocked down CD22ΔE12 in primary B-ALL cells using small interfering RNA (siRNA), they observed inhibition of clonogenicity.

The team therefore theorized that the siRNA-mediated depletion of CD22ΔE12 might be useful for treating B-ALL.

So they designed a nanoparticle formulation of CD22ΔE12-siRNA in which a polypeptide functions as the delivery system. The particle has a diameter of 100 nanometers.

Experiments showed that the nanoparticle could deliver its siRNA cargo into the cytosol of ALL-1 cells, thereby depleting CD22ΔE12 and inhibiting leukemic cell growth in vitro.

The researchers said that further development of this nanoparticle or other nanoformulation platforms for CD22ΔE12-siRNA could facilitate an effective therapeutic RNAi strategy to treat aggressive or chemotherapy-resistant B-lineage lymphoid malignancies.

“The goal is to translate our recent research discoveries in nanotechnology and biotherapy into effective patient-tailored treatment programs for the most common form of childhood cancer,” Dr Uckun said.

He and his colleagues described this research in EBioMedicine.

Warfarin tablets

Dabigatran poses a greater risk of major bleeding and gastrointestinal (GI) bleeding compared to warfarin, according to a study of patients with atrial fibrillation.

The incidence of GI and major bleeding with dabigatran was particularly high in African Americans, patients with chronic kidney disease (CKD), patients age 75

and older, and those with 7 or more comorbidities.

On the other hand, the risk of intracranial hemorrhage was higher in most warfarin-treated patients. African Americans were the exception to this rule.

Researchers reported these results in JAMA Internal Medicine alongside a related editorial.

“Dabigatran was introduced in 2010 and, at the time of approval, it was the only available alternative to warfarin,” noted study author Yuting Zhang, PhD, of the University of Pittsburgh in Pennsylvania.

“Warfarin dosing can be tricky, and regular monitoring with blood tests is required, so doctors and patients were glad to have a drug that was easier to manage. But some recent studies suggest that dabigatran is associated with a higher risk of bleeding.”

To investigate that possibility, Dr Zhang and her colleagues reviewed pharmacy and medical claims data from 2010 and 2011 of a random national sample of Medicare beneficiaries. The team tracked 1302 dabigatran users and 8102 warfarin users to see whether they experienced bleeding episodes.

The researchers classified bleeding events as major, such as intracranial bleeding or GI bleeding requiring a hospital or emergency room stay, or minor, such as GI bleeding that was treated on an outpatient basis or nose bleeds.

The incidence of any bleeding was significantly higher in dabigatran-treated patients than in warfarin-treated patients (32.7% vs 26.5%, P<0.001). The same was true of major bleeding (9% vs 5.9%, P<0.001) and GI bleeding (17.4% vs 10%, P<0.001).

However, the rate of intracranial bleeding was higher with warfarin than with dabigatran (1.8% vs 0.6%, P<0.001), as was the rate of epistaxis (3.1% vs 2%, P=0.002) and not-otherwise-specified hemorrhage (5.9% vs 4.4%, P=0.003).

All other types of bleeding were more frequent in the dabigatran group than the warfarin group. This included hematuria (12% vs 8.8%, P<0.001), vaginal bleeding (0.7% vs 0.3%, P=0.003), hemarthrosis (0.5% vs 0.2%, P=0.007), and hemoptysis (2% vs 1.4%, P=0.03).

The researchers also looked at bleeding episodes in 4 high-risk subgroups: patients who were 75 years of age and older, African Americans, patients with CKD, and those with 7 or more co-existing medical problems.

The risk of major bleeding was higher among dabigatran-treated patients belonging to these subgroups. The hazard ratios (HRs) were 1.60 for patients 75 and older, 2.12 for African Americans, 2.07 for patients with CKD, and 1.88 for patients with 7 or more comorbidities.

Likewise, the risk of GI bleeding was higher among dabigatran-treated patients in the subgroups. The HRs were 1.85 for patients 75 and older, 2.38 for African Americans, 1.81 for patients with CKD, and 1.81 for patients with 7 or more comorbidities.

“These findings indicate that physicians should be cautious when prescribing dabigatran, particularly to African Americans and patients with kidney impairments,” said study author Inmaculada Hernandez, PharmD, of the University of Pittsburgh.

“Also, the incidence of gastrointestinal bleeding was high in all the subgroups, so we recommend doctors explain to patients how to detect it so that it can be treated promptly.”

The researchers also noted that the risk of intracranial bleeding varied among the subgroups. The HRs for dabigatran vs warfarin were 0.10 for patients 75 and older, 2.29 for African Americans, 0.71 for patients with CKD, and 0.59 for patients with 7 or more comorbidities.

“We plan to examine 2012 data to monitor the risk of stroke for patients on dabigatran, which is the primary indication for taking the blood thinner,” Dr Zhang said. “It’s possible that, for some patients, a greater reduction in the risk of stroke will outweigh the higher risk of bleeding with dabigatran compared to warfarin.”

Warfarin tablets

Dabigatran poses a greater risk of major bleeding and gastrointestinal (GI) bleeding compared to warfarin, according to a study of patients with atrial fibrillation.

The incidence of GI and major bleeding with dabigatran was particularly high in African Americans, patients with chronic kidney disease (CKD), patients age 75

and older, and those with 7 or more comorbidities.

On the other hand, the risk of intracranial hemorrhage was higher in most warfarin-treated patients. African Americans were the exception to this rule.

Researchers reported these results in JAMA Internal Medicine alongside a related editorial.

“Dabigatran was introduced in 2010 and, at the time of approval, it was the only available alternative to warfarin,” noted study author Yuting Zhang, PhD, of the University of Pittsburgh in Pennsylvania.

“Warfarin dosing can be tricky, and regular monitoring with blood tests is required, so doctors and patients were glad to have a drug that was easier to manage. But some recent studies suggest that dabigatran is associated with a higher risk of bleeding.”

To investigate that possibility, Dr Zhang and her colleagues reviewed pharmacy and medical claims data from 2010 and 2011 of a random national sample of Medicare beneficiaries. The team tracked 1302 dabigatran users and 8102 warfarin users to see whether they experienced bleeding episodes.

The researchers classified bleeding events as major, such as intracranial bleeding or GI bleeding requiring a hospital or emergency room stay, or minor, such as GI bleeding that was treated on an outpatient basis or nose bleeds.

The incidence of any bleeding was significantly higher in dabigatran-treated patients than in warfarin-treated patients (32.7% vs 26.5%, P<0.001). The same was true of major bleeding (9% vs 5.9%, P<0.001) and GI bleeding (17.4% vs 10%, P<0.001).

However, the rate of intracranial bleeding was higher with warfarin than with dabigatran (1.8% vs 0.6%, P<0.001), as was the rate of epistaxis (3.1% vs 2%, P=0.002) and not-otherwise-specified hemorrhage (5.9% vs 4.4%, P=0.003).

All other types of bleeding were more frequent in the dabigatran group than the warfarin group. This included hematuria (12% vs 8.8%, P<0.001), vaginal bleeding (0.7% vs 0.3%, P=0.003), hemarthrosis (0.5% vs 0.2%, P=0.007), and hemoptysis (2% vs 1.4%, P=0.03).

The researchers also looked at bleeding episodes in 4 high-risk subgroups: patients who were 75 years of age and older, African Americans, patients with CKD, and those with 7 or more co-existing medical problems.

The risk of major bleeding was higher among dabigatran-treated patients belonging to these subgroups. The hazard ratios (HRs) were 1.60 for patients 75 and older, 2.12 for African Americans, 2.07 for patients with CKD, and 1.88 for patients with 7 or more comorbidities.

Likewise, the risk of GI bleeding was higher among dabigatran-treated patients in the subgroups. The HRs were 1.85 for patients 75 and older, 2.38 for African Americans, 1.81 for patients with CKD, and 1.81 for patients with 7 or more comorbidities.

“These findings indicate that physicians should be cautious when prescribing dabigatran, particularly to African Americans and patients with kidney impairments,” said study author Inmaculada Hernandez, PharmD, of the University of Pittsburgh.

“Also, the incidence of gastrointestinal bleeding was high in all the subgroups, so we recommend doctors explain to patients how to detect it so that it can be treated promptly.”

The researchers also noted that the risk of intracranial bleeding varied among the subgroups. The HRs for dabigatran vs warfarin were 0.10 for patients 75 and older, 2.29 for African Americans, 0.71 for patients with CKD, and 0.59 for patients with 7 or more comorbidities.

“We plan to examine 2012 data to monitor the risk of stroke for patients on dabigatran, which is the primary indication for taking the blood thinner,” Dr Zhang said. “It’s possible that, for some patients, a greater reduction in the risk of stroke will outweigh the higher risk of bleeding with dabigatran compared to warfarin.”

