Jen Smith

Marko Lucijanić, MD, PhD

DUBROVNIK, CROATIA—The Glasgow Prognostic Score (GPS) may predict survival in patients with myelofibrosis (MF), according to research presented at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

In a retrospective study, MF patients who were considered intermediate-risk according to the GPS had roughly twice the risk of death as good-risk patients.

High-risk patients had a nearly 24-fold greater risk of death than good-risk patients.

Marko Lucijanić, MD, PhD, of the University Hospital Dubrava in Zagreb, Croatia, presented these findings at the meeting. Results were also published in a recent issue of Blood Cells, Molecules, and Diseases.¹

Dr. Lucijanić and his colleagues analyzed 88 patients—67 with primary MF and 21 with secondary MF—who were treated at the University Hospital Dubrava from 2004 to 2018.

Patients were divided into GPS risk categories:

• Good-risk patients had C reactive protein (CRP) ≤10 mg/L and albumin ≥35 g/L
• Intermediate-risk patients had either CRP >10 mg/L or albumin <35 g/L
• Poor-risk patients had both CRP >10 mg/L and albumin <35 g/L.

Results

The researchers found that CRP and albumin were independent predictors of overall survival (OS) in MF.

“What we saw is that both CRP and albumin were univariately associated with inferior overall survival when the patients were divided at the proposed cutoff levels,” Dr. Lucijanić said.

“And both CRP and albumin remained statistically significant when analyzed together in a Cox regression model additionally adjusted for DIPPS [Dynamic International Prognostic Scoring System].”

In the univariate analysis, the hazard ratio (HR) for death was 3.42 (P<0.001) for patients with CRP >10 mg/L and 4.68 (P<0.001) for patients with albumin <35 g/L.

In a multivariate analysis, the HR for death was 2.49 (P=0.013) for patients with CRP >10 mg/L and 2.74 (P=0.031) for patients with albumin <35 g/L.

“So no surprise that, when [CRP and albumin were] combined into the Glasgow Prognostic Score, the GPS could identify three subgroups of patients with distinct prognosis,” Dr. Lucijanić said.

When the researchers assessed OS according to GPS, they found the HR for death was:

• 2.77 for intermediate-risk patients compared to good-risk patients (P<0.001).
• 15.78 for poor-risk patients compared to good-risk patients (P<0.001).
• 5.82 for poor-risk patients compared to intermediate-risk patients (P<0.001).

In a Cox-regression model for OS that was adjusted for DIPPS, age, and gender, the HR was:

• 2.08 for intermediate-risk patients compared to good-risk patients (P=0.040)
• 23.52 for poor-risk patients compared to good-risk patients (P<0.001).

Dr. Lucijanić noted that patients who were intermediate- or poor-risk according to the GPS were more likely to have symptoms of aggressive disease that are associated with non-response to JAK inhibitors.

The intermediate- or poor-risk patients were more likely to have constitutional symptoms, massive splenomegaly, blast phase disease, circulatory blasts, higher absolute monocyte counts, lower hemoglobin, lower platelets, higher lactate dehydrogenase, higher red cell distribution width, transfusion dependency, and higher ferritin. The patients also had higher DIPSS scores.

“So, to summarize, higher GPS recognizes patients with more aggressive disease features at a higher risk of death,” Dr. Lucijanić said. “And not only does it discriminate survival of myelofibrosis patients, it seems to do so in a DIPPS-independent manner. However, you should be aware that this is a small, retrospective study from a single center with a very long follow-up period during which patients were exposed to different types of therapies.”

Dr. Lucijanić did not declare any conflicts of interest.

1. Lucijanić M et al. Blood Cells Mol Dis. 2018 Sep;72:14-16. doi: 10.1016/j.bcmd.2018.06.001.

Marko Lucijanić, MD, PhD

DUBROVNIK, CROATIA—The Glasgow Prognostic Score (GPS) may predict survival in patients with myelofibrosis (MF), according to research presented at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

In a retrospective study, MF patients who were considered intermediate-risk according to the GPS had roughly twice the risk of death as good-risk patients.

High-risk patients had a nearly 24-fold greater risk of death than good-risk patients.

Marko Lucijanić, MD, PhD, of the University Hospital Dubrava in Zagreb, Croatia, presented these findings at the meeting. Results were also published in a recent issue of Blood Cells, Molecules, and Diseases.¹

Dr. Lucijanić and his colleagues analyzed 88 patients—67 with primary MF and 21 with secondary MF—who were treated at the University Hospital Dubrava from 2004 to 2018.

Patients were divided into GPS risk categories:

• Good-risk patients had C reactive protein (CRP) ≤10 mg/L and albumin ≥35 g/L
• Intermediate-risk patients had either CRP >10 mg/L or albumin <35 g/L
• Poor-risk patients had both CRP >10 mg/L and albumin <35 g/L.

Results

The researchers found that CRP and albumin were independent predictors of overall survival (OS) in MF.

“What we saw is that both CRP and albumin were univariately associated with inferior overall survival when the patients were divided at the proposed cutoff levels,” Dr. Lucijanić said.

“And both CRP and albumin remained statistically significant when analyzed together in a Cox regression model additionally adjusted for DIPPS [Dynamic International Prognostic Scoring System].”

In the univariate analysis, the hazard ratio (HR) for death was 3.42 (P<0.001) for patients with CRP >10 mg/L and 4.68 (P<0.001) for patients with albumin <35 g/L.

In a multivariate analysis, the HR for death was 2.49 (P=0.013) for patients with CRP >10 mg/L and 2.74 (P=0.031) for patients with albumin <35 g/L.

“So no surprise that, when [CRP and albumin were] combined into the Glasgow Prognostic Score, the GPS could identify three subgroups of patients with distinct prognosis,” Dr. Lucijanić said.

When the researchers assessed OS according to GPS, they found the HR for death was:

• 2.77 for intermediate-risk patients compared to good-risk patients (P<0.001).
• 15.78 for poor-risk patients compared to good-risk patients (P<0.001).
• 5.82 for poor-risk patients compared to intermediate-risk patients (P<0.001).

In a Cox-regression model for OS that was adjusted for DIPPS, age, and gender, the HR was:

• 2.08 for intermediate-risk patients compared to good-risk patients (P=0.040)
• 23.52 for poor-risk patients compared to good-risk patients (P<0.001).

Dr. Lucijanić noted that patients who were intermediate- or poor-risk according to the GPS were more likely to have symptoms of aggressive disease that are associated with non-response to JAK inhibitors.

The intermediate- or poor-risk patients were more likely to have constitutional symptoms, massive splenomegaly, blast phase disease, circulatory blasts, higher absolute monocyte counts, lower hemoglobin, lower platelets, higher lactate dehydrogenase, higher red cell distribution width, transfusion dependency, and higher ferritin. The patients also had higher DIPSS scores.

“So, to summarize, higher GPS recognizes patients with more aggressive disease features at a higher risk of death,” Dr. Lucijanić said. “And not only does it discriminate survival of myelofibrosis patients, it seems to do so in a DIPPS-independent manner. However, you should be aware that this is a small, retrospective study from a single center with a very long follow-up period during which patients were exposed to different types of therapies.”

Dr. Lucijanić did not declare any conflicts of interest.

1. Lucijanić M et al. Blood Cells Mol Dis. 2018 Sep;72:14-16. doi: 10.1016/j.bcmd.2018.06.001.

Marko Lucijanić, MD, PhD

DUBROVNIK, CROATIA—The Glasgow Prognostic Score (GPS) may predict survival in patients with myelofibrosis (MF), according to research presented at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

In a retrospective study, MF patients who were considered intermediate-risk according to the GPS had roughly twice the risk of death as good-risk patients.

High-risk patients had a nearly 24-fold greater risk of death than good-risk patients.

Marko Lucijanić, MD, PhD, of the University Hospital Dubrava in Zagreb, Croatia, presented these findings at the meeting. Results were also published in a recent issue of Blood Cells, Molecules, and Diseases.¹

Dr. Lucijanić and his colleagues analyzed 88 patients—67 with primary MF and 21 with secondary MF—who were treated at the University Hospital Dubrava from 2004 to 2018.

Patients were divided into GPS risk categories:

• Good-risk patients had C reactive protein (CRP) ≤10 mg/L and albumin ≥35 g/L
• Intermediate-risk patients had either CRP >10 mg/L or albumin <35 g/L
• Poor-risk patients had both CRP >10 mg/L and albumin <35 g/L.

