Non-Hodgkin Lymphoma

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 Sarah Cannon

Final analysis of the phase 3 DUO trial has shown monotherapy with oral duvelisib results in a statistically significant improvement in progression-free survival (PFS) and overall response rate (ORR) compared to monotherapy with ofatumumab for patients with relapsed or refractory chronic lymphocytic leukemia/small lympchocytic lymphoma (CLL/SLL).

PFS for all patients as assessed by Independent Review Committee (IRC) was a median 13.3 months with duvelisib compared to 9.9 months with ofatumumab (P<0.0001).

ORR was significantly higher with duvelisib, 74% compared to 45%, P<0.0001, regardless of deletion 17p status.

Duvelisib (Copiktra™) was recently approved by the U.S. Food and Drug Administration for CLL/SLL based in part on this head-to-head trial.

The investigators reported the results in Blood.

"The way we treat patients with CLL is changing rapidly as we move from standard chemotherapy-based approaches to more targeted therapies," said principal investigator Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute in Nashville.

"Based on these data, duvelisib may offer a new treatment option for patients who otherwise may have limited options."

Duvelisib is an oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and -γ, which means it blocks the survival and proliferation of malignant B cells and also disrupts the recruitment and differentiation of T cells and macrophages within the tumor microenvironment.

Ofatumumab is a humanized anti-CD20 antibody with single-agent efficacy in refractory CLL. It is approved by the FDA as a treatment option in CLL.

Study design

Investigators randomized 319 relapsed or refractory CLL/SLL patients, 160 to the duvelisib arm and 159 to the ofatumumab arm.

Patients in the duvelisib arm self-administered 25 mg capsules twice daily continuously in 28-day cycles. They could take duvelisib for up to 18 cycles, until disease progression or unacceptable toxicity.

Ofatumumab-treated patients received infusions as approved in the product labeling for monotherapy in relapsed CLL. Dosing of ofatumumab could not exceed 12 doses in 7 cycles.

Prophylaxis for Pneumocystis jirovecci was required for all patients on both treatment arms.

Patients were allowed to crossover to a separate extension study to receive the opposite therapy if they had progressive disease.

They were followed for a median of 22.4 months.

Patient characteristics

According to the investigators, patient characteristics were well balanced between the arms.

The majority (60%) were male and the median age in both arms was 69. Most had an ECOG performance status of 0 or 1; 7% in the duvelisib arm and 10% in the ofatumumab arm had a performance status of 2.

Other patient characteristics in the duvelisib and ofatumumab arms, respectively, were:

• Time from initial diagnosis: 7.5 years, 6.7 years
• CLL/SLL, %: 97/5, 99/2
• Bulky disease: 46%, 45%
• Baseline lymphocyte counts: 38x109/L, 35x109/L
• Deletion 17p and/or TP53 mutation: 31%, 33%
• Median number of prior therapies: 2 in each arm
• Previous alkylating agent: 93%, 95%
• Previous monoclonal antibody: 78%, 83%
• Prior purine analog: 60%, 71%

Of the total patients enrolled, 158 patients in the duvelisib arm and 155 in the ofatumumab arm received treatment, for a median exposure of 50 weeks and 23 weeks, respectively.

Efficacy

In addition to the significantly improved overall PFS and ORR with duvelisib, further analysis revealed that PFS also improved for all predefined subgroups.

High-risk patients with deletion 17p/TP53 mutations also experienced a significant improvement in PFS with duvelisib of 12.7 months compared to 9.0 months with ofatumumab by IRC (P=0.0002).

The estimated probability of being progression-free for these patients at 6 and 12 moths was 73% and 55% with duvelisib and 63% and 30% with ofatumumab.

The investigators pointed out that duvelisib treatment was particularly effective in eliciting a lymph node response—85.0% compared to 15.7% with ofatumumab as assessed by IRC (P<0.0001).

Median overall survival was not reached in either arm. The 12-month probability of survival was 86% for both treatments.

Safety

Median treatment exposure was almost twice as long in the duvelisib arm because ofatumumab treatment was not allowed to exceed 12 doses as specified in the prescribing information.

The investigators explained this resulted in a longer adverse event (AE) reporting period for duvelisib.

One hundred twenty-four duvelisib-treated patients discontinued treatment, most commonly due to AEs (35%), disease progression (22%), subject withdrawal (8%), and death (8%).

All ofatumumab-treated patients discontinued treatment by the time of data cutoff, and 67% had completed treatment as per protocol. Others discontinued due to disease progression (20%), subject withdrawal (5%), and AEs (4%).

Eight (5%) duvelisib patients crossed over to ofatumumab therapy at the time of disease progression, and 89 (57%) ofatumumab-treated patients crossed over to duvelisib.

Nearly all patients in both arms experienced an AE.

The most common hematologic malignancies with duvelisib and ofatumumab, respectively, occurring in 10% or more patients were neutropenia (33%, 21%), anemia (23%, 10%), and thrombocytopenia (15%, 6%).

The most common nonhematologic AES with duvelisib were diarrhea (51%), pyrexia (29%), nausea (23%), and cough (21%).

With ofatumumab, the most common nonhematologic AES were infusion-related reaction (19%), cough (14%), and diarrhea, rash, and fatigue (12% each).

Grade 3 or greater AEs occurred in 87% of duvelisib-treated patients and 48% in the ofatumumab arm.

The most common grade 3 or greater events with duvelisib were neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%).

With ofatumumab, only neutropenia (17%) of grade 3 or higher occurred in 10% or more patients.

Severe immune-related toxicities with duvelisib included colitis (12%) and pneumonitis, alanine transaminase (ALT) or aspartate transaminase (AST) increase (3% each). The events were managed with dose interruptions and steroid therapy for pneumonitis or colitis. All reported events resolved, and none was fatal.

Infectious AEs occurred more frequently with duvelisib, 69% compared to 43% in the ofatumumab arm. Pneumonia (18%) and upper respiratory tract infection (16%) were the most common events.

Three patients in the duvelisib arm and 1 in the ofatumumab arm contracted Pneumocystis jirovecii.