Warfarin tablets

Dabigatran poses a greater risk of major bleeding and gastrointestinal (GI) bleeding compared to warfarin, according to a study of patients with atrial fibrillation.

The incidence of GI and major bleeding with dabigatran was particularly high in African Americans, patients with chronic kidney disease (CKD), patients age 75

and older, and those with 7 or more comorbidities.

On the other hand, the risk of intracranial hemorrhage was higher in most warfarin-treated patients. African Americans were the exception to this rule.

Researchers reported these results in JAMA Internal Medicine alongside a related editorial.

“Dabigatran was introduced in 2010 and, at the time of approval, it was the only available alternative to warfarin,” noted study author Yuting Zhang, PhD, of the University of Pittsburgh in Pennsylvania.

“Warfarin dosing can be tricky, and regular monitoring with blood tests is required, so doctors and patients were glad to have a drug that was easier to manage. But some recent studies suggest that dabigatran is associated with a higher risk of bleeding.”

To investigate that possibility, Dr Zhang and her colleagues reviewed pharmacy and medical claims data from 2010 and 2011 of a random national sample of Medicare beneficiaries. The team tracked 1302 dabigatran users and 8102 warfarin users to see whether they experienced bleeding episodes.

The researchers classified bleeding events as major, such as intracranial bleeding or GI bleeding requiring a hospital or emergency room stay, or minor, such as GI bleeding that was treated on an outpatient basis or nose bleeds.

The incidence of any bleeding was significantly higher in dabigatran-treated patients than in warfarin-treated patients (32.7% vs 26.5%, P<0.001). The same was true of major bleeding (9% vs 5.9%, P<0.001) and GI bleeding (17.4% vs 10%, P<0.001).

However, the rate of intracranial bleeding was higher with warfarin than with dabigatran (1.8% vs 0.6%, P<0.001), as was the rate of epistaxis (3.1% vs 2%, P=0.002) and not-otherwise-specified hemorrhage (5.9% vs 4.4%, P=0.003).

All other types of bleeding were more frequent in the dabigatran group than the warfarin group. This included hematuria (12% vs 8.8%, P<0.001), vaginal bleeding (0.7% vs 0.3%, P=0.003), hemarthrosis (0.5% vs 0.2%, P=0.007), and hemoptysis (2% vs 1.4%, P=0.03).

The researchers also looked at bleeding episodes in 4 high-risk subgroups: patients who were 75 years of age and older, African Americans, patients with CKD, and those with 7 or more co-existing medical problems.

The risk of major bleeding was higher among dabigatran-treated patients belonging to these subgroups. The hazard ratios (HRs) were 1.60 for patients 75 and older, 2.12 for African Americans, 2.07 for patients with CKD, and 1.88 for patients with 7 or more comorbidities.

Likewise, the risk of GI bleeding was higher among dabigatran-treated patients in the subgroups. The HRs were 1.85 for patients 75 and older, 2.38 for African Americans, 1.81 for patients with CKD, and 1.81 for patients with 7 or more comorbidities.

“These findings indicate that physicians should be cautious when prescribing dabigatran, particularly to African Americans and patients with kidney impairments,” said study author Inmaculada Hernandez, PharmD, of the University of Pittsburgh.

“Also, the incidence of gastrointestinal bleeding was high in all the subgroups, so we recommend doctors explain to patients how to detect it so that it can be treated promptly.”

The researchers also noted that the risk of intracranial bleeding varied among the subgroups. The HRs for dabigatran vs warfarin were 0.10 for patients 75 and older, 2.29 for African Americans, 0.71 for patients with CKD, and 0.59 for patients with 7 or more comorbidities.

“We plan to examine 2012 data to monitor the risk of stroke for patients on dabigatran, which is the primary indication for taking the blood thinner,” Dr Zhang said. “It’s possible that, for some patients, a greater reduction in the risk of stroke will outweigh the higher risk of bleeding with dabigatran compared to warfarin.”

Monoclonal antibodies

Credit: Linda Bartlett

The UK’s National Institute for Health and Care Excellence (NICE) has issued a preliminary draft guidance recommending ofatumumab (Arzerra) for use in patients with chronic lymphocytic leukemia (CLL).

The agency is recommending the anti-CD20 monoclonal antibody in combination with chlorambucil for patients with untreated CLL who are ineligible for treatment with fludarabine combination therapy and for whom bendamustine is unsuitable.

NICE believes ofatumumab is a cost-effective use of National Health Service (NHS) resources for this patient population, as GlaxoSmithKline, the company developing ofatumumab, has agreed to provide the drug at a reduced price.

The company has agreed with the Department of Health that the size of the discount be confidential.

Clinical effectiveness

“The information provided by GlaxoSmithKline, who market the drug, showed that ofatumumab with chlorambucil is a clinically effective treatment option for those people unable to take fludarabine combination therapy or bendamustine,” said Sir Andrew Dillon, NICE chief executive.

In the phase 3 COMPLEMENT 1 trial, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).

A NICE advisory committee also considered the use of ofatumumab in combination with bendamustine. But the committee said that, due to limited clinical evidence and the absence of cost-effectiveness estimates, it could not make a recommendation on this combination.

In a phase 2 trial known as OMB115991, ofatumumab plus bendamustine elicited an overall response rate of 95% and a complete response rate of 43%.

Cost-effectiveness

Ofatumumab’s list price is £182 for a 100 mg vial and £1820 for a 1000 mg vial. Assuming 6 cycles and no drug wastage, the mean cost of a treatment course for ofatumumab at its list price is £11,466 for 6300 mg.

GlaxoSmithKline has agreed to a patient access scheme with the Department of Health that makes ofatumumab available with a discount on the list price, though the exact amount is confidential.

The NICE advisory committee said the most plausible cost-effectiveness estimate for ofatumumab plus chlorambucil compared with chlorambucil alone using the

ofatumumab patient access scheme price was £26,000 per quality-adjusted life year gained.

Consultees, including GlaxoSmithKline, healthcare professionals, and members of the public, can now comment on NICE’s preliminary draft guidance. It will be available for public consultation until November 25, 2014.

Until the final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

Monoclonal antibodies

Credit: Linda Bartlett

The UK’s National Institute for Health and Care Excellence (NICE) has issued a preliminary draft guidance recommending ofatumumab (Arzerra) for use in patients with chronic lymphocytic leukemia (CLL).

The agency is recommending the anti-CD20 monoclonal antibody in combination with chlorambucil for patients with untreated CLL who are ineligible for treatment with fludarabine combination therapy and for whom bendamustine is unsuitable.

NICE believes ofatumumab is a cost-effective use of National Health Service (NHS) resources for this patient population, as GlaxoSmithKline, the company developing ofatumumab, has agreed to provide the drug at a reduced price.

The company has agreed with the Department of Health that the size of the discount be confidential.

Clinical effectiveness

“The information provided by GlaxoSmithKline, who market the drug, showed that ofatumumab with chlorambucil is a clinically effective treatment option for those people unable to take fludarabine combination therapy or bendamustine,” said Sir Andrew Dillon, NICE chief executive.

In the phase 3 COMPLEMENT 1 trial, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).

A NICE advisory committee also considered the use of ofatumumab in combination with bendamustine. But the committee said that, due to limited clinical evidence and the absence of cost-effectiveness estimates, it could not make a recommendation on this combination.

In a phase 2 trial known as OMB115991, ofatumumab plus bendamustine elicited an overall response rate of 95% and a complete response rate of 43%.

Cost-effectiveness

Ofatumumab’s list price is £182 for a 100 mg vial and £1820 for a 1000 mg vial. Assuming 6 cycles and no drug wastage, the mean cost of a treatment course for ofatumumab at its list price is £11,466 for 6300 mg.

GlaxoSmithKline has agreed to a patient access scheme with the Department of Health that makes ofatumumab available with a discount on the list price, though the exact amount is confidential.

The NICE advisory committee said the most plausible cost-effectiveness estimate for ofatumumab plus chlorambucil compared with chlorambucil alone using the

ofatumumab patient access scheme price was £26,000 per quality-adjusted life year gained.

Consultees, including GlaxoSmithKline, healthcare professionals, and members of the public, can now comment on NICE’s preliminary draft guidance. It will be available for public consultation until November 25, 2014.

Until the final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

Monoclonal antibodies

Credit: Linda Bartlett

The UK’s National Institute for Health and Care Excellence (NICE) has issued a preliminary draft guidance recommending ofatumumab (Arzerra) for use in patients with chronic lymphocytic leukemia (CLL).

The agency is recommending the anti-CD20 monoclonal antibody in combination with chlorambucil for patients with untreated CLL who are ineligible for treatment with fludarabine combination therapy and for whom bendamustine is unsuitable.