Results

The researchers found that CRP and albumin were independent predictors of overall survival (OS) in MF.

“What we saw is that both CRP and albumin were univariately associated with inferior overall survival when the patients were divided at the proposed cutoff levels,” Dr. Lucijanić said.

“And both CRP and albumin remained statistically significant when analyzed together in a Cox regression model additionally adjusted for DIPPS [Dynamic International Prognostic Scoring System].”

In the univariate analysis, the hazard ratio (HR) for death was 3.42 (P<0.001) for patients with CRP >10 mg/L and 4.68 (P<0.001) for patients with albumin <35 g/L.

In a multivariate analysis, the HR for death was 2.49 (P=0.013) for patients with CRP >10 mg/L and 2.74 (P=0.031) for patients with albumin <35 g/L.

“So no surprise that, when [CRP and albumin were] combined into the Glasgow Prognostic Score, the GPS could identify three subgroups of patients with distinct prognosis,” Dr. Lucijanić said.

When the researchers assessed OS according to GPS, they found the HR for death was:

• 2.77 for intermediate-risk patients compared to good-risk patients (P<0.001).
• 15.78 for poor-risk patients compared to good-risk patients (P<0.001).
• 5.82 for poor-risk patients compared to intermediate-risk patients (P<0.001).

In a Cox-regression model for OS that was adjusted for DIPPS, age, and gender, the HR was:

• 2.08 for intermediate-risk patients compared to good-risk patients (P=0.040)
• 23.52 for poor-risk patients compared to good-risk patients (P<0.001).

Dr. Lucijanić noted that patients who were intermediate- or poor-risk according to the GPS were more likely to have symptoms of aggressive disease that are associated with non-response to JAK inhibitors.

The intermediate- or poor-risk patients were more likely to have constitutional symptoms, massive splenomegaly, blast phase disease, circulatory blasts, higher absolute monocyte counts, lower hemoglobin, lower platelets, higher lactate dehydrogenase, higher red cell distribution width, transfusion dependency, and higher ferritin. The patients also had higher DIPSS scores.

“So, to summarize, higher GPS recognizes patients with more aggressive disease features at a higher risk of death,” Dr. Lucijanić said. “And not only does it discriminate survival of myelofibrosis patients, it seems to do so in a DIPPS-independent manner. However, you should be aware that this is a small, retrospective study from a single center with a very long follow-up period during which patients were exposed to different types of therapies.”

Dr. Lucijanić did not declare any conflicts of interest.

1. Lucijanić M et al. Blood Cells Mol Dis. 2018 Sep;72:14-16. doi: 10.1016/j.bcmd.2018.06.001.

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Audience at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice

DUBROVNIK, CROATIA—An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.

The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients.

Researchers found the updated ThroLy had a positive predictive value of 22% to 25%, a negative predictive value of 96%, sensitivity of 56% to 57%, and specificity of 85% to 87%.

Darko Antić, MD, PhD, of the University of Belgrade in Serbia, presented these findings at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Antić said he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients, and the Khorana score is predominantly for solid tumor malignancies.

“It’s good . . . , but it’s not specific for lymphoma patients,” Dr. Antić said.

With this in mind, he and his colleagues developed ThroLy. They based the scoring system on variables used in the Padua and Khorana systems as well as variables that are specific to lymphoma patients.

In a past study*, the researchers found several variables that were independently associated with risk for VTE in lymphoma:

• Previous VTE
• Previous acute myocardial infarction/stroke
• Mediastinal involvement
• Body mass index > 30 kg/m²
• Reduced mobility
• Extranodal localization
• Development of neutropenia
• Hemoglobin level < 100g/L.

Previous VTE, previous acute myocardial infarction/stroke, obesity, and mediastinal involvement were all worth 2 points, and the other factors were worth a single point.

Patients with scores of 0 to 1 were considered low-risk, patients with scores of 2 to 3 were considered intermediate-risk, and patients with scores of 4 or greater were considered high-risk.

Prospective validation

To validate and refine ThroLy, Dr. Antić and his colleagues used it to assess 1723 lymphoma patients treated at 8 institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.

Patients had indolent non-Hodgkin lymphoma (n=467), aggressive non-Hodgkin lymphoma (n=647), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=235), and Hodgkin lymphoma (n=366). Most subjects (84%) were outpatients.

Nine percent of patients had thrombosis (n=142), with 7% having VTE (n=121).

ThroLy had a positive predictive value of 17%, compared to 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively.

The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua. The specificity was 72%, 64%, and 52%, respectively.

“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antić noted.

Updated models

To further improve ThroLy, the researchers updated the system, creating two new models.

Model 1 included the following variables:

• Type of lymphoma/clinical stage (aggressive/advanced)—1 point
• Previous VTE—5 points
• Reduced mobility—2 points
• Hemoglobin level < 100 g/L—1 point
• Presence of vascular devices—1 point.

Model 2 included all of the aforementioned variables as well as thrombophilic condition, which was worth 1 point.

With these models, patients were divided into two risk groups—low-risk (≤ 2 points) and high-risk (>2 points).

For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%.

For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.

Dr. Antić said there were no major differences in model discrimination and calibration according to the country in which a patient was treated or whether patients were treated in inpatient or outpatient settings.

Dr. Antić did not report any conflicts of interest.

*Antić D et al. Am J Hematol. 2016 Oct;91(10):1014-9. doi: 10.1002/ajh.24466.

Audience at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice

DUBROVNIK, CROATIA—An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.

The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients.

Researchers found the updated ThroLy had a positive predictive value of 22% to 25%, a negative predictive value of 96%, sensitivity of 56% to 57%, and specificity of 85% to 87%.

Darko Antić, MD, PhD, of the University of Belgrade in Serbia, presented these findings at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Antić said he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients, and the Khorana score is predominantly for solid tumor malignancies.

“It’s good . . . , but it’s not specific for lymphoma patients,” Dr. Antić said.

With this in mind, he and his colleagues developed ThroLy. They based the scoring system on variables used in the Padua and Khorana systems as well as variables that are specific to lymphoma patients.

In a past study*, the researchers found several variables that were independently associated with risk for VTE in lymphoma:

• Previous VTE
• Previous acute myocardial infarction/stroke
• Mediastinal involvement
• Body mass index > 30 kg/m²
• Reduced mobility
• Extranodal localization
• Development of neutropenia
• Hemoglobin level < 100g/L.

Previous VTE, previous acute myocardial infarction/stroke, obesity, and mediastinal involvement were all worth 2 points, and the other factors were worth a single point.

Patients with scores of 0 to 1 were considered low-risk, patients with scores of 2 to 3 were considered intermediate-risk, and patients with scores of 4 or greater were considered high-risk.

Prospective validation

To validate and refine ThroLy, Dr. Antić and his colleagues used it to assess 1723 lymphoma patients treated at 8 institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.

Patients had indolent non-Hodgkin lymphoma (n=467), aggressive non-Hodgkin lymphoma (n=647), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=235), and Hodgkin lymphoma (n=366). Most subjects (84%) were outpatients.

Nine percent of patients had thrombosis (n=142), with 7% having VTE (n=121).

ThroLy had a positive predictive value of 17%, compared to 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively.

The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua. The specificity was 72%, 64%, and 52%, respectively.

“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antić noted.

Updated models

To further improve ThroLy, the researchers updated the system, creating two new models.

Model 1 included the following variables:

• Type of lymphoma/clinical stage (aggressive/advanced)—1 point
• Previous VTE—5 points
• Reduced mobility—2 points
• Hemoglobin level < 100 g/L—1 point
• Presence of vascular devices—1 point.

Model 2 included all of the aforementioned variables as well as thrombophilic condition, which was worth 1 point.

With these models, patients were divided into two risk groups—low-risk (≤ 2 points) and high-risk (>2 points).

For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%.

For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.

Dr. Antić said there were no major differences in model discrimination and calibration according to the country in which a patient was treated or whether patients were treated in inpatient or outpatient settings.

Dr. Antić did not report any conflicts of interest.

*Antić D et al. Am J Hematol. 2016 Oct;91(10):1014-9. doi: 10.1002/ajh.24466.

Audience at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice

DUBROVNIK, CROATIA—An updated scoring system can more accurately identify lymphoma patients who may require thromboprophylaxis, according to researchers.

The revised scoring system, ThroLy, proved more effective than other systems for predicting thromboembolic events in lymphoma patients.

Researchers found the updated ThroLy had a positive predictive value of 22% to 25%, a negative predictive value of 96%, sensitivity of 56% to 57%, and specificity of 85% to 87%.