The most frequently reported serious AE was pneumonia (duvelisib 15%; ofatumumab 3%).

Nineteen fatal AEs occurred in patients on the duvelisib arm, 4 of which were related to the study drug: staphylococcal pneumonia (n = 2), sepsis (n=1), and general health deterioration (n = 1).

Seven fatal AEs occurred in patients on the ofatumumab arm, although none was attributed to ofatumumab.

The DUO trial was sponsored by Verastem Oncology and Infinity Pharmaceuticals , Inc. 

Photo from Sarah Cannon

Final analysis of the phase 3 DUO trial has shown monotherapy with oral duvelisib results in a statistically significant improvement in progression-free survival (PFS) and overall response rate (ORR) compared to monotherapy with ofatumumab for patients with relapsed or refractory chronic lymphocytic leukemia/small lympchocytic lymphoma (CLL/SLL).

PFS for all patients as assessed by Independent Review Committee (IRC) was a median 13.3 months with duvelisib compared to 9.9 months with ofatumumab (P<0.0001).

ORR was significantly higher with duvelisib, 74% compared to 45%, P<0.0001, regardless of deletion 17p status.

Duvelisib (Copiktra™) was recently approved by the U.S. Food and Drug Administration for CLL/SLL based in part on this head-to-head trial.

The investigators reported the results in Blood.

"The way we treat patients with CLL is changing rapidly as we move from standard chemotherapy-based approaches to more targeted therapies," said principal investigator Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute in Nashville.

"Based on these data, duvelisib may offer a new treatment option for patients who otherwise may have limited options."

Duvelisib is an oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and -γ, which means it blocks the survival and proliferation of malignant B cells and also disrupts the recruitment and differentiation of T cells and macrophages within the tumor microenvironment.

Ofatumumab is a humanized anti-CD20 antibody with single-agent efficacy in refractory CLL. It is approved by the FDA as a treatment option in CLL.

Study design

Investigators randomized 319 relapsed or refractory CLL/SLL patients, 160 to the duvelisib arm and 159 to the ofatumumab arm.

Patients in the duvelisib arm self-administered 25 mg capsules twice daily continuously in 28-day cycles. They could take duvelisib for up to 18 cycles, until disease progression or unacceptable toxicity.

Ofatumumab-treated patients received infusions as approved in the product labeling for monotherapy in relapsed CLL. Dosing of ofatumumab could not exceed 12 doses in 7 cycles.

Prophylaxis for Pneumocystis jirovecci was required for all patients on both treatment arms.

Patients were allowed to crossover to a separate extension study to receive the opposite therapy if they had progressive disease.

They were followed for a median of 22.4 months.

Patient characteristics

According to the investigators, patient characteristics were well balanced between the arms.

The majority (60%) were male and the median age in both arms was 69. Most had an ECOG performance status of 0 or 1; 7% in the duvelisib arm and 10% in the ofatumumab arm had a performance status of 2.

Other patient characteristics in the duvelisib and ofatumumab arms, respectively, were:

• Time from initial diagnosis: 7.5 years, 6.7 years
• CLL/SLL, %: 97/5, 99/2
• Bulky disease: 46%, 45%
• Baseline lymphocyte counts: 38x109/L, 35x109/L
• Deletion 17p and/or TP53 mutation: 31%, 33%
• Median number of prior therapies: 2 in each arm
• Previous alkylating agent: 93%, 95%
• Previous monoclonal antibody: 78%, 83%
• Prior purine analog: 60%, 71%

Of the total patients enrolled, 158 patients in the duvelisib arm and 155 in the ofatumumab arm received treatment, for a median exposure of 50 weeks and 23 weeks, respectively.

Efficacy

In addition to the significantly improved overall PFS and ORR with duvelisib, further analysis revealed that PFS also improved for all predefined subgroups.

High-risk patients with deletion 17p/TP53 mutations also experienced a significant improvement in PFS with duvelisib of 12.7 months compared to 9.0 months with ofatumumab by IRC (P=0.0002).

The estimated probability of being progression-free for these patients at 6 and 12 moths was 73% and 55% with duvelisib and 63% and 30% with ofatumumab.

The investigators pointed out that duvelisib treatment was particularly effective in eliciting a lymph node response—85.0% compared to 15.7% with ofatumumab as assessed by IRC (P<0.0001).

Median overall survival was not reached in either arm. The 12-month probability of survival was 86% for both treatments.

Safety

Median treatment exposure was almost twice as long in the duvelisib arm because ofatumumab treatment was not allowed to exceed 12 doses as specified in the prescribing information.

The investigators explained this resulted in a longer adverse event (AE) reporting period for duvelisib.

One hundred twenty-four duvelisib-treated patients discontinued treatment, most commonly due to AEs (35%), disease progression (22%), subject withdrawal (8%), and death (8%).

All ofatumumab-treated patients discontinued treatment by the time of data cutoff, and 67% had completed treatment as per protocol. Others discontinued due to disease progression (20%), subject withdrawal (5%), and AEs (4%).

Eight (5%) duvelisib patients crossed over to ofatumumab therapy at the time of disease progression, and 89 (57%) ofatumumab-treated patients crossed over to duvelisib.

Nearly all patients in both arms experienced an AE.

The most common hematologic malignancies with duvelisib and ofatumumab, respectively, occurring in 10% or more patients were neutropenia (33%, 21%), anemia (23%, 10%), and thrombocytopenia (15%, 6%).

The most common nonhematologic AES with duvelisib were diarrhea (51%), pyrexia (29%), nausea (23%), and cough (21%).

With ofatumumab, the most common nonhematologic AES were infusion-related reaction (19%), cough (14%), and diarrhea, rash, and fatigue (12% each).

Grade 3 or greater AEs occurred in 87% of duvelisib-treated patients and 48% in the ofatumumab arm.

The most common grade 3 or greater events with duvelisib were neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%).

With ofatumumab, only neutropenia (17%) of grade 3 or higher occurred in 10% or more patients.