NICE believes ofatumumab is a cost-effective use of National Health Service (NHS) resources for this patient population, as GlaxoSmithKline, the company developing ofatumumab, has agreed to provide the drug at a reduced price.

The company has agreed with the Department of Health that the size of the discount be confidential.

Clinical effectiveness

“The information provided by GlaxoSmithKline, who market the drug, showed that ofatumumab with chlorambucil is a clinically effective treatment option for those people unable to take fludarabine combination therapy or bendamustine,” said Sir Andrew Dillon, NICE chief executive.

In the phase 3 COMPLEMENT 1 trial, ofatumumab plus chlorambucil improved progression-free survival compared to chlorambucil alone. The median times were 22.4 months and 13.1 months, respectively, and the hazard ratio was 0.57 (P<0.001).

A NICE advisory committee also considered the use of ofatumumab in combination with bendamustine. But the committee said that, due to limited clinical evidence and the absence of cost-effectiveness estimates, it could not make a recommendation on this combination.

In a phase 2 trial known as OMB115991, ofatumumab plus bendamustine elicited an overall response rate of 95% and a complete response rate of 43%.

Cost-effectiveness

Ofatumumab’s list price is £182 for a 100 mg vial and £1820 for a 1000 mg vial. Assuming 6 cycles and no drug wastage, the mean cost of a treatment course for ofatumumab at its list price is £11,466 for 6300 mg.

GlaxoSmithKline has agreed to a patient access scheme with the Department of Health that makes ofatumumab available with a discount on the list price, though the exact amount is confidential.

The NICE advisory committee said the most plausible cost-effectiveness estimate for ofatumumab plus chlorambucil compared with chlorambucil alone using the

ofatumumab patient access scheme price was £26,000 per quality-adjusted life year gained.

Consultees, including GlaxoSmithKline, healthcare professionals, and members of the public, can now comment on NICE’s preliminary draft guidance. It will be available for public consultation until November 25, 2014.

Until the final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

The US Food and Drug Administration (FDA) has removed the full clinical hold placed on the investigational new drug application for the telomerase inhibitor imetelstat.

The hold, which was placed in March, suspended a phase 2 study of imetelstat in patients with essential thrombocythemia (ET) or polycythemia vera (PV), as well as a phase 2 study of the drug in patients with multiple myeloma (MM).

The hold also delayed a planned phase 2 trial in patients with myelofibrosis (MF).

And it temporarily suspended an investigator-sponsored trial of imetelstat in MF. The FDA lifted the hold on the investigator-sponsored trial in June.

The FDA halted these trials due to reports of persistent, low-grade liver function test (LFT) abnormalities observed in the phase 2 study of ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat. The FDA expressed concern about whether these LFT abnormalities are reversible.

Now, data provided by the Geron Corporation, the company developing imetelstat, has convinced the FDA to lift the hold on all trials.

The FDA said the proposed clinical development plan for imetelstat, which is focused on high-risk myeloid disorders such as MF, is acceptable. Geron Corporation has said it does not intend to conduct further studies with, or develop imetelstat for, patients with ET or PV.

To address the clinical hold, the FDA required Geron to provide follow-up information from imetelstat-treated patients who experienced LFT abnormalities until such abnormalities resolved to normal or baseline.

Geron obtained follow-up information from patients in the previously ongoing company-sponsored phase 2 trials in ET/PV and MM. These data were submitted to the FDA as part of the company’s complete response.

The company’s analysis of these data showed that, in the ET/PV trial, LFT abnormalities resolved to normal or baseline in 14 of 18 follow-up patients. For the remaining 4 patients, at the time of the data cut-off, 3 patients showed improvement in LFT abnormalities, and 1 patient had unresolved LFT abnormalities. Two of the remaining 4 patients continue in follow-up.

In the MM trial, LFT abnormalities resolved to normal or baseline in all 9 follow-up patients. In addition, no emergent hepatic adverse events were reported during follow-up for either study.

The FDA also requested information regarding the reversibility of liver toxicity after chronic imetelstat administration in animals. Geron submitted data from its non-clinical toxicology studies, which included a 6-month study in mice and a 9-month study in cynomolgus monkeys.

In these studies, no clinical pathology changes indicative of hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified.

With the clinical hold lifted, a multicenter phase 2 trial in MF is projected to begin in the first half of 2015.

The US Food and Drug Administration (FDA) has removed the full clinical hold placed on the investigational new drug application for the telomerase inhibitor imetelstat.

The hold, which was placed in March, suspended a phase 2 study of imetelstat in patients with essential thrombocythemia (ET) or polycythemia vera (PV), as well as a phase 2 study of the drug in patients with multiple myeloma (MM).

The hold also delayed a planned phase 2 trial in patients with myelofibrosis (MF).

And it temporarily suspended an investigator-sponsored trial of imetelstat in MF. The FDA lifted the hold on the investigator-sponsored trial in June.

The FDA halted these trials due to reports of persistent, low-grade liver function test (LFT) abnormalities observed in the phase 2 study of ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat. The FDA expressed concern about whether these LFT abnormalities are reversible.

Now, data provided by the Geron Corporation, the company developing imetelstat, has convinced the FDA to lift the hold on all trials.

The FDA said the proposed clinical development plan for imetelstat, which is focused on high-risk myeloid disorders such as MF, is acceptable. Geron Corporation has said it does not intend to conduct further studies with, or develop imetelstat for, patients with ET or PV.

To address the clinical hold, the FDA required Geron to provide follow-up information from imetelstat-treated patients who experienced LFT abnormalities until such abnormalities resolved to normal or baseline.

Geron obtained follow-up information from patients in the previously ongoing company-sponsored phase 2 trials in ET/PV and MM. These data were submitted to the FDA as part of the company’s complete response.

The company’s analysis of these data showed that, in the ET/PV trial, LFT abnormalities resolved to normal or baseline in 14 of 18 follow-up patients. For the remaining 4 patients, at the time of the data cut-off, 3 patients showed improvement in LFT abnormalities, and 1 patient had unresolved LFT abnormalities. Two of the remaining 4 patients continue in follow-up.

In the MM trial, LFT abnormalities resolved to normal or baseline in all 9 follow-up patients. In addition, no emergent hepatic adverse events were reported during follow-up for either study.

The FDA also requested information regarding the reversibility of liver toxicity after chronic imetelstat administration in animals. Geron submitted data from its non-clinical toxicology studies, which included a 6-month study in mice and a 9-month study in cynomolgus monkeys.

In these studies, no clinical pathology changes indicative of hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified.

With the clinical hold lifted, a multicenter phase 2 trial in MF is projected to begin in the first half of 2015.

The US Food and Drug Administration (FDA) has removed the full clinical hold placed on the investigational new drug application for the telomerase inhibitor imetelstat.

The hold, which was placed in March, suspended a phase 2 study of imetelstat in patients with essential thrombocythemia (ET) or polycythemia vera (PV), as well as a phase 2 study of the drug in patients with multiple myeloma (MM).

The hold also delayed a planned phase 2 trial in patients with myelofibrosis (MF).

And it temporarily suspended an investigator-sponsored trial of imetelstat in MF. The FDA lifted the hold on the investigator-sponsored trial in June.

The FDA halted these trials due to reports of persistent, low-grade liver function test (LFT) abnormalities observed in the phase 2 study of ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat. The FDA expressed concern about whether these LFT abnormalities are reversible.

Now, data provided by the Geron Corporation, the company developing imetelstat, has convinced the FDA to lift the hold on all trials.

The FDA said the proposed clinical development plan for imetelstat, which is focused on high-risk myeloid disorders such as MF, is acceptable. Geron Corporation has said it does not intend to conduct further studies with, or develop imetelstat for, patients with ET or PV.

To address the clinical hold, the FDA required Geron to provide follow-up information from imetelstat-treated patients who experienced LFT abnormalities until such abnormalities resolved to normal or baseline.

Geron obtained follow-up information from patients in the previously ongoing company-sponsored phase 2 trials in ET/PV and MM. These data were submitted to the FDA as part of the company’s complete response.

The company’s analysis of these data showed that, in the ET/PV trial, LFT abnormalities resolved to normal or baseline in 14 of 18 follow-up patients. For the remaining 4 patients, at the time of the data cut-off, 3 patients showed improvement in LFT abnormalities, and 1 patient had unresolved LFT abnormalities. Two of the remaining 4 patients continue in follow-up.

In the MM trial, LFT abnormalities resolved to normal or baseline in all 9 follow-up patients. In addition, no emergent hepatic adverse events were reported during follow-up for either study.

The FDA also requested information regarding the reversibility of liver toxicity after chronic imetelstat administration in animals. Geron submitted data from its non-clinical toxicology studies, which included a 6-month study in mice and a 9-month study in cynomolgus monkeys.

In these studies, no clinical pathology changes indicative of hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified.