Darko Antić, MD, PhD, of the University of Belgrade in Serbia, presented these findings at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Antić said he and his colleagues developed ThroLy because other systems used to predict venous thromboembolism (VTE) are not quite right for lymphoma. He noted that the Padua score is not designed for cancer patients, and the Khorana score is predominantly for solid tumor malignancies.

“It’s good . . . , but it’s not specific for lymphoma patients,” Dr. Antić said.

With this in mind, he and his colleagues developed ThroLy. They based the scoring system on variables used in the Padua and Khorana systems as well as variables that are specific to lymphoma patients.

In a past study*, the researchers found several variables that were independently associated with risk for VTE in lymphoma:

• Previous VTE
• Previous acute myocardial infarction/stroke
• Mediastinal involvement
• Body mass index > 30 kg/m²
• Reduced mobility
• Extranodal localization
• Development of neutropenia
• Hemoglobin level < 100g/L.

Previous VTE, previous acute myocardial infarction/stroke, obesity, and mediastinal involvement were all worth 2 points, and the other factors were worth a single point.

Patients with scores of 0 to 1 were considered low-risk, patients with scores of 2 to 3 were considered intermediate-risk, and patients with scores of 4 or greater were considered high-risk.

Prospective validation

To validate and refine ThroLy, Dr. Antić and his colleagues used it to assess 1723 lymphoma patients treated at 8 institutions in Austria, Croatia, France, Jordan, Macedonia, Spain, Switzerland, and the United States.

Patients had indolent non-Hodgkin lymphoma (n=467), aggressive non-Hodgkin lymphoma (n=647), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=235), and Hodgkin lymphoma (n=366). Most subjects (84%) were outpatients.

Nine percent of patients had thrombosis (n=142), with 7% having VTE (n=121).

ThroLy had a positive predictive value of 17%, compared to 11% with Khorana and 13% with Padua. The negative predictive value was 93%, 92%, and 95%, respectively.

The sensitivity was 51% with ThroLy, 42% with Khorana, and 70% with Padua. The specificity was 72%, 64%, and 52%, respectively.

“The positive predictive value was low [with ThroLy] but definitely higher than the positive predictive value of the other two [scoring systems],” Dr. Antić noted.

Updated models

To further improve ThroLy, the researchers updated the system, creating two new models.

Model 1 included the following variables:

• Type of lymphoma/clinical stage (aggressive/advanced)—1 point
• Previous VTE—5 points
• Reduced mobility—2 points
• Hemoglobin level < 100 g/L—1 point
• Presence of vascular devices—1 point.

Model 2 included all of the aforementioned variables as well as thrombophilic condition, which was worth 1 point.

With these models, patients were divided into two risk groups—low-risk (≤ 2 points) and high-risk (>2 points).

For Model 1, the positive predictive value was 22%, the negative predictive value was 96%, the sensitivity was 56%, and the specificity was 85%.

For Model 2, the positive predictive value was 25%, the negative predictive value was 96%, the sensitivity was 57%, and the specificity was 87%.

Dr. Antić said there were no major differences in model discrimination and calibration according to the country in which a patient was treated or whether patients were treated in inpatient or outpatient settings.

Dr. Antić did not report any conflicts of interest.

*Antić D et al. Am J Hematol. 2016 Oct;91(10):1014-9. doi: 10.1002/ajh.24466.

Photo from EHA

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

The trial was sponsored by Stemline Therapeutics.

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

Efficacy

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

Safety

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

Next steps

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”

Photo from EHA

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

The trial was sponsored by Stemline Therapeutics.

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

Efficacy

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

Safety

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

Next steps

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”

Photo from EHA

STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.

Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.

Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).

Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.

The trial was sponsored by Stemline Therapeutics.

Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.

“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”

And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.

With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.

The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.

Efficacy

Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.

Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.

Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.

“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.

The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.

Safety

Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.

“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.

Next steps

The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.

Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.

Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.

“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”

The 23rd Congress of the European Hematology Association

STOCKHOLM—Follow-up data suggest that ropeginterferon alfa-2b (ropeg) provides an advantage over hydroxyurea (HU) for patients with polycythemia vera (PV), regardless of their age.

Two-year results from an extension study have shown that, compared to HU, ropeg produces higher rates of complete hematologic response (CHR) and molecular response (MR) in PV patients, including patients age 60 and older.

Additionally, rates of adverse events (AEs) and serious AEs were similar between the ropeg and HU arms.

“In all, I think these data suggest that ropeginterferon alfa-2b provides a valuable, efficacious, and safe new treatment option for PV patients of all ages, including those older than 60 years,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis, Université Paris Diderot in Paris, France.

Dr Kiladjian presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S132.

The research was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Kiladjian presented data from CONTINUATION-PV, an extension trial of PROUD-PV. Results from PROUD-PV were presented at the 2016 ASH Annual Meeting.

PROUD-PV enrolled 254 patients who were treatment-naive or pretreated with HU. They were randomized to receive ropeg (n=127) or HU (n=127).

CONTINUATION-PV included 95 of the patients on ropeg and 76 of the patients on HU. Dr Kiladjian noted that baseline characteristics were similar between these groups.

CHR

At 24 months, the rate of CHR was 70.5% (67/95) in the ropeg arm and 49.3% (33/67) in the HU arm (RR=1.42, P<0.05).

In patients younger than 60, the rate of CHR was 77.6% in the ropeg arm and 55.9% in the HU arm. In patients age 60 and older, rates of CHR were 63% and 42.4%, respectively.

Dr Kiladjian noted that CHR rates increased over time in ropeg recipients. In PROUD-PV, CHR rates were similar between the ropeg and HU arms at 12 months. However, at 24 months, the CHR rates were higher in ropeg recipients.

Ropeg recipients were also more likely than HU recipients to maintain their CHR from the first occurrence to 24 months.

In patients younger than 60, 49% of the ropeg arm and 17.9% of the HU arm maintained a CHR (P<0.001). In patients age 60 and older, rates of CHR maintenance were 37% and 18.9%, respectively.

MR and JAK2V617F allele burden

Rates of MR at 24 months were 68.1% (64/94) in the ropeg arm and 34.7% (26/75) in the HU arm (RR=1.85, P<0.01).

In patients younger than 60, the rate of MR was 77.1% in the ropeg arm and 33.3% in the HU arm (P<0.001). In patients age 60 and older, MR rates were 58.7% and 36.1%, respectively.

For patients younger than 60, the reduction in JAK2V617F allele burden at 12 months was 29.9% in the ropeg arm and 42.3% in the HU arm. At 24 months, the reductions were 54.8% and 4.5%, respectively (P<0.001).

For patients 60 and older, the reduction in JAK2V617F allele burden at 12 months was 25.2% in the ropeg arm and 37.5% in the HU arm. At 24 months, the reductions were 35.1% and 18.4%, respectively.

Safety          

“I think an important point here is the safety because we assume that [ropeg] is not well tolerated in elderly patients,” Dr Kiladjian said. “So what are the results in this prospective, controlled trial? There was a comparable number of adverse events and serious adverse events in the treatment arms, irrespective of age.”

Dr Kiladjian also pointed out that the number of adverse drug reactions (ADRs) was comparable between the treatment arms for younger patients, and there was a trend toward a lower number of ADRs in the ropeg arm for the patients age 60 and older.

The 4 serious ADRs in the HU patients age 60 and older were acute leukemia, anemia, leukopenia, and granulocytopenia.

The 23rd Congress of the European Hematology Association

STOCKHOLM—Follow-up data suggest that ropeginterferon alfa-2b (ropeg) provides an advantage over hydroxyurea (HU) for patients with polycythemia vera (PV), regardless of their age.

Two-year results from an extension study have shown that, compared to HU, ropeg produces higher rates of complete hematologic response (CHR) and molecular response (MR) in PV patients, including patients age 60 and older.

Additionally, rates of adverse events (AEs) and serious AEs were similar between the ropeg and HU arms.

“In all, I think these data suggest that ropeginterferon alfa-2b provides a valuable, efficacious, and safe new treatment option for PV patients of all ages, including those older than 60 years,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis, Université Paris Diderot in Paris, France.

Dr Kiladjian presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S132.

The research was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Kiladjian presented data from CONTINUATION-PV, an extension trial of PROUD-PV. Results from PROUD-PV were presented at the 2016 ASH Annual Meeting.

PROUD-PV enrolled 254 patients who were treatment-naive or pretreated with HU. They were randomized to receive ropeg (n=127) or HU (n=127).