Severe immune-related toxicities with duvelisib included colitis (12%) and pneumonitis, alanine transaminase (ALT) or aspartate transaminase (AST) increase (3% each). The events were managed with dose interruptions and steroid therapy for pneumonitis or colitis. All reported events resolved, and none was fatal.

Infectious AEs occurred more frequently with duvelisib, 69% compared to 43% in the ofatumumab arm. Pneumonia (18%) and upper respiratory tract infection (16%) were the most common events.

Three patients in the duvelisib arm and 1 in the ofatumumab arm contracted Pneumocystis jirovecii.

The most frequently reported serious AE was pneumonia (duvelisib 15%; ofatumumab 3%).

Nineteen fatal AEs occurred in patients on the duvelisib arm, 4 of which were related to the study drug: staphylococcal pneumonia (n = 2), sepsis (n=1), and general health deterioration (n = 1).

Seven fatal AEs occurred in patients on the ofatumumab arm, although none was attributed to ofatumumab.

The DUO trial was sponsored by Verastem Oncology and Infinity Pharmaceuticals , Inc. 

Photo from Sarah Cannon

Final analysis of the phase 3 DUO trial has shown monotherapy with oral duvelisib results in a statistically significant improvement in progression-free survival (PFS) and overall response rate (ORR) compared to monotherapy with ofatumumab for patients with relapsed or refractory chronic lymphocytic leukemia/small lympchocytic lymphoma (CLL/SLL).

PFS for all patients as assessed by Independent Review Committee (IRC) was a median 13.3 months with duvelisib compared to 9.9 months with ofatumumab (P<0.0001).

ORR was significantly higher with duvelisib, 74% compared to 45%, P<0.0001, regardless of deletion 17p status.

Duvelisib (Copiktra™) was recently approved by the U.S. Food and Drug Administration for CLL/SLL based in part on this head-to-head trial.

The investigators reported the results in Blood.

"The way we treat patients with CLL is changing rapidly as we move from standard chemotherapy-based approaches to more targeted therapies," said principal investigator Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute in Nashville.

"Based on these data, duvelisib may offer a new treatment option for patients who otherwise may have limited options."

Duvelisib is an oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and -γ, which means it blocks the survival and proliferation of malignant B cells and also disrupts the recruitment and differentiation of T cells and macrophages within the tumor microenvironment.

Ofatumumab is a humanized anti-CD20 antibody with single-agent efficacy in refractory CLL. It is approved by the FDA as a treatment option in CLL.

Study design

Investigators randomized 319 relapsed or refractory CLL/SLL patients, 160 to the duvelisib arm and 159 to the ofatumumab arm.

Patients in the duvelisib arm self-administered 25 mg capsules twice daily continuously in 28-day cycles. They could take duvelisib for up to 18 cycles, until disease progression or unacceptable toxicity.

Ofatumumab-treated patients received infusions as approved in the product labeling for monotherapy in relapsed CLL. Dosing of ofatumumab could not exceed 12 doses in 7 cycles.

Prophylaxis for Pneumocystis jirovecci was required for all patients on both treatment arms.

Patients were allowed to crossover to a separate extension study to receive the opposite therapy if they had progressive disease.

They were followed for a median of 22.4 months.

Patient characteristics

According to the investigators, patient characteristics were well balanced between the arms.

The majority (60%) were male and the median age in both arms was 69. Most had an ECOG performance status of 0 or 1; 7% in the duvelisib arm and 10% in the ofatumumab arm had a performance status of 2.

Other patient characteristics in the duvelisib and ofatumumab arms, respectively, were:

• Time from initial diagnosis: 7.5 years, 6.7 years
• CLL/SLL, %: 97/5, 99/2
• Bulky disease: 46%, 45%
• Baseline lymphocyte counts: 38x109/L, 35x109/L
• Deletion 17p and/or TP53 mutation: 31%, 33%
• Median number of prior therapies: 2 in each arm
• Previous alkylating agent: 93%, 95%
• Previous monoclonal antibody: 78%, 83%
• Prior purine analog: 60%, 71%

Of the total patients enrolled, 158 patients in the duvelisib arm and 155 in the ofatumumab arm received treatment, for a median exposure of 50 weeks and 23 weeks, respectively.

Efficacy

In addition to the significantly improved overall PFS and ORR with duvelisib, further analysis revealed that PFS also improved for all predefined subgroups.

High-risk patients with deletion 17p/TP53 mutations also experienced a significant improvement in PFS with duvelisib of 12.7 months compared to 9.0 months with ofatumumab by IRC (P=0.0002).

The estimated probability of being progression-free for these patients at 6 and 12 moths was 73% and 55% with duvelisib and 63% and 30% with ofatumumab.

The investigators pointed out that duvelisib treatment was particularly effective in eliciting a lymph node response—85.0% compared to 15.7% with ofatumumab as assessed by IRC (P<0.0001).

Median overall survival was not reached in either arm. The 12-month probability of survival was 86% for both treatments.

Safety

Median treatment exposure was almost twice as long in the duvelisib arm because ofatumumab treatment was not allowed to exceed 12 doses as specified in the prescribing information.

The investigators explained this resulted in a longer adverse event (AE) reporting period for duvelisib.

One hundred twenty-four duvelisib-treated patients discontinued treatment, most commonly due to AEs (35%), disease progression (22%), subject withdrawal (8%), and death (8%).

All ofatumumab-treated patients discontinued treatment by the time of data cutoff, and 67% had completed treatment as per protocol. Others discontinued due to disease progression (20%), subject withdrawal (5%), and AEs (4%).

Eight (5%) duvelisib patients crossed over to ofatumumab therapy at the time of disease progression, and 89 (57%) ofatumumab-treated patients crossed over to duvelisib.

Nearly all patients in both arms experienced an AE.

The most common hematologic malignancies with duvelisib and ofatumumab, respectively, occurring in 10% or more patients were neutropenia (33%, 21%), anemia (23%, 10%), and thrombocytopenia (15%, 6%).

The most common nonhematologic AES with duvelisib were diarrhea (51%), pyrexia (29%), nausea (23%), and cough (21%).