With the clinical hold lifted, a multicenter phase 2 trial in MF is projected to begin in the first half of 2015.

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

Vials of a drug

NEW YORK—Brentuximab vendotin—not conventional chemotherapy—is the second-line regimen of choice for recurrent Hodgkin lymphoma (HL) patients prior to stem cell transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Catherine Diefenbach, MD, of New York University’s Langone Medical Center in New York, argued that conventional chemotherapy, the existing paradigm for first salvage therapy, does not maximize a cure or minimize toxicity, is inconvenient, and is not cost-effective.

She noted that a quarter of HL patients relapse or have a primary refractory diagnosis.

“These are young patients,” Dr Diefenbach said. “Autologous stem cell transplant [ASCT] cures only half of them. There is no other established curative salvage therapy.”

She noted that the median time to progression with relapse after transplant is 3.8 months in patients treated with subsequent therapy, with a median survival of 26 months.

After ASCT, the median progression-free survival with relapse is 1.3 years. And about three-quarters of relapses occur within the first year.

“Achieving a complete response [CR] before ASCT is the most important factor in determining long-term disease-free survival and to maximizing transplant-related benefit,” Dr Diefenbach said. “High overall response rates [ORRs] do not equal high CR. Only one-third of patients achieve a CR [with chemotherapy].”

She said studies have shown that chemotherapy with ICE (ifosfamide, carboplatin, and etoposide) leads to a 3-year event-free survival rate of 22%. Post-ASCT, event-free survival increases to more than 52%.

The overall survival post-ASCT is 44%. The median survival of patients who do not get therapy is 3.7 months. Myelosuppression and deaths are common.

“Conventional chemotherapy fails,” Dr Diefenbach continued. “There is inadequate disease control, unacceptable toxicity, it’s not cost-effective, requires patients to be hospitalized, and there is no clear standard of care.”

On the other hand, brentuximab as first salvage is highly active with minimal adverse events in relapsed HL.

“Rash is the only grade 3-4 toxicity,” Dr Diefenbach said. “There are no significant cytopenias [and] no febrile neutropenia. Growth factor support is not required, and it’s administered outpatient.”

Using brentuximab as second-line therapy results in an ORR of 85.7% and a CR of 50%, she added. And ASCT after brentuximab shows similar successes and toxicities.

Brentuximab followed by ICE leads to high rates of PET normalization, allows successful transplantation of virtually all evaluable patients, and poses no issues with stem cell collection.

Furthermore, studies show a 92% disease-free survival, with minimal toxicity at 10 months of follow-up.

In conclusion, Dr Diefenbach said, “Maximizing disease control prior to ASCT will maximize cure from ASCT. Brentuximab vedotin is a novel agent that leads to a high ORR and high CR rate with low toxicity and outpatient administration. In contrast, conventional chemotherapy fails to provide a high CR rate, has unacceptable toxicity, and there is no single standard of care.”

For an opposing opinion on salvage in HL, see “Speaker adovcates chemo-based salvage in HL.”

PHILADELPHIA—Blood transfusions can provide pain relief in adults with sickle cell disease (SCD) who have failed treatment with hydroxyurea, a pilot study suggests.

Patients had fewer visits to the emergency department (ED) and fewer hospital admissions for pain control after they received chronic transfusions for pain prophylaxis than they did prior to receiving transfusions.

Matthew S. Karafin, MD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the AABB Annual Meeting 2014 (abstract S42-030G).

“Pain in adults with sickle cell disease is probably one of the most important things that we deal with in our clinics,” he began. “It is the leading cause of morbidity in this population.”

Dr Karafin also noted that adults with SCD seem to experience pain differently from children, reporting more of a constant pain, as opposed to the episodic pain observed in kids. And although previous studies have suggested that transfusions do provide pain relief in SCD, most of those studies have focused on children.

So Dr Karafin and his colleagues set out to determine the impact of prophylactic transfusions on the rate of serious pain episodes in adults with SCD. The team retrospectively analyzed a cohort of patients who received chronic transfusions at 3- to 8-week intervals from January 2009 to October 2013.

The researchers defined chronic transfusions as receiving blood—either simple transfusions or red cell exchanges—in an outpatient setting 3 days a week with the goal of controlling hemoglobin (Hb) S percentage, maintaining it at less than 30%.

Patients had to have at least 1 ED or hospital visit for severe pain per month prior to starting transfusions, they were required to have failed hydroxyurea therapy, and they had to have at least 3 months both on and off chronic transfusions. The patients could have no other reason for receiving chronic transfusions (ie, no previous stroke).

So the study included 17 patients, 12 of whom were female. Fifteen (88.1%) had Hb SS disease, and 2 had Hb SC disease. Their median age was 26 (range, 20-54).

“We were able to record 541 total ED admissions over the study period and 404 total hospital admissions,” Dr Karafin said. “The median study evaluation period pre-transfusion was about 3.5 years, and we were able to study [patients for] a median of more than a year for the post-transfusion protocol period.”

Dr Karafin also noted that most of the patients were not transfusion-naïve, but they received significantly more units after being placed on the transfusion protocol.

The median number of red cell units received per 100 days was 1.2 (range, 0-7.2) pre-transfusion and 10.2 (range, 6.7-24.3) post-transfusion (P=0.0003). Nine of the patients received simple transfusions, and 8 received red cell exchanges.

There was a significant difference in the median Hb S pre- and post-transfusion—79% (range, 26.5%-89.6%) and 30.2% (range, 10.9%-57.4%), respectively (P=0.0003).

But there was no significant difference in median ferritin levels—1128.2 ng/mL (range, 65.4-11,130) and 2632.8 ng/mL (range, 16.7-8023.6), respectively (P=0.18). Dr Karafin said this could be explained by the fact that patients were not transfusion-naïve prior to starting the protocol.

Similarly, the median new alloantibody rate per 100 units was 0 both pre- and post-transfusion. This may be due to the fact that all patients received C-, E-, and KEL-matched blood, as well as the freshest available units, Dr Karafin said.

He and his colleagues also found that the median ED admission rate was significantly lower post-transfusion compared to pre-transfusion—0.79 (range, 0-6.6) and 2 (range, 0.4-11) visits every 100 days, respectively (P=0.04).

Thirteen patients (76.5%) had a reduced ED visit rate after chronic transfusion, and there was a 60.5% reduction in the ED visit rate overall.

Likewise, the median hospital admission rate decreased from 1.7 per 100 days (range, 0.05-5.8) pre-transfusion to 1.3 per 100 days (range, 0.2-3.2) post-transfusion (P=0.004).

Fifteen patients (88.2%) had reduced hospital admissions after chronic transfusion, and there was a 20.3% reduction in hospital admissions overall.

Dr Karafin noted that this study had a number of limitations, including a small number of patients, its retrospective nature, and the fact that it was conducted at a comprehensive SCD clinic.

“However, limitations aside, we found significant evidence to support that the findings observed in children seem to be similar in the adult population,” he said.

Namely, chronic transfusions can prevent serious pain episodes in adults with SCD who have failed treatment with hydroxyurea.

PHILADELPHIA—Blood transfusions can provide pain relief in adults with sickle cell disease (SCD) who have failed treatment with hydroxyurea, a pilot study suggests.

Patients had fewer visits to the emergency department (ED) and fewer hospital admissions for pain control after they received chronic transfusions for pain prophylaxis than they did prior to receiving transfusions.

Matthew S. Karafin, MD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the AABB Annual Meeting 2014 (abstract S42-030G).

“Pain in adults with sickle cell disease is probably one of the most important things that we deal with in our clinics,” he began. “It is the leading cause of morbidity in this population.”

Dr Karafin also noted that adults with SCD seem to experience pain differently from children, reporting more of a constant pain, as opposed to the episodic pain observed in kids. And although previous studies have suggested that transfusions do provide pain relief in SCD, most of those studies have focused on children.

So Dr Karafin and his colleagues set out to determine the impact of prophylactic transfusions on the rate of serious pain episodes in adults with SCD. The team retrospectively analyzed a cohort of patients who received chronic transfusions at 3- to 8-week intervals from January 2009 to October 2013.

The researchers defined chronic transfusions as receiving blood—either simple transfusions or red cell exchanges—in an outpatient setting 3 days a week with the goal of controlling hemoglobin (Hb) S percentage, maintaining it at less than 30%.

Patients had to have at least 1 ED or hospital visit for severe pain per month prior to starting transfusions, they were required to have failed hydroxyurea therapy, and they had to have at least 3 months both on and off chronic transfusions. The patients could have no other reason for receiving chronic transfusions (ie, no previous stroke).

So the study included 17 patients, 12 of whom were female. Fifteen (88.1%) had Hb SS disease, and 2 had Hb SC disease. Their median age was 26 (range, 20-54).