CONTINUATION-PV included 95 of the patients on ropeg and 76 of the patients on HU. Dr Kiladjian noted that baseline characteristics were similar between these groups.

CHR

At 24 months, the rate of CHR was 70.5% (67/95) in the ropeg arm and 49.3% (33/67) in the HU arm (RR=1.42, P<0.05).

In patients younger than 60, the rate of CHR was 77.6% in the ropeg arm and 55.9% in the HU arm. In patients age 60 and older, rates of CHR were 63% and 42.4%, respectively.

Dr Kiladjian noted that CHR rates increased over time in ropeg recipients. In PROUD-PV, CHR rates were similar between the ropeg and HU arms at 12 months. However, at 24 months, the CHR rates were higher in ropeg recipients.

Ropeg recipients were also more likely than HU recipients to maintain their CHR from the first occurrence to 24 months.

In patients younger than 60, 49% of the ropeg arm and 17.9% of the HU arm maintained a CHR (P<0.001). In patients age 60 and older, rates of CHR maintenance were 37% and 18.9%, respectively.

MR and JAK2V617F allele burden

Rates of MR at 24 months were 68.1% (64/94) in the ropeg arm and 34.7% (26/75) in the HU arm (RR=1.85, P<0.01).

In patients younger than 60, the rate of MR was 77.1% in the ropeg arm and 33.3% in the HU arm (P<0.001). In patients age 60 and older, MR rates were 58.7% and 36.1%, respectively.

For patients younger than 60, the reduction in JAK2V617F allele burden at 12 months was 29.9% in the ropeg arm and 42.3% in the HU arm. At 24 months, the reductions were 54.8% and 4.5%, respectively (P<0.001).

For patients 60 and older, the reduction in JAK2V617F allele burden at 12 months was 25.2% in the ropeg arm and 37.5% in the HU arm. At 24 months, the reductions were 35.1% and 18.4%, respectively.

Safety          

“I think an important point here is the safety because we assume that [ropeg] is not well tolerated in elderly patients,” Dr Kiladjian said. “So what are the results in this prospective, controlled trial? There was a comparable number of adverse events and serious adverse events in the treatment arms, irrespective of age.”

Dr Kiladjian also pointed out that the number of adverse drug reactions (ADRs) was comparable between the treatment arms for younger patients, and there was a trend toward a lower number of ADRs in the ropeg arm for the patients age 60 and older.

The 4 serious ADRs in the HU patients age 60 and older were acute leukemia, anemia, leukopenia, and granulocytopenia.

The 23rd Congress of the European Hematology Association

STOCKHOLM—Follow-up data suggest that ropeginterferon alfa-2b (ropeg) provides an advantage over hydroxyurea (HU) for patients with polycythemia vera (PV), regardless of their age.

Two-year results from an extension study have shown that, compared to HU, ropeg produces higher rates of complete hematologic response (CHR) and molecular response (MR) in PV patients, including patients age 60 and older.

Additionally, rates of adverse events (AEs) and serious AEs were similar between the ropeg and HU arms.

“In all, I think these data suggest that ropeginterferon alfa-2b provides a valuable, efficacious, and safe new treatment option for PV patients of all ages, including those older than 60 years,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis, Université Paris Diderot in Paris, France.

Dr Kiladjian presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S132.

The research was sponsored by AOP Orphan Pharmaceuticals AG.

Dr Kiladjian presented data from CONTINUATION-PV, an extension trial of PROUD-PV. Results from PROUD-PV were presented at the 2016 ASH Annual Meeting.

PROUD-PV enrolled 254 patients who were treatment-naive or pretreated with HU. They were randomized to receive ropeg (n=127) or HU (n=127).

CONTINUATION-PV included 95 of the patients on ropeg and 76 of the patients on HU. Dr Kiladjian noted that baseline characteristics were similar between these groups.

CHR

At 24 months, the rate of CHR was 70.5% (67/95) in the ropeg arm and 49.3% (33/67) in the HU arm (RR=1.42, P<0.05).

In patients younger than 60, the rate of CHR was 77.6% in the ropeg arm and 55.9% in the HU arm. In patients age 60 and older, rates of CHR were 63% and 42.4%, respectively.

Dr Kiladjian noted that CHR rates increased over time in ropeg recipients. In PROUD-PV, CHR rates were similar between the ropeg and HU arms at 12 months. However, at 24 months, the CHR rates were higher in ropeg recipients.

Ropeg recipients were also more likely than HU recipients to maintain their CHR from the first occurrence to 24 months.

In patients younger than 60, 49% of the ropeg arm and 17.9% of the HU arm maintained a CHR (P<0.001). In patients age 60 and older, rates of CHR maintenance were 37% and 18.9%, respectively.

MR and JAK2V617F allele burden

Rates of MR at 24 months were 68.1% (64/94) in the ropeg arm and 34.7% (26/75) in the HU arm (RR=1.85, P<0.01).

In patients younger than 60, the rate of MR was 77.1% in the ropeg arm and 33.3% in the HU arm (P<0.001). In patients age 60 and older, MR rates were 58.7% and 36.1%, respectively.

For patients younger than 60, the reduction in JAK2V617F allele burden at 12 months was 29.9% in the ropeg arm and 42.3% in the HU arm. At 24 months, the reductions were 54.8% and 4.5%, respectively (P<0.001).

For patients 60 and older, the reduction in JAK2V617F allele burden at 12 months was 25.2% in the ropeg arm and 37.5% in the HU arm. At 24 months, the reductions were 35.1% and 18.4%, respectively.

Safety          

“I think an important point here is the safety because we assume that [ropeg] is not well tolerated in elderly patients,” Dr Kiladjian said. “So what are the results in this prospective, controlled trial? There was a comparable number of adverse events and serious adverse events in the treatment arms, irrespective of age.”

Dr Kiladjian also pointed out that the number of adverse drug reactions (ADRs) was comparable between the treatment arms for younger patients, and there was a trend toward a lower number of ADRs in the ropeg arm for the patients age 60 and older.

The 4 serious ADRs in the HU patients age 60 and older were acute leukemia, anemia, leukopenia, and granulocytopenia.

Daria Pagliara, MD, PhD

STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.

Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.

In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.

Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).

The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.

Patients and transplant characteristics

Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.

Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).

The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).

About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.

The median CD34 dose was 22.0 x 10⁶/kg, and the median α/β T-cell dose was 0.4 x 10⁵/kg.

The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).

The median follow-up was 536 days (range, 32-1252).

Engraftment and survival

The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.

Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.

The cumulative incidence of transplant-related mortality was 8.7%.

There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.

“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.

The rate of disease-free survival and overall survival were both 87.6%.

GVHD and adverse events

Dr Pagliara said there were low rates of acute GVHD in the first 100 days.

The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.

Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.

Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.

“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.

Nine patients (15.2%) had at least 1 adverse event (AE).

AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.

There were no severe AEs attributed to BPX-501.

Daria Pagliara, MD, PhD

STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.

Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.

In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.

Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).

The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.

Patients and transplant characteristics

Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.

Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).

The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).

About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.

The median CD34 dose was 22.0 x 10⁶/kg, and the median α/β T-cell dose was 0.4 x 10⁵/kg.

The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).

The median follow-up was 536 days (range, 32-1252).

Engraftment and survival

The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.

Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.

The cumulative incidence of transplant-related mortality was 8.7%.

There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.

“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.

The rate of disease-free survival and overall survival were both 87.6%.

GVHD and adverse events

Dr Pagliara said there were low rates of acute GVHD in the first 100 days.

The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.

Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.

Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.

“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.

Nine patients (15.2%) had at least 1 adverse event (AE).

AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.

There were no severe AEs attributed to BPX-501.

Daria Pagliara, MD, PhD

STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.

Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.

In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.

Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.

The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).

The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.

Patients and transplant characteristics

Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.

Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).

The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).

About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.

The median CD34 dose was 22.0 x 10⁶/kg, and the median α/β T-cell dose was 0.4 x 10⁵/kg.

The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).

The median follow-up was 536 days (range, 32-1252).

Engraftment and survival

The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.

Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.

The cumulative incidence of transplant-related mortality was 8.7%.

There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.

“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.

The rate of disease-free survival and overall survival were both 87.6%.

GVHD and adverse events

Dr Pagliara said there were low rates of acute GVHD in the first 100 days.

The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.

Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.

Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.

“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.

Nine patients (15.2%) had at least 1 adverse event (AE).

AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.

There were no severe AEs attributed to BPX-501.