With ofatumumab, the most common nonhematologic AES were infusion-related reaction (19%), cough (14%), and diarrhea, rash, and fatigue (12% each).

Grade 3 or greater AEs occurred in 87% of duvelisib-treated patients and 48% in the ofatumumab arm.

The most common grade 3 or greater events with duvelisib were neutropenia (30%), diarrhea (15%), pneumonia (14%), and anemia (13%).

With ofatumumab, only neutropenia (17%) of grade 3 or higher occurred in 10% or more patients.

Severe immune-related toxicities with duvelisib included colitis (12%) and pneumonitis, alanine transaminase (ALT) or aspartate transaminase (AST) increase (3% each). The events were managed with dose interruptions and steroid therapy for pneumonitis or colitis. All reported events resolved, and none was fatal.

Infectious AEs occurred more frequently with duvelisib, 69% compared to 43% in the ofatumumab arm. Pneumonia (18%) and upper respiratory tract infection (16%) were the most common events.

Three patients in the duvelisib arm and 1 in the ofatumumab arm contracted Pneumocystis jirovecii.

The most frequently reported serious AE was pneumonia (duvelisib 15%; ofatumumab 3%).

Nineteen fatal AEs occurred in patients on the duvelisib arm, 4 of which were related to the study drug: staphylococcal pneumonia (n = 2), sepsis (n=1), and general health deterioration (n = 1).

Seven fatal AEs occurred in patients on the ofatumumab arm, although none was attributed to ofatumumab.

The DUO trial was sponsored by Verastem Oncology and Infinity Pharmaceuticals , Inc. 

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Micrograph showing CLL

The U.S. Food and Drug Administration (FDA) has approved duvelisib (Copiktra™), a dual PI3K delta/gamma inhibitor, for two indications.

Duvelisib has full FDA approval to treat adults with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies.

Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem Inc., the company marketing the drug.

Verastem said it will help patients access duvelisib through the Verastem Cares™ program, which is designed to provide information and assistance to patients who are prescribed duvelisib.

The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug—infections, diarrhea or colitis, cutaneous reactions, and pneumonitis.

Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA assessed the new drug application for duvelisib under priority review. The FDA also granted duvelisib fast track designation in CLL and FL as well as orphan drug designation for CLL/SLL and FL.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. Updated results from both studies are available in the prescribing information for duvelisib.

DUO trial

DUO included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).

The following efficacy results were observed in patients who had received at least two prior therapies, which includes 95 patients in the duvelisib arm and 101 in the ofatumumab arm.

The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab (hazard ratio=0.40).

The safety results include all patients treated with duvelisib or ofatumumab.

Twelve percent of patients in the duvelisib arm had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab.

Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection (38%) and diarrhea/colitis (23%).

Thirty-six percent of patients discontinued duvelisib. Most discontinuations were due to diarrhea/ colitis, infection, and rash. Twenty-nine percent of patients in the duvelisib arm required dose reductions, most often due to diarrhea/colitis and rash.

DYNAMO trial

DYNAMO enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.

There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).

The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

AEs occurring in at least 20% of FL patients included diarrhea/colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.

Twenty-nine percent of FL patients discontinued duvelisib, and 23% had dose reductions. Most discontinuations were due to diarrhea/colitis and rash, and most dose reductions were due to transaminase elevation, diarrhea/colitis, lipase increase, and infection.

Micrograph showing CLL

The U.S. Food and Drug Administration (FDA) has approved duvelisib (Copiktra™), a dual PI3K delta/gamma inhibitor, for two indications.

Duvelisib has full FDA approval to treat adults with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies.

Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem Inc., the company marketing the drug.

Verastem said it will help patients access duvelisib through the Verastem Cares™ program, which is designed to provide information and assistance to patients who are prescribed duvelisib.

The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug—infections, diarrhea or colitis, cutaneous reactions, and pneumonitis.

Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA assessed the new drug application for duvelisib under priority review. The FDA also granted duvelisib fast track designation in CLL and FL as well as orphan drug designation for CLL/SLL and FL.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. Updated results from both studies are available in the prescribing information for duvelisib.

DUO trial

DUO included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).

The following efficacy results were observed in patients who had received at least two prior therapies, which includes 95 patients in the duvelisib arm and 101 in the ofatumumab arm.

The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab (hazard ratio=0.40).

The safety results include all patients treated with duvelisib or ofatumumab.

Twelve percent of patients in the duvelisib arm had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab.

Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection (38%) and diarrhea/colitis (23%).

Thirty-six percent of patients discontinued duvelisib. Most discontinuations were due to diarrhea/ colitis, infection, and rash. Twenty-nine percent of patients in the duvelisib arm required dose reductions, most often due to diarrhea/colitis and rash.

DYNAMO trial

DYNAMO enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.

There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).

The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

AEs occurring in at least 20% of FL patients included diarrhea/colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.

Twenty-nine percent of FL patients discontinued duvelisib, and 23% had dose reductions. Most discontinuations were due to diarrhea/colitis and rash, and most dose reductions were due to transaminase elevation, diarrhea/colitis, lipase increase, and infection.

Micrograph showing CLL

The U.S. Food and Drug Administration (FDA) has approved duvelisib (Copiktra™), a dual PI3K delta/gamma inhibitor, for two indications.

Duvelisib has full FDA approval to treat adults with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior therapies.

Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem Inc., the company marketing the drug.

Verastem said it will help patients access duvelisib through the Verastem Cares™ program, which is designed to provide information and assistance to patients who are prescribed duvelisib.

The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug—infections, diarrhea or colitis, cutaneous reactions, and pneumonitis.

Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA assessed the new drug application for duvelisib under priority review. The FDA also granted duvelisib fast track designation in CLL and FL as well as orphan drug designation for CLL/SLL and FL.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. Updated results from both studies are available in the prescribing information for duvelisib.

DUO trial

DUO included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2000 mg).

The following efficacy results were observed in patients who had received at least two prior therapies, which includes 95 patients in the duvelisib arm and 101 in the ofatumumab arm.

The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab (hazard ratio=0.40).