“We were able to record 541 total ED admissions over the study period and 404 total hospital admissions,” Dr Karafin said. “The median study evaluation period pre-transfusion was about 3.5 years, and we were able to study [patients for] a median of more than a year for the post-transfusion protocol period.”

Dr Karafin also noted that most of the patients were not transfusion-naïve, but they received significantly more units after being placed on the transfusion protocol.

The median number of red cell units received per 100 days was 1.2 (range, 0-7.2) pre-transfusion and 10.2 (range, 6.7-24.3) post-transfusion (P=0.0003). Nine of the patients received simple transfusions, and 8 received red cell exchanges.

There was a significant difference in the median Hb S pre- and post-transfusion—79% (range, 26.5%-89.6%) and 30.2% (range, 10.9%-57.4%), respectively (P=0.0003).

But there was no significant difference in median ferritin levels—1128.2 ng/mL (range, 65.4-11,130) and 2632.8 ng/mL (range, 16.7-8023.6), respectively (P=0.18). Dr Karafin said this could be explained by the fact that patients were not transfusion-naïve prior to starting the protocol.

Similarly, the median new alloantibody rate per 100 units was 0 both pre- and post-transfusion. This may be due to the fact that all patients received C-, E-, and KEL-matched blood, as well as the freshest available units, Dr Karafin said.

He and his colleagues also found that the median ED admission rate was significantly lower post-transfusion compared to pre-transfusion—0.79 (range, 0-6.6) and 2 (range, 0.4-11) visits every 100 days, respectively (P=0.04).

Thirteen patients (76.5%) had a reduced ED visit rate after chronic transfusion, and there was a 60.5% reduction in the ED visit rate overall.

Likewise, the median hospital admission rate decreased from 1.7 per 100 days (range, 0.05-5.8) pre-transfusion to 1.3 per 100 days (range, 0.2-3.2) post-transfusion (P=0.004).

Fifteen patients (88.2%) had reduced hospital admissions after chronic transfusion, and there was a 20.3% reduction in hospital admissions overall.

Dr Karafin noted that this study had a number of limitations, including a small number of patients, its retrospective nature, and the fact that it was conducted at a comprehensive SCD clinic.

“However, limitations aside, we found significant evidence to support that the findings observed in children seem to be similar in the adult population,” he said.

Namely, chronic transfusions can prevent serious pain episodes in adults with SCD who have failed treatment with hydroxyurea.

PHILADELPHIA—Blood transfusions can provide pain relief in adults with sickle cell disease (SCD) who have failed treatment with hydroxyurea, a pilot study suggests.

Patients had fewer visits to the emergency department (ED) and fewer hospital admissions for pain control after they received chronic transfusions for pain prophylaxis than they did prior to receiving transfusions.

Matthew S. Karafin, MD, of the Blood Center of Wisconsin in Milwaukee, presented these results at the AABB Annual Meeting 2014 (abstract S42-030G).

“Pain in adults with sickle cell disease is probably one of the most important things that we deal with in our clinics,” he began. “It is the leading cause of morbidity in this population.”

Dr Karafin also noted that adults with SCD seem to experience pain differently from children, reporting more of a constant pain, as opposed to the episodic pain observed in kids. And although previous studies have suggested that transfusions do provide pain relief in SCD, most of those studies have focused on children.

So Dr Karafin and his colleagues set out to determine the impact of prophylactic transfusions on the rate of serious pain episodes in adults with SCD. The team retrospectively analyzed a cohort of patients who received chronic transfusions at 3- to 8-week intervals from January 2009 to October 2013.

The researchers defined chronic transfusions as receiving blood—either simple transfusions or red cell exchanges—in an outpatient setting 3 days a week with the goal of controlling hemoglobin (Hb) S percentage, maintaining it at less than 30%.

Patients had to have at least 1 ED or hospital visit for severe pain per month prior to starting transfusions, they were required to have failed hydroxyurea therapy, and they had to have at least 3 months both on and off chronic transfusions. The patients could have no other reason for receiving chronic transfusions (ie, no previous stroke).

So the study included 17 patients, 12 of whom were female. Fifteen (88.1%) had Hb SS disease, and 2 had Hb SC disease. Their median age was 26 (range, 20-54).

“We were able to record 541 total ED admissions over the study period and 404 total hospital admissions,” Dr Karafin said. “The median study evaluation period pre-transfusion was about 3.5 years, and we were able to study [patients for] a median of more than a year for the post-transfusion protocol period.”

Dr Karafin also noted that most of the patients were not transfusion-naïve, but they received significantly more units after being placed on the transfusion protocol.

The median number of red cell units received per 100 days was 1.2 (range, 0-7.2) pre-transfusion and 10.2 (range, 6.7-24.3) post-transfusion (P=0.0003). Nine of the patients received simple transfusions, and 8 received red cell exchanges.

There was a significant difference in the median Hb S pre- and post-transfusion—79% (range, 26.5%-89.6%) and 30.2% (range, 10.9%-57.4%), respectively (P=0.0003).

But there was no significant difference in median ferritin levels—1128.2 ng/mL (range, 65.4-11,130) and 2632.8 ng/mL (range, 16.7-8023.6), respectively (P=0.18). Dr Karafin said this could be explained by the fact that patients were not transfusion-naïve prior to starting the protocol.

Similarly, the median new alloantibody rate per 100 units was 0 both pre- and post-transfusion. This may be due to the fact that all patients received C-, E-, and KEL-matched blood, as well as the freshest available units, Dr Karafin said.

He and his colleagues also found that the median ED admission rate was significantly lower post-transfusion compared to pre-transfusion—0.79 (range, 0-6.6) and 2 (range, 0.4-11) visits every 100 days, respectively (P=0.04).

Thirteen patients (76.5%) had a reduced ED visit rate after chronic transfusion, and there was a 60.5% reduction in the ED visit rate overall.

Likewise, the median hospital admission rate decreased from 1.7 per 100 days (range, 0.05-5.8) pre-transfusion to 1.3 per 100 days (range, 0.2-3.2) post-transfusion (P=0.004).

Fifteen patients (88.2%) had reduced hospital admissions after chronic transfusion, and there was a 20.3% reduction in hospital admissions overall.

Dr Karafin noted that this study had a number of limitations, including a small number of patients, its retrospective nature, and the fact that it was conducted at a comprehensive SCD clinic.

“However, limitations aside, we found significant evidence to support that the findings observed in children seem to be similar in the adult population,” he said.

Namely, chronic transfusions can prevent serious pain episodes in adults with SCD who have failed treatment with hydroxyurea.

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”

Patient receiving chemotherapy

Credit: Rhoda Baer

NEW YORK—Physicians should use chemotherapy-based approaches—not brentuximab vedotin—as second-line therapy for recurrent

Hodgkin lymphoma (HL) prior to transplant, according to a speaker at the Lymphoma & Myeloma 2014 congress.

Nina Wagner-Johnston, MD, of Washington University in St Louis, Missouri, provided the meeting’s audience with a handful of arguments to support chemotherapy-based salvage regimens and a number of reasons why brentuximab is not ideal as salvage therapy in HL.

First, there is data supporting the use of chemotherapy-based salvage regimens in these patients, but the brentuximab data is lacking.

“Other issues include chemosensitivity, stem cell collection, unknown progressive multifocal leukoencephalopathy (PML) risk with brentuximab pre-ASCT [autologous stem cell transplant], cost, and alternative roles for brentuximab to enhance cure upfront post-ASCT maintenance,” Dr Wagner-Johnston said.

She also noted that chemotherapy-based salvage regimens yield high response rates with adequate stem cell collections.

“The vast majority of patients proceed to ASCT, 86% with ICE chemotherapy [ifosfamide, carboplatin, and etoposide],” she said. “Many are cured with a chemotherapy-based approach, with a 5-year PFS [progression-free survival] of 50% to 60%, with a low incidence of febrile neutropenia.”

Dr Wagner-Johnston also raised the possibility that giving patients brentuximab prior to ASCT might increase the risk of PML. The risk is already increased with lymphoma and ASCT. And in cases of PML in which patients are treated with brentuximab, the onset is rapid, with a median of about 2 months after initiation.

Furthermore, the cost of therapy clearly favors chemotherapy over brentuximab, she said. Three cycles of brentuximab at 1.8 mg/kg cost more than $58,000, and 2 cycles of brentuximab (3 weeks on, 1 week off) at 1.2 mg/kg cost more than $78,000.

In comparison, 3 cycles of ICE cost less than $38,000 and 3 cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) cost $17,000. These costs do not account for the increased risk of febrile neutropenia.

Dr Wagner-Johnston expressed other concerns about brentuximab as well.

“Brentuximab is probably not effective to pursue as a single agent,” she said. “The addition of brentuximab to chemotherapy increases toxicity and cost. Continuous progressions years after ASCT call into question a 2-year benchmark and further highlight the importance of a maintenance approach.”