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Photo from EHA

STOCKHOLM—Results of a phase 3 study suggest the long-acting C5 complement inhibitor ravulizumab produces similar results as eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Treatment with ravulizumab every 8 weeks proved noninferior to treatment with eculizumab every 2 weeks for the co-primary endpoints of transfusion avoidance and hemolysis as measured by lactate dehydrogenase (LDH) normalization.

Ravulizumab also proved noninferior with regard to secondary efficacy endpoints and had a safety profile similar to that of eculizumab.

These results suggest ravulizumab could be a more convenient alternative for PNH patients, according to Jong Wook Lee, MD, of Seoul St. Mary’s Hospital in Seoul, South Korea.

Dr Lee presented these results as a late-breaking abstract (LB2603) at the 23rd Congress of the European Hematology Association (EHA).

The study was sponsored by Alexion Pharmaceuticals.

The trial enrolled adults with PNH naive to complement inhibitor therapy. They were randomized to receive ravulizumab (n=125) or eculizumab (n=121) for 183 days.

More than half of patients were male—52% in the ravulizumab arm and 57% in the eculizumab arm.  Most patients were Asian (57.6% in the ravulizumab arm and 47.1% in the eculizumab arm) or white (34.4% and 42.1%, respectively).

Patients’ mean age at first infusion was 44.8 in the ravulizumab arm and 46.2 in the eculizumab arm. The mean number of years from PNH diagnosis to consent was 6.7 and 6.4, respectively.

The mean LDH at baseline was 1634 U/L in the ravulizumab arm and 1578 U/L in the eculizumab arm. The mean FACIT-Fatigue score was 36.7 and 36.9, respectively.

All 125 ravulizumab patients completed 26 weeks of treatment, as did 119 of the eculizumab patients. One hundred twenty-four ravulizumab patients entered the extension phase, as did 119 eculizumab patients.

Efficacy

The study’s primary efficacy endpoints were transfusion avoidance and LDH normalization from day 29 to 183. Dr Lee said ravulizumab proved noninferior to eculizumab for both endpoints, and point estimates favored ravulizumab.

The proportion of patients who remained transfusion-free was 73.6% in the ravulizumab arm and 66.1% in the eculizumab arm (difference, 6.8; 95% CI, -4.66, 18.14).

The proportion of patients who achieved LDH normalization was 53.6% and 49.4%, respectively (difference, 1.19; 95% CI, 0.8, 1.77).

Secondary efficacy endpoints included the percentage change in LDH from baseline, change in FACIT-Fatigue score from baseline, and the proportions of patients with breakthrough hemolysis and stabilized hemoglobin.

Again, ravulizumab was noninferior to eculizumab for all endpoints, with point estimates favoring ravulizumab.

The LDH percentage change was -76.84% in the ravulizumab arm and -76.02% in the eculizumab arm (difference, 0.83; 95% CI, -3.56, 5.21).

The change (improvement) in FACIT-Fatigue score was 7.07 and 6.40, respectively (difference, 0.67; 95% CI, -1.21, 2.55).

The percentage of patients with hemoglobin stabilization was 68.0% in the ravulizumab arm and 64.5% in the eculizumab arm (difference, 2.9; 95% CI, -8.80, 14.64).

The percentage of patients with breakthrough hemolysis was 4.0% and 10.7%, respectively (difference, 6.7; 95% CI, -0.18, 14.21).

Dr Lee noted that the proportion of patients with breakthrough hemolysis was more than 2.5-fold higher in the eculizumab arm than the ravulizumab arm—13 patients with 15 events and 5 patients with 5 events, respectively.

He said this was likely due to the immediate, complete, and sustained inhibition of C5 (mean free C5 <0.5 μg/mL) achieved by ravulizumab. Complete inhibition was observed after the first ravulizumab infusion and was sustained throughout the 26-week treatment period.

Safety

Dr Lee said ravulizumab had a similar safety profile to eculizumab, and both drugs were well tolerated.

Most patients experienced a treatment-emergent adverse event (TEAE)—88% in the ravulizumab arm and 86.8% in the eculizumab arm.

The most common TEAEs (in the ravulizumab and eculizumab arms, respectively) were headache (36.0% and 33.1%), nasopharyngitis (8.8% and 14.9%), upper respiratory tract infection (10.4% and 5.8%), and pyrexia (4.8% and 10.7%).

Serious AEs occurred in 8.8% of patients in the ravulizumab arm and 7.4% of those in the eculizumab arm.

Major adverse vascular events occurred in 2 patients in the ravulizumab arm and 1 in the eculizumab arm. There were no meningococcal infections in either arm.

One patient in the eculizumab arm was discontinued from the study and died of lung cancer (which was unrelated to treatment).

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Amandeep Salhotra, MD

STOCKHOLM—The ROCK2 inhibitor KD025 produced responses in about two-thirds of patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2 trial.

KD025 elicited improvements in Lee Symptom Scale score, and patients were able to reduce doses of corticosteroids and other immunosuppressants.

There were no serious adverse events (AEs) related to KD025 and no apparent increased risk of infection with the drug.

Amandeep Salhotra, MD, of City of Hope in Duarte, California, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S873. The research was sponsored by Kadmon Holdings, Inc.

This ongoing phase 2 trial has enrolled 48 adults with steroid-dependent or steroid-refractory cGVHD and active disease.

The patients were divided into 3 cohorts, in which they received different dose levels of KD025—200 mg daily (cohort 1), 200 mg twice daily (cohort 2), and 400 mg daily (cohort 3).

Dr Salhotra presented results in cohorts 1 (n=17) and 2 (n=16). These patients had cGVHD for a median of 18.9 months before enrollment and had received a median of 3 prior lines of cGVHD therapy. They had cGVHD involvement across all organ systems.

The median age was 50 (range, 20-63) in cohort 1 and 55 (range, 30-75) in cohort 2. The median time to cGHVD diagnosis was 9.1 months in cohort 1 and 7.7 months in cohort 2. The median time from cGVHD diagnosis to enrollment was 25.9 months and 15.8 months, respectively.

All patients in cohort 1 had at least 2 organs involved, as did 94% of patients in cohort 2. Forty-seven percent and 69%, respectively, had at least 4 organs involved.

Treatment duration

The median treatment duration was 37 weeks in cohort 1 and 33 weeks in cohort 2. Four patients in cohort 1 had cGVHD progression, as did 8 patients in cohort 2.

Seven patients in cohort 1 withdrew from the study—2 due to cancer relapse, 2 due to AEs (headache and diarrhea), 1 due to investigator decision, and 2 due to voluntary withdrawal. Three patients in cohort 2 withdrew—1 due to investigator decision and 2 due to voluntary withdrawal.

Six patients are still active in cohort 1, with a median treatment duration of 70 weeks. Five patients are still active in cohort 2, with a median treatment duration of 58 weeks.

Safety

“The adverse events were, overall, consistent with those expected in patients with chronic GVHD receiving corticosteroids,” Dr Salhotra said. “There were no treatment-related serious adverse events, and there was no increased signal of infection.”

Ninety-four percent of patients in both cohorts had AEs. Thirty-five percent of patients in cohort 1 and 63% in cohort 2 had treatment-related AEs. Twelve percent and 31%, respectively, had grade 3 or higher related AEs. Twelve percent of patients in cohort 1 had a related AE leading to discontinuation (2 events, headache and diarrhea).

Commonly reported AEs (in cohorts 1 and 2, respectively) included ALT/AST elevation (35% and 25%), upper respiratory tract infection (24% and 38%), anemia (29% and 25%), gamma-glutamyltransferase elevation (24% and 31%), diarrhea (35% and 13%), and nausea (35% and 13%).

Response

The overall response rate (ORR) was 65% (11/17) in cohort 1 and 69% (11/16) in cohort 2.

In patients with at least 2 prior lines of systemic therapy, the ORR was 65% (11/17) in cohort 1 and 64% (9/14) in cohort 2. In patients with severe cGVHD, the ORR was 67% (8/12) in cohort 1 and 64% (9/14) in cohort 2.

“Responses were rapid,” Dr Salhotra noted. “Seventy-seven percent of the responders achieved a response by the time of first assessment, which was at 8 weeks.”

“These responses were durable. Seventy-three percent (8/11) of responders in cohort 1 and 55% (6/11) of responders in cohort 2 have sustained responses for more than 20 weeks. At the 32-week endpoint, there were 45% (5/11) responders in cohort 1 and 18% (2/11) in cohort 2.”