The safety results include all patients treated with duvelisib or ofatumumab.

Twelve percent of patients in the duvelisib arm had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab.

Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection (38%) and diarrhea/colitis (23%).

Thirty-six percent of patients discontinued duvelisib. Most discontinuations were due to diarrhea/ colitis, infection, and rash. Twenty-nine percent of patients in the duvelisib arm required dose reductions, most often due to diarrhea/colitis and rash.

DYNAMO trial

DYNAMO enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy.

There were 83 patients with FL. They had a median of 3 prior anticancer regimens (range, 1-10).

The patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

AEs occurring in at least 20% of FL patients included diarrhea/colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.

Twenty-nine percent of FL patients discontinued duvelisib, and 23% had dose reductions. Most discontinuations were due to diarrhea/colitis and rash, and most dose reductions were due to transaminase elevation, diarrhea/colitis, lipase increase, and infection.

Photo courtesy of Abbvie

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission (EC) approve a new indication for venetoclax (Venclyxto®).

AbbVie is seeking EC approval for venetoclax in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

The EC typically makes an approval decision within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

Venetoclax is already EC-approved as monotherapy for:

• Adults with CLL who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with a B-cell receptor pathway inhibitor
• Adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

The CHMP’s recommendation to approve venetoclax in combination with rituximab is supported by the phase 3 MURANO trial. Results from MURANO were published in The New England Journal of Medicine in March.

The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.

According to investigators, the median progression-free survival was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio, 0.17; P<0.0001).

According to an independent review committee, the median progression-free survival was not reached in the VEN+R arm and was 18.1 months in the B+R arm (hazard ratio, 0.20; P<0.0001).

Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) included:

• Neutropenia (57.7% and 38.8%)
• Infections and infestations (17.5% and 21.8%)
• Anemia (10.8% and 13.8%)
• Thrombocytopenia (5.7% and 10.1%)
• Febrile neutropenia (3.6% and 9.6%)
• Pneumonia (5.2% and 8.0%)
• Infusion-related reaction (1.5% and 5.3%)
• Tumor lysis syndrome (3.1% and 1.1%)
• Hypotension (0% and 2.7%)
• Hyperglycemia (2.1% and 0%)
• Hypogammaglobulinemia (2.1% and 0%).

Serious AEs with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) were:

• Pneumonia (8.2% and 8.0%)
• Febrile neutropenia (3.6% and 8.5%)
• Pyrexia (2.6% and 6.9%)
• Anemia (1.5% and 2.7%)
• Infusion-related reaction (0.5% and 3.2%)
• Sepsis (0.5% and 2.1%)
• Tumor lysis syndrome (2.1% and 0.5%)
• Hypotension (0% and 2.7%).

Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.

Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter transformation.

Photo courtesy of Abbvie

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission (EC) approve a new indication for venetoclax (Venclyxto®).

AbbVie is seeking EC approval for venetoclax in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

The EC typically makes an approval decision within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

Venetoclax is already EC-approved as monotherapy for:

• Adults with CLL who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with a B-cell receptor pathway inhibitor
• Adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

The CHMP’s recommendation to approve venetoclax in combination with rituximab is supported by the phase 3 MURANO trial. Results from MURANO were published in The New England Journal of Medicine in March.

The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.

According to investigators, the median progression-free survival was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio, 0.17; P<0.0001).

According to an independent review committee, the median progression-free survival was not reached in the VEN+R arm and was 18.1 months in the B+R arm (hazard ratio, 0.20; P<0.0001).

Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) included:

• Neutropenia (57.7% and 38.8%)
• Infections and infestations (17.5% and 21.8%)
• Anemia (10.8% and 13.8%)
• Thrombocytopenia (5.7% and 10.1%)
• Febrile neutropenia (3.6% and 9.6%)
• Pneumonia (5.2% and 8.0%)
• Infusion-related reaction (1.5% and 5.3%)
• Tumor lysis syndrome (3.1% and 1.1%)
• Hypotension (0% and 2.7%)
• Hyperglycemia (2.1% and 0%)
• Hypogammaglobulinemia (2.1% and 0%).

Serious AEs with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) were:

• Pneumonia (8.2% and 8.0%)
• Febrile neutropenia (3.6% and 8.5%)
• Pyrexia (2.6% and 6.9%)
• Anemia (1.5% and 2.7%)
• Infusion-related reaction (0.5% and 3.2%)
• Sepsis (0.5% and 2.1%)
• Tumor lysis syndrome (2.1% and 0.5%)
• Hypotension (0% and 2.7%).

Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.

Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter transformation.

Photo courtesy of Abbvie

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission (EC) approve a new indication for venetoclax (Venclyxto®).

AbbVie is seeking EC approval for venetoclax in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

The EC typically makes an approval decision within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

Venetoclax is already EC-approved as monotherapy for:

• Adults with CLL who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with a B-cell receptor pathway inhibitor
• Adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

The CHMP’s recommendation to approve venetoclax in combination with rituximab is supported by the phase 3 MURANO trial. Results from MURANO were published in The New England Journal of Medicine in March.

The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.

According to investigators, the median progression-free survival was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio, 0.17; P<0.0001).

According to an independent review committee, the median progression-free survival was not reached in the VEN+R arm and was 18.1 months in the B+R arm (hazard ratio, 0.20; P<0.0001).

Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) included:

• Neutropenia (57.7% and 38.8%)
• Infections and infestations (17.5% and 21.8%)
• Anemia (10.8% and 13.8%)
• Thrombocytopenia (5.7% and 10.1%)
• Febrile neutropenia (3.6% and 9.6%)
• Pneumonia (5.2% and 8.0%)
• Infusion-related reaction (1.5% and 5.3%)
• Tumor lysis syndrome (3.1% and 1.1%)
• Hypotension (0% and 2.7%)
• Hyperglycemia (2.1% and 0%)
• Hypogammaglobulinemia (2.1% and 0%).