There are several unanswered pivotal questions about brentuximab, Dr Wagner-Johnston continued.

“Is brentuximab sensitivity equivalent to chemosensitivity?” she asked. “Does improved CR [complete response] rate with brentuximab-based treatment equate to better outcomes? Is the likelihood of cure higher with brentuximab-based approaches?”

She said brentuximab may be best in the upfront setting. There are more upfront cures in the highest-risk group with this novel agent, and it may allow a greater number of patients to avoid the toxicity of ASCT.

Brentuximab has demonstrated safety in phase 1/2 studies, Dr Wagner-Johnston said, adding “we await data from an ongoing phase 3 trial to determine a PFS benefit with brentuximab.”

Furthermore, post-ASCT maintenance with brentuximab may be a better alternative than salvage brentuximab pre-ASCT. In the relapsed setting, the median duration of response for brentuximab is short (6.7 months in a phase 2 study) after a median of 9 cycles.

In the phase 3 placebo-controlled trial of maintenance brentuximab following ASCT, “an interim analysis based on safety and utility recommends continuation,” Dr Wagner-Johnston said.

In conclusion, she said, “Before letting brentuximab take over, we need to confirm its safety, efficacy, and determine the best positioning of brentuximab to enhance outcomes. In the meantime, stick with what we know works.”

For the dissenting opinion on salvage in HL, see “Brentuximab tops chemo in HL, doc says.”

Blood for transfusion

Credit: UAB Hospital

PHILADELPHIA—As the medical community continues to debate whether transfusing older blood has a negative outcome on patients, results of the RECESS trial add fuel to the fire.

The study showed no significant differences in clinical outcomes between cardiac surgery patients who received newer red blood cells (RBCs) and those who received older RBCs.

There were no differences in multi-organ dysfunction scores (MODS), mortality rates, or the incidence of serious adverse events.

Marie E. Stein, MD, of the University of Minnesota in Minneapolis, presented the results of RECESS at the AABB Annual Meeting 2014 (abstract P2-020A).

The findings contradict results from another recent study presented at the Canadian Cardiovascular Congress.

“There are many studies of the effects of red blood cell storage duration on clinical outcomes, most of which are observational and include only a few randomized trials to date,” Dr Stein noted. “When studying cardiac surgery patients, some studies have found significant adverse outcomes of subjects who are transfused with red cells stored for a longer duration compared to shorter duration, and other studies have not.”

“Based on this equipoise, the primary hypothesis for RECESS was that there would be an important difference between the effect of transfusing shorter-storage-age-duration red cells compared to transfusing longer-storage-age-duration red cells on clinical outcomes in cardiac surgery patients.”

Patient characteristics

Dr Stein and her colleagues enrolled 1481 patients who were 12 years of age and older, weighed 40 kg or more, were undergoing complex cardiac surgery, and were considered “highly likely” to be transfused. They had to have a TRUST score of 3 or greater if they were older than 18 years of age, but this was not required for children.

Patients were split into two groups: those set to receive RBCs stored for 10 days or fewer and those set to receive RBCs stored for 21 days or more. Patients were stratified by age (those 12 to 17 years vs patients 18 and older) and according to whether they were in the intensive care unit prior to surgery. They were balanced by site as well.

In all, there were 538 subjects evaluable for the newer RBC arm and 560 subjects evaluable for the older RBC arm. (Subjects were evaluable if they underwent surgery and received at least 1 RBC unit.) The median patient age was 73 and 72 years, respectively, and males made up 42% and 44% of the patients, respectively.

The same percentage of patients in each arm—96%—underwent cardiopulmonary bypass, and 23% of patients in each arm underwent coronary artery bypass grafting. Seventeen percent of patients in the newer RBC arm and 14% in the older RBC arm underwent valve surgery only.

“Red cells were leukoreduced, stored in additive solution, and provided according to storage duration arm assignment for all pre-op, post-op, and intra-operative transfusions through day 28, discharge, or death, whichever occurred first,” Dr Stein noted.

The number of RBC units did not differ significantly between the two arms (P=0.80), and there was a comparable number of highly transfused subjects in each arm (P=0.81).

Eighty-seven percent of patients in the newer RBC arm and 89% in the older RBC arm received all their RBC units as assigned (P=0.35).

Six percent and 8%, respectively, received 1 or more unit aged 11 to 20 days but none belonging to the opposite arm to which they were assigned. Five percent and 4%, respectively, received 1 or more RBC unit from the opposite arm to which they were assigned.

“There was a 20-day difference in the mean storage duration between the two arms: 8 vs 28 days,” Dr Stein pointed out.

Outcomes

The study’s primary outcome was the change in multi-organ dysfunction score (ΔMODS) at 7 days. The MODS system includes assessments of respiratory, renal, hepatic, cardiovascular, hematologic, and neurologic function.

“The MODS system was chosen as the primary endpoint because the data elements are objective and readily available,” Dr Stein said. “MODS also incorporates organ dysfunction and not just frank organ failure. It correlates with mortality, with length of stay, and does incorporate death. MODS has been validated in other studies and has been used in other transfusion trials, including TRICC.”

To calculate 7-day ΔMODS, the researchers identified the worst score for each organ system through day 7 after surgery, discharge, or death. The 7-day MODS was the sum of the worst score for each organ system, and the 7-day ΔMODS was the pre-surgery MODS subtracted from the 7-day MODS.

Secondary outcomes were the 28-day ΔMODS, 28-day mortality, and the incidence of serious adverse events.

There was no significant difference between the arms with regard to 7-day or 28-day ΔMODS.

For the 7-day ΔMODS, the mean was 8.5±3.6 in the newer RBC arm and 8.7±3.6 in the older RBC arm. The unadjusted difference and the difference adjusted for baseline MODS were both -0.02.

For the 28-day ΔMODS, the mean was 8.7±4.0 in the newer RBC arm and 9.1±4.2 in the older RBC arm. The unadjusted difference and the difference adjusted for baseline MODS were both -0.3.

There was no significant difference between the arms in time to death (P=0.50), 7-day mortality (P=0.43), or 28-day mortality (P=0.57). The rate of 7-day mortality was 2.8% in the newer RBC arm and 2.0% in the older RBC arm. The 28-day mortality was 4.4% and 5.3%, respectively.

There was no significant difference in the percentage of subjects with 1 or more serious adverse events. The rate was 53% in the newer RBC arm and 51% in the older RBC arm (P=0.72).

Taking these results together, Dr Stein concluded that differences in the storage duration of RBCs did not translate to significant differences in “key clinical outcomes.”

Blood for transfusion

Credit: UAB Hospital

PHILADELPHIA—As the medical community continues to debate whether transfusing older blood has a negative outcome on patients, results of the RECESS trial add fuel to the fire.

The study showed no significant differences in clinical outcomes between cardiac surgery patients who received newer red blood cells (RBCs) and those who received older RBCs.

There were no differences in multi-organ dysfunction scores (MODS), mortality rates, or the incidence of serious adverse events.

Marie E. Stein, MD, of the University of Minnesota in Minneapolis, presented the results of RECESS at the AABB Annual Meeting 2014 (abstract P2-020A).

The findings contradict results from another recent study presented at the Canadian Cardiovascular Congress.

“There are many studies of the effects of red blood cell storage duration on clinical outcomes, most of which are observational and include only a few randomized trials to date,” Dr Stein noted. “When studying cardiac surgery patients, some studies have found significant adverse outcomes of subjects who are transfused with red cells stored for a longer duration compared to shorter duration, and other studies have not.”

“Based on this equipoise, the primary hypothesis for RECESS was that there would be an important difference between the effect of transfusing shorter-storage-age-duration red cells compared to transfusing longer-storage-age-duration red cells on clinical outcomes in cardiac surgery patients.”

Patient characteristics

Dr Stein and her colleagues enrolled 1481 patients who were 12 years of age and older, weighed 40 kg or more, were undergoing complex cardiac surgery, and were considered “highly likely” to be transfused. They had to have a TRUST score of 3 or greater if they were older than 18 years of age, but this was not required for children.

Patients were split into two groups: those set to receive RBCs stored for 10 days or fewer and those set to receive RBCs stored for 21 days or more. Patients were stratified by age (those 12 to 17 years vs patients 18 and older) and according to whether they were in the intensive care unit prior to surgery. They were balanced by site as well.

In all, there were 538 subjects evaluable for the newer RBC arm and 560 subjects evaluable for the older RBC arm. (Subjects were evaluable if they underwent surgery and received at least 1 RBC unit.) The median patient age was 73 and 72 years, respectively, and males made up 42% and 44% of the patients, respectively.

The same percentage of patients in each arm—96%—underwent cardiopulmonary bypass, and 23% of patients in each arm underwent coronary artery bypass grafting. Seventeen percent of patients in the newer RBC arm and 14% in the older RBC arm underwent valve surgery only.