Dr Salhotra added that responses were observed across all affected organ systems, including complete responses in upper and lower gastrointestinal systems, mouth, joints/fascia, skin, eyes, and liver.

Of the 13 responders in cohorts 1 and 2 with at least 4 organs involved, 46% (n=6) achieved responses in 4 or more organs.

In cohort 1, 73% (8/11) of responders and 83% (5/6) of non-responders had corticosteroid dose reductions. In cohort 2, 55% (6/11) of responders and 60% (3/5) of non-responders had dose reductions.

Five patients have completely discontinued steroids—4 (24%) in cohort 1 and 1 (6%) in cohort 2.

There were 6 patients each in cohorts 1 and 2 who were receiving tacrolimus. Each cohort had 5 patients (83%) who had tacrolimus dose reductions on KD025. One patient completely discontinued tacrolimus.

Sixty-five percent of patients in cohort 1 and 44% in cohort 2 had a clinically meaningful improvement in cGVHD symptoms, which was defined as at least a 7-point decrease in the Lee Symptom Scale score. Both responders and non-responders had such improvements.

Based on these results, Kadmon Holdings, Inc., is planning a pivotal study of KD025 in cGVHD, which is expected to begin in the third quarter of 2018.

Dr Salhotra said the study will enroll adults who have received at least 2 prior lines of systemic therapy for cGVHD. Patients will be randomized to receive KD025 at 200 mg daily or 200 mg twice daily. The primary endpoint will be ORR.

Bristol-Myers Squibb

STOCKHOLM—Adding elotuzumab (E) to treatment with pomalidomide (P) and low-dose dexamethasone (d) can produce “clinically meaningful” results in patients with relapsed/refractory multiple myeloma (MM), according to an investigator for the ELOQUENT-3 trial.

In this phase 2 trial, patients who received EPd had double the overall response rate (ORR) and median progression-free survival (PFS) of patients who received Pd.

Additionally, adverse events (AEs) were comparable between the treatment arms.

Meletios Dimopoulos, MD, of National and Kapodistrian University of Athens in Greece, presented these results as a late-breaking abstract (LB2606) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Bristol-Myers Squibb.

The ELOQUENT-3 trial enrolled MM patients who had refractory or relapsed and refractory MM. They had to have received lenalidomide and a proteasome inhibitor (PI).

The patients were randomized to receive EPd (n=60) or Pd (n=57) in 28-day cycles until disease progression or unacceptable toxicity.

Pomalidomide was given orally at 4 mg on days 1 to 21 of each cycle. In the Pd arm, dexamethasone was given as a 20 mg (for patients older than 75) or 40 mg (75 and younger) tablet weekly.

In the EPd arm, dexamethasone was split between oral (8 mg, 20 mg, or 40 mg tablets) and intravenous doses (8 mg or 28 mg).

Elotuzumab was given at 10 mg/kg intravenously weekly for the first 2 cycles and 20 mg/kg monthly from cycle 3 on.

Patient characteristics

The patients’ median age was 69 (range, 43-81) in the EPd arm and 66 (range, 36-81) in the Pd arm. They were a median of 4.8 years (EPd) or 4.4 years (Pd) from diagnosis.

The median number of prior therapies was 3 (range, 2-8) in both groups.

Ninety percent of patients in the EPd arm and 84% of those in the Pd arm were refractory to lenalidomide. Seventy-eight percent and 82%, respectively, were refractory to a PI. And 68% and 72%, respectively, were refractory to both lenalidomide and a PI.

Treatment duration

Dr Dimopoulos noted that twice as many patients remained on treatment with EPd compared to Pd at the time of database lock (February 21, 2018). Forty percent of EPd patients (n=24) and 20% of Pd patients (n=11) were still on treatment at that time.

Patients’ primary reason for treatment discontinuation was disease progression—43% of EPd recipients and 56% of Pd recipients. Two percent of EPd recipients and 4% of Pd recipients withdrew due to treatment-related toxicity. Four percent of patients in the Pd arm (and none in the EPd arm) withdrew due to maximum clinical benefit.

The median number of treatment cycles was 9 (range, 4-13) in the EPd arm and 5 (range, 3-10) in the Pd arm.

Efficacy

The ORR was 53% in the EPd arm and 26% in the Pd arm. The odds ratio was 3.25 (P=0.0029).

Eight percent of patients in the EPd arm had a complete response or stringent complete response, as did 2% of patients in the Pd arm.

The median duration of response was 8.3 months in the Pd arm and has not been reached in the EPd arm.

“Elotuzumab with pomalidomide and dexamethasone showed a significant and clinically meaningful 46% reduction in the risk of progression or death,” Dr Dimopoulos said.

The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.0078).

Although overall survival data are not yet mature, there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 deaths in the Pd arm.

Safety

Dr Dimopoulos said AEs were comparable between the treatment arms. He pointed out that neutropenia was less common with EPd compared to Pd, despite similar pomalidomide dose intensity. And exposure-adjusted hematologic AEs and infections were lower with EPd than with Pd.

Ninety-seven percent of patients in the EPd arm and 95% in the Pd arm had at least 1 AE.

Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).

Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).

Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).

There were 5 grade 5 AEs in the EPd arm and 8 in the Pd arm.

In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure, and general physical health deterioration.

In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection, multiple organ failure and infection, myocardial infarction, and plasma cell myeloma.

Bristol-Myers Squibb

STOCKHOLM—Adding elotuzumab (E) to treatment with pomalidomide (P) and low-dose dexamethasone (d) can produce “clinically meaningful” results in patients with relapsed/refractory multiple myeloma (MM), according to an investigator for the ELOQUENT-3 trial.

In this phase 2 trial, patients who received EPd had double the overall response rate (ORR) and median progression-free survival (PFS) of patients who received Pd.

Additionally, adverse events (AEs) were comparable between the treatment arms.

Meletios Dimopoulos, MD, of National and Kapodistrian University of Athens in Greece, presented these results as a late-breaking abstract (LB2606) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Bristol-Myers Squibb.

The ELOQUENT-3 trial enrolled MM patients who had refractory or relapsed and refractory MM. They had to have received lenalidomide and a proteasome inhibitor (PI).

The patients were randomized to receive EPd (n=60) or Pd (n=57) in 28-day cycles until disease progression or unacceptable toxicity.

Pomalidomide was given orally at 4 mg on days 1 to 21 of each cycle. In the Pd arm, dexamethasone was given as a 20 mg (for patients older than 75) or 40 mg (75 and younger) tablet weekly.

In the EPd arm, dexamethasone was split between oral (8 mg, 20 mg, or 40 mg tablets) and intravenous doses (8 mg or 28 mg).

Elotuzumab was given at 10 mg/kg intravenously weekly for the first 2 cycles and 20 mg/kg monthly from cycle 3 on.

Patient characteristics

The patients’ median age was 69 (range, 43-81) in the EPd arm and 66 (range, 36-81) in the Pd arm. They were a median of 4.8 years (EPd) or 4.4 years (Pd) from diagnosis.

The median number of prior therapies was 3 (range, 2-8) in both groups.

Ninety percent of patients in the EPd arm and 84% of those in the Pd arm were refractory to lenalidomide. Seventy-eight percent and 82%, respectively, were refractory to a PI. And 68% and 72%, respectively, were refractory to both lenalidomide and a PI.

Treatment duration

Dr Dimopoulos noted that twice as many patients remained on treatment with EPd compared to Pd at the time of database lock (February 21, 2018). Forty percent of EPd patients (n=24) and 20% of Pd patients (n=11) were still on treatment at that time.

Patients’ primary reason for treatment discontinuation was disease progression—43% of EPd recipients and 56% of Pd recipients. Two percent of EPd recipients and 4% of Pd recipients withdrew due to treatment-related toxicity. Four percent of patients in the Pd arm (and none in the EPd arm) withdrew due to maximum clinical benefit.

The median number of treatment cycles was 9 (range, 4-13) in the EPd arm and 5 (range, 3-10) in the Pd arm.

Efficacy

The ORR was 53% in the EPd arm and 26% in the Pd arm. The odds ratio was 3.25 (P=0.0029).

Eight percent of patients in the EPd arm had a complete response or stringent complete response, as did 2% of patients in the Pd arm.

The median duration of response was 8.3 months in the Pd arm and has not been reached in the EPd arm.

“Elotuzumab with pomalidomide and dexamethasone showed a significant and clinically meaningful 46% reduction in the risk of progression or death,” Dr Dimopoulos said.

The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.0078).