Serious AEs with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) were:

• Pneumonia (8.2% and 8.0%)
• Febrile neutropenia (3.6% and 8.5%)
• Pyrexia (2.6% and 6.9%)
• Anemia (1.5% and 2.7%)
• Infusion-related reaction (0.5% and 3.2%)
• Sepsis (0.5% and 2.1%)
• Tumor lysis syndrome (2.1% and 0.5%)
• Hypotension (0% and 2.7%).

Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.

Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter transformation.

mycosis fungoides

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for mogamulizumab (Poteligeo).

Kyowa Kirin Limited is seeking European Commission (EC) approval for mogamulizumab as a treatment for adults with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

The CHMP’s recommendation to approve mogamulizumab will be reviewed by the EC, and the EC is expected to make its decision about the drug by the end of this year.

The decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were published in The Lancet Oncology in August.

MAVORIC was a comparison of mogamulizumab and vorinostat in 372 adults with MF or SS who had received at least one prior systemic therapy.

Mogamulizumab provided a significant improvement in progression-free survival (PFS), the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in overall response rate (ORR) with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Grade 3 adverse events (AEs) in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

mycosis fungoides

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for mogamulizumab (Poteligeo).

Kyowa Kirin Limited is seeking European Commission (EC) approval for mogamulizumab as a treatment for adults with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

The CHMP’s recommendation to approve mogamulizumab will be reviewed by the EC, and the EC is expected to make its decision about the drug by the end of this year.

The decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were published in The Lancet Oncology in August.

MAVORIC was a comparison of mogamulizumab and vorinostat in 372 adults with MF or SS who had received at least one prior systemic therapy.

Mogamulizumab provided a significant improvement in progression-free survival (PFS), the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in overall response rate (ORR) with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Grade 3 adverse events (AEs) in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

mycosis fungoides

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for mogamulizumab (Poteligeo).

Kyowa Kirin Limited is seeking European Commission (EC) approval for mogamulizumab as a treatment for adults with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

The CHMP’s recommendation to approve mogamulizumab will be reviewed by the EC, and the EC is expected to make its decision about the drug by the end of this year.

The decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were published in The Lancet Oncology in August.

MAVORIC was a comparison of mogamulizumab and vorinostat in 372 adults with MF or SS who had received at least one prior systemic therapy.

Mogamulizumab provided a significant improvement in progression-free survival (PFS), the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to independent review, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in overall response rate (ORR) with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Grade 3 adverse events (AEs) in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

Mantle cell lymphoma

Researchers say they have found evidence to suggest that patients with mantle cell lymphoma (MCL) should be evaluated for TP53 mutation and complex karyotype (CK) simultaneously before treatment.

The team’s study showed that TP53 mutation and CK occurred independently, but patients with both characteristics had poor prognosis.

All patients with TP53 mutation and CK died within 1.2 years of diagnosis, whereas about 94% of patients with neither characteristic were still alive at 2 years.

The researchers also found that, by combining TP53 mutation and CK, patients could be stratified into three prognostic groups that had distinct outcomes, regardless of treatment.

Vít Procházka, MD, PhD, of Palacký University in Olomouc, Czech Republic, and his colleagues reported these findings in Clinical Lymphoma, Myeloma & Leukemia.

The study included 74 consecutive adults newly diagnosed with MCL from 2000 through 2014. Seventy-three patients were treated with a rituximab-containing regimen. One patient, who did not have TP53 mutation or CK, was under observation without therapy.

Altogether, 48 patients (64.9%) had biological material available to perform analyses for TP53 mutation and CK. Of those, 4 patients were found to have both TP53 mutation and CK, 12 had one of the two markers, and 32 had neither.

While all patients with both markers died within 1.2 years, 2-year overall survival was 50.0% for those with one marker and 93.8% for those with neither marker (P<0.001).

Progression-free survival analyses showed similar results. The 2-year progression-free survival rate was 41.7% for patients with one marker and 78% for patients with neither marker (P<0.001).

Multivariate analysis showed that both TP53 mutation and CK were predictors of inferior progression-free survival and overall survival, independent of age and scores on the MCL International Prognostic Index.

While larger studies are needed to confirm these results, the researchers suggested that novel treatment approaches might be warranted for patients in the highest risk subgroup.

“The patients harboring the negative prognostic markers [TP53 mutation] and CK might be indicated for a novel induction treatment strategy probably in combination with maintenance therapy different from rituximab,” the researchers said.

This study was supported by grants from the Czech Ministry of Health and Palacký University. The researchers reported having no conflicts of interest.

Mantle cell lymphoma

Researchers say they have found evidence to suggest that patients with mantle cell lymphoma (MCL) should be evaluated for TP53 mutation and complex karyotype (CK) simultaneously before treatment.

The team’s study showed that TP53 mutation and CK occurred independently, but patients with both characteristics had poor prognosis.

All patients with TP53 mutation and CK died within 1.2 years of diagnosis, whereas about 94% of patients with neither characteristic were still alive at 2 years.

The researchers also found that, by combining TP53 mutation and CK, patients could be stratified into three prognostic groups that had distinct outcomes, regardless of treatment.

Vít Procházka, MD, PhD, of Palacký University in Olomouc, Czech Republic, and his colleagues reported these findings in Clinical Lymphoma, Myeloma & Leukemia.

The study included 74 consecutive adults newly diagnosed with MCL from 2000 through 2014. Seventy-three patients were treated with a rituximab-containing regimen. One patient, who did not have TP53 mutation or CK, was under observation without therapy.

Altogether, 48 patients (64.9%) had biological material available to perform analyses for TP53 mutation and CK. Of those, 4 patients were found to have both TP53 mutation and CK, 12 had one of the two markers, and 32 had neither.

While all patients with both markers died within 1.2 years, 2-year overall survival was 50.0% for those with one marker and 93.8% for those with neither marker (P<0.001).

Progression-free survival analyses showed similar results. The 2-year progression-free survival rate was 41.7% for patients with one marker and 78% for patients with neither marker (P<0.001).

Multivariate analysis showed that both TP53 mutation and CK were predictors of inferior progression-free survival and overall survival, independent of age and scores on the MCL International Prognostic Index.