“Red cells were leukoreduced, stored in additive solution, and provided according to storage duration arm assignment for all pre-op, post-op, and intra-operative transfusions through day 28, discharge, or death, whichever occurred first,” Dr Stein noted.

The number of RBC units did not differ significantly between the two arms (P=0.80), and there was a comparable number of highly transfused subjects in each arm (P=0.81).

Eighty-seven percent of patients in the newer RBC arm and 89% in the older RBC arm received all their RBC units as assigned (P=0.35).

Six percent and 8%, respectively, received 1 or more unit aged 11 to 20 days but none belonging to the opposite arm to which they were assigned. Five percent and 4%, respectively, received 1 or more RBC unit from the opposite arm to which they were assigned.

“There was a 20-day difference in the mean storage duration between the two arms: 8 vs 28 days,” Dr Stein pointed out.

Outcomes

The study’s primary outcome was the change in multi-organ dysfunction score (ΔMODS) at 7 days. The MODS system includes assessments of respiratory, renal, hepatic, cardiovascular, hematologic, and neurologic function.

“The MODS system was chosen as the primary endpoint because the data elements are objective and readily available,” Dr Stein said. “MODS also incorporates organ dysfunction and not just frank organ failure. It correlates with mortality, with length of stay, and does incorporate death. MODS has been validated in other studies and has been used in other transfusion trials, including TRICC.”

To calculate 7-day ΔMODS, the researchers identified the worst score for each organ system through day 7 after surgery, discharge, or death. The 7-day MODS was the sum of the worst score for each organ system, and the 7-day ΔMODS was the pre-surgery MODS subtracted from the 7-day MODS.

Secondary outcomes were the 28-day ΔMODS, 28-day mortality, and the incidence of serious adverse events.

There was no significant difference between the arms with regard to 7-day or 28-day ΔMODS.

For the 7-day ΔMODS, the mean was 8.5±3.6 in the newer RBC arm and 8.7±3.6 in the older RBC arm. The unadjusted difference and the difference adjusted for baseline MODS were both -0.02.

For the 28-day ΔMODS, the mean was 8.7±4.0 in the newer RBC arm and 9.1±4.2 in the older RBC arm. The unadjusted difference and the difference adjusted for baseline MODS were both -0.3.

There was no significant difference between the arms in time to death (P=0.50), 7-day mortality (P=0.43), or 28-day mortality (P=0.57). The rate of 7-day mortality was 2.8% in the newer RBC arm and 2.0% in the older RBC arm. The 28-day mortality was 4.4% and 5.3%, respectively.

There was no significant difference in the percentage of subjects with 1 or more serious adverse events. The rate was 53% in the newer RBC arm and 51% in the older RBC arm (P=0.72).

Taking these results together, Dr Stein concluded that differences in the storage duration of RBCs did not translate to significant differences in “key clinical outcomes.”

Blood for transfusion

Credit: UAB Hospital

PHILADELPHIA—As the medical community continues to debate whether transfusing older blood has a negative outcome on patients, results of the RECESS trial add fuel to the fire.

The study showed no significant differences in clinical outcomes between cardiac surgery patients who received newer red blood cells (RBCs) and those who received older RBCs.

There were no differences in multi-organ dysfunction scores (MODS), mortality rates, or the incidence of serious adverse events.

Marie E. Stein, MD, of the University of Minnesota in Minneapolis, presented the results of RECESS at the AABB Annual Meeting 2014 (abstract P2-020A).

The findings contradict results from another recent study presented at the Canadian Cardiovascular Congress.

“There are many studies of the effects of red blood cell storage duration on clinical outcomes, most of which are observational and include only a few randomized trials to date,” Dr Stein noted. “When studying cardiac surgery patients, some studies have found significant adverse outcomes of subjects who are transfused with red cells stored for a longer duration compared to shorter duration, and other studies have not.”

“Based on this equipoise, the primary hypothesis for RECESS was that there would be an important difference between the effect of transfusing shorter-storage-age-duration red cells compared to transfusing longer-storage-age-duration red cells on clinical outcomes in cardiac surgery patients.”

Patient characteristics

Dr Stein and her colleagues enrolled 1481 patients who were 12 years of age and older, weighed 40 kg or more, were undergoing complex cardiac surgery, and were considered “highly likely” to be transfused. They had to have a TRUST score of 3 or greater if they were older than 18 years of age, but this was not required for children.

Patients were split into two groups: those set to receive RBCs stored for 10 days or fewer and those set to receive RBCs stored for 21 days or more. Patients were stratified by age (those 12 to 17 years vs patients 18 and older) and according to whether they were in the intensive care unit prior to surgery. They were balanced by site as well.

In all, there were 538 subjects evaluable for the newer RBC arm and 560 subjects evaluable for the older RBC arm. (Subjects were evaluable if they underwent surgery and received at least 1 RBC unit.) The median patient age was 73 and 72 years, respectively, and males made up 42% and 44% of the patients, respectively.

The same percentage of patients in each arm—96%—underwent cardiopulmonary bypass, and 23% of patients in each arm underwent coronary artery bypass grafting. Seventeen percent of patients in the newer RBC arm and 14% in the older RBC arm underwent valve surgery only.

“Red cells were leukoreduced, stored in additive solution, and provided according to storage duration arm assignment for all pre-op, post-op, and intra-operative transfusions through day 28, discharge, or death, whichever occurred first,” Dr Stein noted.

The number of RBC units did not differ significantly between the two arms (P=0.80), and there was a comparable number of highly transfused subjects in each arm (P=0.81).

Eighty-seven percent of patients in the newer RBC arm and 89% in the older RBC arm received all their RBC units as assigned (P=0.35).

Six percent and 8%, respectively, received 1 or more unit aged 11 to 20 days but none belonging to the opposite arm to which they were assigned. Five percent and 4%, respectively, received 1 or more RBC unit from the opposite arm to which they were assigned.

“There was a 20-day difference in the mean storage duration between the two arms: 8 vs 28 days,” Dr Stein pointed out.

Outcomes

The study’s primary outcome was the change in multi-organ dysfunction score (ΔMODS) at 7 days. The MODS system includes assessments of respiratory, renal, hepatic, cardiovascular, hematologic, and neurologic function.

“The MODS system was chosen as the primary endpoint because the data elements are objective and readily available,” Dr Stein said. “MODS also incorporates organ dysfunction and not just frank organ failure. It correlates with mortality, with length of stay, and does incorporate death. MODS has been validated in other studies and has been used in other transfusion trials, including TRICC.”

To calculate 7-day ΔMODS, the researchers identified the worst score for each organ system through day 7 after surgery, discharge, or death. The 7-day MODS was the sum of the worst score for each organ system, and the 7-day ΔMODS was the pre-surgery MODS subtracted from the 7-day MODS.

Secondary outcomes were the 28-day ΔMODS, 28-day mortality, and the incidence of serious adverse events.

There was no significant difference between the arms with regard to 7-day or 28-day ΔMODS.

For the 7-day ΔMODS, the mean was 8.5±3.6 in the newer RBC arm and 8.7±3.6 in the older RBC arm. The unadjusted difference and the difference adjusted for baseline MODS were both -0.02.

For the 28-day ΔMODS, the mean was 8.7±4.0 in the newer RBC arm and 9.1±4.2 in the older RBC arm. The unadjusted difference and the difference adjusted for baseline MODS were both -0.3.

There was no significant difference between the arms in time to death (P=0.50), 7-day mortality (P=0.43), or 28-day mortality (P=0.57). The rate of 7-day mortality was 2.8% in the newer RBC arm and 2.0% in the older RBC arm. The 28-day mortality was 4.4% and 5.3%, respectively.

There was no significant difference in the percentage of subjects with 1 or more serious adverse events. The rate was 53% in the newer RBC arm and 51% in the older RBC arm (P=0.72).

Taking these results together, Dr Stein concluded that differences in the storage duration of RBCs did not translate to significant differences in “key clinical outcomes.”

Obese mouse

Immunotherapy that can be effective against tumors in young, thin mice can be lethal to obese ones, according to research published in The Journal of Experimental Medicine.

Investigators conducted experiments in mouse models to determine if there is a subset of cancer patients for whom certain immunotherapies might be especially toxic.

The group found a potential link between body fat and the risk of toxicity from some types of immunotherapy.

“Cancer is primarily considered a disease of the aged, and yet preclinical studies generally use young, lean animal models that may not be reflective of the ‘typical’ cancer patient,” said study author Annie Mirsoian, a PhD candidate at the University of California, Davis in Sacramento.

“Aging is a dynamic process that is characterized by increases in inflammatory factors, as well as a shift in body composition where there is a gradual loss of lean muscle mass and an increase in fat accumulation, which effect how the immune system functions.”