Although overall survival data are not yet mature, there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 deaths in the Pd arm.

Safety

Dr Dimopoulos said AEs were comparable between the treatment arms. He pointed out that neutropenia was less common with EPd compared to Pd, despite similar pomalidomide dose intensity. And exposure-adjusted hematologic AEs and infections were lower with EPd than with Pd.

Ninety-seven percent of patients in the EPd arm and 95% in the Pd arm had at least 1 AE.

Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).

Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).

Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).

There were 5 grade 5 AEs in the EPd arm and 8 in the Pd arm.

In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure, and general physical health deterioration.

In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection, multiple organ failure and infection, myocardial infarction, and plasma cell myeloma.

Bristol-Myers Squibb

STOCKHOLM—Adding elotuzumab (E) to treatment with pomalidomide (P) and low-dose dexamethasone (d) can produce “clinically meaningful” results in patients with relapsed/refractory multiple myeloma (MM), according to an investigator for the ELOQUENT-3 trial.

In this phase 2 trial, patients who received EPd had double the overall response rate (ORR) and median progression-free survival (PFS) of patients who received Pd.

Additionally, adverse events (AEs) were comparable between the treatment arms.

Meletios Dimopoulos, MD, of National and Kapodistrian University of Athens in Greece, presented these results as a late-breaking abstract (LB2606) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Bristol-Myers Squibb.

The ELOQUENT-3 trial enrolled MM patients who had refractory or relapsed and refractory MM. They had to have received lenalidomide and a proteasome inhibitor (PI).

The patients were randomized to receive EPd (n=60) or Pd (n=57) in 28-day cycles until disease progression or unacceptable toxicity.

Pomalidomide was given orally at 4 mg on days 1 to 21 of each cycle. In the Pd arm, dexamethasone was given as a 20 mg (for patients older than 75) or 40 mg (75 and younger) tablet weekly.

In the EPd arm, dexamethasone was split between oral (8 mg, 20 mg, or 40 mg tablets) and intravenous doses (8 mg or 28 mg).

Elotuzumab was given at 10 mg/kg intravenously weekly for the first 2 cycles and 20 mg/kg monthly from cycle 3 on.

Patient characteristics

The patients’ median age was 69 (range, 43-81) in the EPd arm and 66 (range, 36-81) in the Pd arm. They were a median of 4.8 years (EPd) or 4.4 years (Pd) from diagnosis.

The median number of prior therapies was 3 (range, 2-8) in both groups.

Ninety percent of patients in the EPd arm and 84% of those in the Pd arm were refractory to lenalidomide. Seventy-eight percent and 82%, respectively, were refractory to a PI. And 68% and 72%, respectively, were refractory to both lenalidomide and a PI.

Treatment duration

Dr Dimopoulos noted that twice as many patients remained on treatment with EPd compared to Pd at the time of database lock (February 21, 2018). Forty percent of EPd patients (n=24) and 20% of Pd patients (n=11) were still on treatment at that time.

Patients’ primary reason for treatment discontinuation was disease progression—43% of EPd recipients and 56% of Pd recipients. Two percent of EPd recipients and 4% of Pd recipients withdrew due to treatment-related toxicity. Four percent of patients in the Pd arm (and none in the EPd arm) withdrew due to maximum clinical benefit.

The median number of treatment cycles was 9 (range, 4-13) in the EPd arm and 5 (range, 3-10) in the Pd arm.

Efficacy

The ORR was 53% in the EPd arm and 26% in the Pd arm. The odds ratio was 3.25 (P=0.0029).

Eight percent of patients in the EPd arm had a complete response or stringent complete response, as did 2% of patients in the Pd arm.

The median duration of response was 8.3 months in the Pd arm and has not been reached in the EPd arm.

“Elotuzumab with pomalidomide and dexamethasone showed a significant and clinically meaningful 46% reduction in the risk of progression or death,” Dr Dimopoulos said.

The median PFS was 10.3 months with EPd and 4.7 months with Pd (hazard ratio=0.54, P=0.0078).

Although overall survival data are not yet mature, there was a trend favoring EPd over Pd (hazard ratio=0.62). There were 13 deaths in the EPd arm and 18 deaths in the Pd arm.

Safety

Dr Dimopoulos said AEs were comparable between the treatment arms. He pointed out that neutropenia was less common with EPd compared to Pd, despite similar pomalidomide dose intensity. And exposure-adjusted hematologic AEs and infections were lower with EPd than with Pd.

Ninety-seven percent of patients in the EPd arm and 95% in the Pd arm had at least 1 AE.

Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).

Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).

Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).

There were 5 grade 5 AEs in the EPd arm and 8 in the Pd arm.

In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure, and general physical health deterioration.

In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection, multiple organ failure and infection, myocardial infarction, and plasma cell myeloma.

Poster session at the 23rd Congress of the European Hematology Association

STOCKHOLM—The dual SYK/JAK inhibitor cerdulatinib has demonstrated efficacy in a phase 2 trial of patients with heavily pretreated B- and T-cell non-Hodgkin lymphomas (NHLs).

There were a few deaths due to sepsis or septic shock that were considered related to cerdulatinib, but investigators have taken steps to prevent additional deaths.

Cerdulatinib produced responses in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other NHLs.

The 5 deaths due to sepsis or septic shock (3 concomitant with pneumonia) occurred early on in the trial, and dose reductions, monitoring, and antibiotic prophylaxis appeared to be effective in preventing additional deaths.

Results from this trial were presented in a poster (abstract PF437) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Portola Pharmaceuticals, Inc.

The trial enrolled 114 patients. They had FL (grade 1-3A; n=39), PTCL (n=25), CTCL (n=5), CLL/SLL (n=28), other indolent NHLs (Waldenstrom’s macroglobulinemia and marginal zone lymphoma; n=12), or aggressive NHL (defined as diffuse large B-cell lymphoma [DLBCL], grade 3B FL, mantle cell lymphoma, and transformed NHL with relapsed disease; n=5).

The patients’ median age was 68 (range, 34-93), and 59% were male. The median number of prior treatment regimens was 3 (range, 1-13), and 37% of patients had refractory disease.

Patients received cerdulatinib at 25, 30, or 35 mg twice daily (BID). A total of 101 patients were evaluable as of May 4, 2018.

Response

The objective response rate (ORR) was 47% in the entire population. Thirteen patients achieved a complete response (CR), and 34 had a partial response (PR). Thirty-four patients remained on cerdulatinib at the data cut-off.

The ORR was 46% in the FL patients, with 3 patients achieving a CR and 13 achieving a PR. Thirteen FL patients remained on cerdulatinib.

In the CLL/SLL patients, the ORR was 61%. Two patients had a CR, and 15 had a PR. Four CLL/SLL patients remained on cerdulatinib.

In PTCL, the ORR was 35%. All 7 responders had a CR. Eleven PTCL patients remained on cerdulatinib.

Only 1 CTCL patient was evaluable, but this patient achieved a CR and remained on cerdulatinib.

The ORR was 42% for patients with other indolent NHLs, with 5 PRs and no CRs. Only 1 patient in this group remained on cerdulatinib.

For aggressive NHL, the ORR was 20%, with 1 PR and no CRs. None of the patients in this group stayed on cerdulatinib.

“Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said study investigator Paul Hamlin, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail frontline therapy.”

Safety

Grade 3 or higher adverse events included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

The 5 deaths due to sepsis or septic shock (3 of which were concomitant with pneumonia) were considered related to cerdulatinib. Three of the deaths occurred in patients with CLL, 1 in a DLBCL patient, and 1 in an FL patient.

“One of the things we have seen [with CLL patients] is the background infection rate is quite a bit higher,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development at Portola Pharmaceuticals.

“You see this with multiple other agents, so we were not particularly surprised to see [sepsis/septic shock in CLL].”

Dr Curnutte noted that grade 5 sepsis/septic shock tended to occur in patients who were pre-colonized and/or had high plasma levels of cerdulatinib.

So, to prevent these adverse events, the starting dose of cerdulatinib was lowered, investigators began monitoring patients’ plasma levels, and all patients began receiving antibiotic prophylaxis. (Previously, only CLL patients had received this prophylaxis.)

The investigators found that lowering the starting dose from 35 mg BID to 30 mg or even 25 mg BID reduced plasma levels.

“At the 35 mg dose, 1 out of every 4 patients showed accumulation of the drug,” Dr Curnutte said. “In general, the use of the 30 mg BID or step-down 25 mg BID did not result in accumulation of drug.”