While larger studies are needed to confirm these results, the researchers suggested that novel treatment approaches might be warranted for patients in the highest risk subgroup.

“The patients harboring the negative prognostic markers [TP53 mutation] and CK might be indicated for a novel induction treatment strategy probably in combination with maintenance therapy different from rituximab,” the researchers said.

This study was supported by grants from the Czech Ministry of Health and Palacký University. The researchers reported having no conflicts of interest.

Mantle cell lymphoma

Researchers say they have found evidence to suggest that patients with mantle cell lymphoma (MCL) should be evaluated for TP53 mutation and complex karyotype (CK) simultaneously before treatment.

The team’s study showed that TP53 mutation and CK occurred independently, but patients with both characteristics had poor prognosis.

All patients with TP53 mutation and CK died within 1.2 years of diagnosis, whereas about 94% of patients with neither characteristic were still alive at 2 years.

The researchers also found that, by combining TP53 mutation and CK, patients could be stratified into three prognostic groups that had distinct outcomes, regardless of treatment.

Vít Procházka, MD, PhD, of Palacký University in Olomouc, Czech Republic, and his colleagues reported these findings in Clinical Lymphoma, Myeloma & Leukemia.

The study included 74 consecutive adults newly diagnosed with MCL from 2000 through 2014. Seventy-three patients were treated with a rituximab-containing regimen. One patient, who did not have TP53 mutation or CK, was under observation without therapy.

Altogether, 48 patients (64.9%) had biological material available to perform analyses for TP53 mutation and CK. Of those, 4 patients were found to have both TP53 mutation and CK, 12 had one of the two markers, and 32 had neither.

While all patients with both markers died within 1.2 years, 2-year overall survival was 50.0% for those with one marker and 93.8% for those with neither marker (P<0.001).

Progression-free survival analyses showed similar results. The 2-year progression-free survival rate was 41.7% for patients with one marker and 78% for patients with neither marker (P<0.001).

Multivariate analysis showed that both TP53 mutation and CK were predictors of inferior progression-free survival and overall survival, independent of age and scores on the MCL International Prognostic Index.

While larger studies are needed to confirm these results, the researchers suggested that novel treatment approaches might be warranted for patients in the highest risk subgroup.

“The patients harboring the negative prognostic markers [TP53 mutation] and CK might be indicated for a novel induction treatment strategy probably in combination with maintenance therapy different from rituximab,” the researchers said.

This study was supported by grants from the Czech Ministry of Health and Palacký University. The researchers reported having no conflicts of interest.

Micrograph showing CLL

New research has linked stress levels to markers of progressive disease in patients with chronic lymphocytic leukemia (CLL).

Researchers found that CLL patients who reported more stress also had higher absolute lymphocyte counts and elevated levels of three other markers of more advanced disease—tumor necrosis factor-α (TNFα), interleukin 16 (IL-16), and chemokine ligand 3 (CCL3).

“All four variables we measured are related to prognosis in CLL patients, so they have a lot of relevance,” said study author Barbara L. Andersen, PhD, of The Ohio State University in Columbus.

She and her colleagues described this research in Cancer.

The study involved 96 patients with relapsed/refractory CLL who were entering a phase 2 trial of ibrutinib (NCT01589302). Data collection for this study was done before patients received their first dose of ibrutinib.

All patients completed a survey that measured CLL-related stress. They were asked questions like how often they had intrusive thoughts about their disease, how often they tried to avoid thinking about it, and how often they felt jumpy and easily startled.

The researchers used blood samples to determine patients’ absolute lymphocyte counts and to measure levels of eight cytokines known to promote unhealthy levels of inflammation—IL-6, IL-10, IL-16, TNFα, a proliferation‐inducing ligand (APRIL), B‐cell activating factor (BAFF), vascular endothelial growth factor (VEGF), and CCL3.

In an analysis controlling for demographic characteristics, comorbidities, the presence of 17p deletion, and correlates of inflammation, higher stress was significantly associated with higher:

• Absolute lymphocyte counts (P<0.05)
• Levels of TNFα (P<0.05)
• Levels of IL‐16 (P<0.01)
• Levels of CCL3 (P<0.05).

“The fact that stress shows an effect on CLL even after we controlled for other factors suggests it may be relevant to the course of CLL,” Dr. Andersen said.

She added that the researchers are still following these patients and will examine the relationship between stress and disease markers throughout treatment.

This study was supported by the National Cancer Institute, Pharmacylics (the company developing ibrutinib), and a Pelotonia Idea Award from The Ohio State University Comprehensive Cancer Center.

Micrograph showing CLL

New research has linked stress levels to markers of progressive disease in patients with chronic lymphocytic leukemia (CLL).

Researchers found that CLL patients who reported more stress also had higher absolute lymphocyte counts and elevated levels of three other markers of more advanced disease—tumor necrosis factor-α (TNFα), interleukin 16 (IL-16), and chemokine ligand 3 (CCL3).

“All four variables we measured are related to prognosis in CLL patients, so they have a lot of relevance,” said study author Barbara L. Andersen, PhD, of The Ohio State University in Columbus.

She and her colleagues described this research in Cancer.

The study involved 96 patients with relapsed/refractory CLL who were entering a phase 2 trial of ibrutinib (NCT01589302). Data collection for this study was done before patients received their first dose of ibrutinib.

All patients completed a survey that measured CLL-related stress. They were asked questions like how often they had intrusive thoughts about their disease, how often they tried to avoid thinking about it, and how often they felt jumpy and easily startled.

The researchers used blood samples to determine patients’ absolute lymphocyte counts and to measure levels of eight cytokines known to promote unhealthy levels of inflammation—IL-6, IL-10, IL-16, TNFα, a proliferation‐inducing ligand (APRIL), B‐cell activating factor (BAFF), vascular endothelial growth factor (VEGF), and CCL3.

In an analysis controlling for demographic characteristics, comorbidities, the presence of 17p deletion, and correlates of inflammation, higher stress was significantly associated with higher:

• Absolute lymphocyte counts (P<0.05)
• Levels of TNFα (P<0.05)
• Levels of IL‐16 (P<0.01)
• Levels of CCL3 (P<0.05).