Mirsoian and her colleagues sought to determine if, by adjusting the mouse model to more closely reflect the cancer patient phenotype (advanced age and overweight), they could better understand the discrepancies between animal study outcomes and those in patients in the clinic.

So the team examined aged mice on standard diets and compared those to aged mice that were calorie-restricted throughout their lives.

The investigators found that calorie restriction plays a protective role against toxicity. When aged mice ate their standard diet freely throughout life, they became obese and ultimately experienced lethal adverse reactions after receiving a systemic immunotherapy regimen.

“We know that people who are obese in general are at higher risk for complications from surgery, radiation, and chemotherapy,” said study author Arta Monjazeb, MD, PhD, of the University of California, Davis.

“We know that obese people have higher levels of inflammatory markers in their blood, but there is a lack of data examining the effects of obesity on cancer treatment outcomes.”

In follow-up experiments, the investigators found that young mice that are obese also endure similar toxic consequences, demonstrating that fat is a critical factor in toxic responses to stimulatory anticancer immunotherapy regimens.

“It is important to note, however, that the aged mice on standard diets succumbed to lethality at a quicker rate than young obese mice,” Mirsoian said. “Although our data demonstrate that obesity plays a central role in the development of adverse effects, future studies will focus on examining the aged immune system and cellular characteristics that may have enhanced the sensitivity of these mice to inflammation.”

This study follows an earlier paper, which demonstrated that while young, lean mice tolerate immunotherapy regimens without toxicity, the same regimen for an aged cohort resulted in lethal consequences. The new paper takes a deeper look into how fat deposition throughout aging can be critical in determining treatment tolerance and efficacy.

“Obesity has become an epidemic in our society and is now also affecting younger populations,” Mirsoian said. “Therefore, it’s likely that what the ‘typical’ cancer patient looks like will change. Our findings demonstrate the importance of having preclinical animal models that reflect the clinical scenario.”

“Changing the characteristics of our mouse models allowed for a more accurate determination of possible adverse reactions to therapy and more closely modeled what has been reported in the clinic with stimulatory immunotherapies.”

The investigators said factors like age, fat content, and the types of infections experienced throughout life together shape how the immune system reacts, and they will continue to work on improving their modeling system to reflect these changes.

They project that improvements in mouse modeling may help produce data that can better modulate treatment choices for patients, as well as identify early which patients would benefit from the inclusion of drugs to prevent adverse reactions while maintaining anticancer efficacy.

Obese mouse

Immunotherapy that can be effective against tumors in young, thin mice can be lethal to obese ones, according to research published in The Journal of Experimental Medicine.

Investigators conducted experiments in mouse models to determine if there is a subset of cancer patients for whom certain immunotherapies might be especially toxic.

The group found a potential link between body fat and the risk of toxicity from some types of immunotherapy.

“Cancer is primarily considered a disease of the aged, and yet preclinical studies generally use young, lean animal models that may not be reflective of the ‘typical’ cancer patient,” said study author Annie Mirsoian, a PhD candidate at the University of California, Davis in Sacramento.

“Aging is a dynamic process that is characterized by increases in inflammatory factors, as well as a shift in body composition where there is a gradual loss of lean muscle mass and an increase in fat accumulation, which effect how the immune system functions.”

Mirsoian and her colleagues sought to determine if, by adjusting the mouse model to more closely reflect the cancer patient phenotype (advanced age and overweight), they could better understand the discrepancies between animal study outcomes and those in patients in the clinic.

So the team examined aged mice on standard diets and compared those to aged mice that were calorie-restricted throughout their lives.

The investigators found that calorie restriction plays a protective role against toxicity. When aged mice ate their standard diet freely throughout life, they became obese and ultimately experienced lethal adverse reactions after receiving a systemic immunotherapy regimen.

“We know that people who are obese in general are at higher risk for complications from surgery, radiation, and chemotherapy,” said study author Arta Monjazeb, MD, PhD, of the University of California, Davis.

“We know that obese people have higher levels of inflammatory markers in their blood, but there is a lack of data examining the effects of obesity on cancer treatment outcomes.”

In follow-up experiments, the investigators found that young mice that are obese also endure similar toxic consequences, demonstrating that fat is a critical factor in toxic responses to stimulatory anticancer immunotherapy regimens.

“It is important to note, however, that the aged mice on standard diets succumbed to lethality at a quicker rate than young obese mice,” Mirsoian said. “Although our data demonstrate that obesity plays a central role in the development of adverse effects, future studies will focus on examining the aged immune system and cellular characteristics that may have enhanced the sensitivity of these mice to inflammation.”

This study follows an earlier paper, which demonstrated that while young, lean mice tolerate immunotherapy regimens without toxicity, the same regimen for an aged cohort resulted in lethal consequences. The new paper takes a deeper look into how fat deposition throughout aging can be critical in determining treatment tolerance and efficacy.

“Obesity has become an epidemic in our society and is now also affecting younger populations,” Mirsoian said. “Therefore, it’s likely that what the ‘typical’ cancer patient looks like will change. Our findings demonstrate the importance of having preclinical animal models that reflect the clinical scenario.”

“Changing the characteristics of our mouse models allowed for a more accurate determination of possible adverse reactions to therapy and more closely modeled what has been reported in the clinic with stimulatory immunotherapies.”

The investigators said factors like age, fat content, and the types of infections experienced throughout life together shape how the immune system reacts, and they will continue to work on improving their modeling system to reflect these changes.

They project that improvements in mouse modeling may help produce data that can better modulate treatment choices for patients, as well as identify early which patients would benefit from the inclusion of drugs to prevent adverse reactions while maintaining anticancer efficacy.

Obese mouse

Immunotherapy that can be effective against tumors in young, thin mice can be lethal to obese ones, according to research published in The Journal of Experimental Medicine.

Investigators conducted experiments in mouse models to determine if there is a subset of cancer patients for whom certain immunotherapies might be especially toxic.

The group found a potential link between body fat and the risk of toxicity from some types of immunotherapy.

“Cancer is primarily considered a disease of the aged, and yet preclinical studies generally use young, lean animal models that may not be reflective of the ‘typical’ cancer patient,” said study author Annie Mirsoian, a PhD candidate at the University of California, Davis in Sacramento.

“Aging is a dynamic process that is characterized by increases in inflammatory factors, as well as a shift in body composition where there is a gradual loss of lean muscle mass and an increase in fat accumulation, which effect how the immune system functions.”

Mirsoian and her colleagues sought to determine if, by adjusting the mouse model to more closely reflect the cancer patient phenotype (advanced age and overweight), they could better understand the discrepancies between animal study outcomes and those in patients in the clinic.

So the team examined aged mice on standard diets and compared those to aged mice that were calorie-restricted throughout their lives.

The investigators found that calorie restriction plays a protective role against toxicity. When aged mice ate their standard diet freely throughout life, they became obese and ultimately experienced lethal adverse reactions after receiving a systemic immunotherapy regimen.

“We know that people who are obese in general are at higher risk for complications from surgery, radiation, and chemotherapy,” said study author Arta Monjazeb, MD, PhD, of the University of California, Davis.

“We know that obese people have higher levels of inflammatory markers in their blood, but there is a lack of data examining the effects of obesity on cancer treatment outcomes.”

In follow-up experiments, the investigators found that young mice that are obese also endure similar toxic consequences, demonstrating that fat is a critical factor in toxic responses to stimulatory anticancer immunotherapy regimens.

“It is important to note, however, that the aged mice on standard diets succumbed to lethality at a quicker rate than young obese mice,” Mirsoian said. “Although our data demonstrate that obesity plays a central role in the development of adverse effects, future studies will focus on examining the aged immune system and cellular characteristics that may have enhanced the sensitivity of these mice to inflammation.”

This study follows an earlier paper, which demonstrated that while young, lean mice tolerate immunotherapy regimens without toxicity, the same regimen for an aged cohort resulted in lethal consequences. The new paper takes a deeper look into how fat deposition throughout aging can be critical in determining treatment tolerance and efficacy.

“Obesity has become an epidemic in our society and is now also affecting younger populations,” Mirsoian said. “Therefore, it’s likely that what the ‘typical’ cancer patient looks like will change. Our findings demonstrate the importance of having preclinical animal models that reflect the clinical scenario.”

“Changing the characteristics of our mouse models allowed for a more accurate determination of possible adverse reactions to therapy and more closely modeled what has been reported in the clinic with stimulatory immunotherapies.”

The investigators said factors like age, fat content, and the types of infections experienced throughout life together shape how the immune system reacts, and they will continue to work on improving their modeling system to reflect these changes.

They project that improvements in mouse modeling may help produce data that can better modulate treatment choices for patients, as well as identify early which patients would benefit from the inclusion of drugs to prevent adverse reactions while maintaining anticancer efficacy.