Dr Curnutte also noted that enrollment of CLL/SLL patients is complete, and investigators would be “very careful” if the study were to be re-opened to these patients.

For now, Portola is focused on completing enrollment in other patient groups on this phase 2 trial. The company is also hoping to conduct a phase 3 trial of cerdulatinib in PTCL that could begin as early as the end of this year.

Poster session at the 23rd Congress of the European Hematology Association

STOCKHOLM—The dual SYK/JAK inhibitor cerdulatinib has demonstrated efficacy in a phase 2 trial of patients with heavily pretreated B- and T-cell non-Hodgkin lymphomas (NHLs).

There were a few deaths due to sepsis or septic shock that were considered related to cerdulatinib, but investigators have taken steps to prevent additional deaths.

Cerdulatinib produced responses in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other NHLs.

The 5 deaths due to sepsis or septic shock (3 concomitant with pneumonia) occurred early on in the trial, and dose reductions, monitoring, and antibiotic prophylaxis appeared to be effective in preventing additional deaths.

Results from this trial were presented in a poster (abstract PF437) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Portola Pharmaceuticals, Inc.

The trial enrolled 114 patients. They had FL (grade 1-3A; n=39), PTCL (n=25), CTCL (n=5), CLL/SLL (n=28), other indolent NHLs (Waldenstrom’s macroglobulinemia and marginal zone lymphoma; n=12), or aggressive NHL (defined as diffuse large B-cell lymphoma [DLBCL], grade 3B FL, mantle cell lymphoma, and transformed NHL with relapsed disease; n=5).

The patients’ median age was 68 (range, 34-93), and 59% were male. The median number of prior treatment regimens was 3 (range, 1-13), and 37% of patients had refractory disease.

Patients received cerdulatinib at 25, 30, or 35 mg twice daily (BID). A total of 101 patients were evaluable as of May 4, 2018.

Response

The objective response rate (ORR) was 47% in the entire population. Thirteen patients achieved a complete response (CR), and 34 had a partial response (PR). Thirty-four patients remained on cerdulatinib at the data cut-off.

The ORR was 46% in the FL patients, with 3 patients achieving a CR and 13 achieving a PR. Thirteen FL patients remained on cerdulatinib.

In the CLL/SLL patients, the ORR was 61%. Two patients had a CR, and 15 had a PR. Four CLL/SLL patients remained on cerdulatinib.

In PTCL, the ORR was 35%. All 7 responders had a CR. Eleven PTCL patients remained on cerdulatinib.

Only 1 CTCL patient was evaluable, but this patient achieved a CR and remained on cerdulatinib.

The ORR was 42% for patients with other indolent NHLs, with 5 PRs and no CRs. Only 1 patient in this group remained on cerdulatinib.

For aggressive NHL, the ORR was 20%, with 1 PR and no CRs. None of the patients in this group stayed on cerdulatinib.

“Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said study investigator Paul Hamlin, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail frontline therapy.”

Safety

Grade 3 or higher adverse events included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

The 5 deaths due to sepsis or septic shock (3 of which were concomitant with pneumonia) were considered related to cerdulatinib. Three of the deaths occurred in patients with CLL, 1 in a DLBCL patient, and 1 in an FL patient.

“One of the things we have seen [with CLL patients] is the background infection rate is quite a bit higher,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development at Portola Pharmaceuticals.

“You see this with multiple other agents, so we were not particularly surprised to see [sepsis/septic shock in CLL].”

Dr Curnutte noted that grade 5 sepsis/septic shock tended to occur in patients who were pre-colonized and/or had high plasma levels of cerdulatinib.

So, to prevent these adverse events, the starting dose of cerdulatinib was lowered, investigators began monitoring patients’ plasma levels, and all patients began receiving antibiotic prophylaxis. (Previously, only CLL patients had received this prophylaxis.)

The investigators found that lowering the starting dose from 35 mg BID to 30 mg or even 25 mg BID reduced plasma levels.

“At the 35 mg dose, 1 out of every 4 patients showed accumulation of the drug,” Dr Curnutte said. “In general, the use of the 30 mg BID or step-down 25 mg BID did not result in accumulation of drug.”

Dr Curnutte also noted that enrollment of CLL/SLL patients is complete, and investigators would be “very careful” if the study were to be re-opened to these patients.

For now, Portola is focused on completing enrollment in other patient groups on this phase 2 trial. The company is also hoping to conduct a phase 3 trial of cerdulatinib in PTCL that could begin as early as the end of this year.

Poster session at the 23rd Congress of the European Hematology Association

STOCKHOLM—The dual SYK/JAK inhibitor cerdulatinib has demonstrated efficacy in a phase 2 trial of patients with heavily pretreated B- and T-cell non-Hodgkin lymphomas (NHLs).

There were a few deaths due to sepsis or septic shock that were considered related to cerdulatinib, but investigators have taken steps to prevent additional deaths.

Cerdulatinib produced responses in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other NHLs.

The 5 deaths due to sepsis or septic shock (3 concomitant with pneumonia) occurred early on in the trial, and dose reductions, monitoring, and antibiotic prophylaxis appeared to be effective in preventing additional deaths.

Results from this trial were presented in a poster (abstract PF437) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Portola Pharmaceuticals, Inc.

The trial enrolled 114 patients. They had FL (grade 1-3A; n=39), PTCL (n=25), CTCL (n=5), CLL/SLL (n=28), other indolent NHLs (Waldenstrom’s macroglobulinemia and marginal zone lymphoma; n=12), or aggressive NHL (defined as diffuse large B-cell lymphoma [DLBCL], grade 3B FL, mantle cell lymphoma, and transformed NHL with relapsed disease; n=5).

The patients’ median age was 68 (range, 34-93), and 59% were male. The median number of prior treatment regimens was 3 (range, 1-13), and 37% of patients had refractory disease.

Patients received cerdulatinib at 25, 30, or 35 mg twice daily (BID). A total of 101 patients were evaluable as of May 4, 2018.

Response

The objective response rate (ORR) was 47% in the entire population. Thirteen patients achieved a complete response (CR), and 34 had a partial response (PR). Thirty-four patients remained on cerdulatinib at the data cut-off.

The ORR was 46% in the FL patients, with 3 patients achieving a CR and 13 achieving a PR. Thirteen FL patients remained on cerdulatinib.

In the CLL/SLL patients, the ORR was 61%. Two patients had a CR, and 15 had a PR. Four CLL/SLL patients remained on cerdulatinib.

In PTCL, the ORR was 35%. All 7 responders had a CR. Eleven PTCL patients remained on cerdulatinib.

Only 1 CTCL patient was evaluable, but this patient achieved a CR and remained on cerdulatinib.

The ORR was 42% for patients with other indolent NHLs, with 5 PRs and no CRs. Only 1 patient in this group remained on cerdulatinib.

For aggressive NHL, the ORR was 20%, with 1 PR and no CRs. None of the patients in this group stayed on cerdulatinib.

“Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said study investigator Paul Hamlin, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail frontline therapy.”

Safety

Grade 3 or higher adverse events included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

The 5 deaths due to sepsis or septic shock (3 of which were concomitant with pneumonia) were considered related to cerdulatinib. Three of the deaths occurred in patients with CLL, 1 in a DLBCL patient, and 1 in an FL patient.

“One of the things we have seen [with CLL patients] is the background infection rate is quite a bit higher,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development at Portola Pharmaceuticals.

“You see this with multiple other agents, so we were not particularly surprised to see [sepsis/septic shock in CLL].”

Dr Curnutte noted that grade 5 sepsis/septic shock tended to occur in patients who were pre-colonized and/or had high plasma levels of cerdulatinib.

So, to prevent these adverse events, the starting dose of cerdulatinib was lowered, investigators began monitoring patients’ plasma levels, and all patients began receiving antibiotic prophylaxis. (Previously, only CLL patients had received this prophylaxis.)

The investigators found that lowering the starting dose from 35 mg BID to 30 mg or even 25 mg BID reduced plasma levels.

“At the 35 mg dose, 1 out of every 4 patients showed accumulation of the drug,” Dr Curnutte said. “In general, the use of the 30 mg BID or step-down 25 mg BID did not result in accumulation of drug.”

Dr Curnutte also noted that enrollment of CLL/SLL patients is complete, and investigators would be “very careful” if the study were to be re-opened to these patients.

For now, Portola is focused on completing enrollment in other patient groups on this phase 2 trial. The company is also hoping to conduct a phase 3 trial of cerdulatinib in PTCL that could begin as early as the end of this year.