“The fact that stress shows an effect on CLL even after we controlled for other factors suggests it may be relevant to the course of CLL,” Dr. Andersen said.

She added that the researchers are still following these patients and will examine the relationship between stress and disease markers throughout treatment.

This study was supported by the National Cancer Institute, Pharmacylics (the company developing ibrutinib), and a Pelotonia Idea Award from The Ohio State University Comprehensive Cancer Center.

Micrograph showing CLL

New research has linked stress levels to markers of progressive disease in patients with chronic lymphocytic leukemia (CLL).

Researchers found that CLL patients who reported more stress also had higher absolute lymphocyte counts and elevated levels of three other markers of more advanced disease—tumor necrosis factor-α (TNFα), interleukin 16 (IL-16), and chemokine ligand 3 (CCL3).

“All four variables we measured are related to prognosis in CLL patients, so they have a lot of relevance,” said study author Barbara L. Andersen, PhD, of The Ohio State University in Columbus.

She and her colleagues described this research in Cancer.

The study involved 96 patients with relapsed/refractory CLL who were entering a phase 2 trial of ibrutinib (NCT01589302). Data collection for this study was done before patients received their first dose of ibrutinib.

All patients completed a survey that measured CLL-related stress. They were asked questions like how often they had intrusive thoughts about their disease, how often they tried to avoid thinking about it, and how often they felt jumpy and easily startled.

The researchers used blood samples to determine patients’ absolute lymphocyte counts and to measure levels of eight cytokines known to promote unhealthy levels of inflammation—IL-6, IL-10, IL-16, TNFα, a proliferation‐inducing ligand (APRIL), B‐cell activating factor (BAFF), vascular endothelial growth factor (VEGF), and CCL3.

In an analysis controlling for demographic characteristics, comorbidities, the presence of 17p deletion, and correlates of inflammation, higher stress was significantly associated with higher:

• Absolute lymphocyte counts (P<0.05)
• Levels of TNFα (P<0.05)
• Levels of IL‐16 (P<0.01)
• Levels of CCL3 (P<0.05).

“The fact that stress shows an effect on CLL even after we controlled for other factors suggests it may be relevant to the course of CLL,” Dr. Andersen said.

She added that the researchers are still following these patients and will examine the relationship between stress and disease markers throughout treatment.

This study was supported by the National Cancer Institute, Pharmacylics (the company developing ibrutinib), and a Pelotonia Idea Award from The Ohio State University Comprehensive Cancer Center.

Photo from Novartis

The National Institute for Health and Care Excellence (NICE) has issued a draft guidance saying it cannot recommend tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission (EC) to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also EC-approved to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.

Earlier this month, the National Health Service (NHS) of England announced that tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, NICE’s new draft guidance, issued September 19, says tisagenlecleucel cannot be made available for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy.

NICE noted that there is no standard treatment for this patient group, and salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial¹ suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy.

In addition, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

Furthermore, NICE said all cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is £282,000. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

All of the aforementioned issues aside, NICE said it does recognize that tisagenlecleucel has significant clinical benefits, and the agency welcomes further discussions on the CAR T-cell therapy’s cost-effectiveness.

NICE will consider comments on its draft guidance for tisagenlecleucel, together with any new evidence, at its next meeting on October 23, 2018.

Last month, NICE expressed similar sentiments about another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta).

Axicabtagene ciloleucel is EC-approved to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. Additionally, the cost of axicabtagene ciloleucel is too high for it to be considered a cost-effective use of NHS resources, and the therapy does not meet criteria for inclusion in the Cancer Drugs Fund.

1. Borchmann P et al. AN UPDATED ANALYSIS OF JULIET, A GLOBAL PIVOTAL PHASE 2 TRIAL OF TISAGENLECLEUCEL IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). EHA 2018. Abstract S799.

Photo from Novartis

The National Institute for Health and Care Excellence (NICE) has issued a draft guidance saying it cannot recommend tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission (EC) to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also EC-approved to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.

Earlier this month, the National Health Service (NHS) of England announced that tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, NICE’s new draft guidance, issued September 19, says tisagenlecleucel cannot be made available for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy.

NICE noted that there is no standard treatment for this patient group, and salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial¹ suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy.

In addition, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

Furthermore, NICE said all cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is £282,000. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

All of the aforementioned issues aside, NICE said it does recognize that tisagenlecleucel has significant clinical benefits, and the agency welcomes further discussions on the CAR T-cell therapy’s cost-effectiveness.

NICE will consider comments on its draft guidance for tisagenlecleucel, together with any new evidence, at its next meeting on October 23, 2018.

Last month, NICE expressed similar sentiments about another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta).

Axicabtagene ciloleucel is EC-approved to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. Additionally, the cost of axicabtagene ciloleucel is too high for it to be considered a cost-effective use of NHS resources, and the therapy does not meet criteria for inclusion in the Cancer Drugs Fund.

1. Borchmann P et al. AN UPDATED ANALYSIS OF JULIET, A GLOBAL PIVOTAL PHASE 2 TRIAL OF TISAGENLECLEUCEL IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). EHA 2018. Abstract S799.

Photo from Novartis

The National Institute for Health and Care Excellence (NICE) has issued a draft guidance saying it cannot recommend tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission (EC) to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also EC-approved to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.

Earlier this month, the National Health Service (NHS) of England announced that tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, NICE’s new draft guidance, issued September 19, says tisagenlecleucel cannot be made available for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy.

NICE noted that there is no standard treatment for this patient group, and salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial¹ suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy.

In addition, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

Furthermore, NICE said all cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is £282,000. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

All of the aforementioned issues aside, NICE said it does recognize that tisagenlecleucel has significant clinical benefits, and the agency welcomes further discussions on the CAR T-cell therapy’s cost-effectiveness.

NICE will consider comments on its draft guidance for tisagenlecleucel, together with any new evidence, at its next meeting on October 23, 2018.

Last month, NICE expressed similar sentiments about another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta).

Axicabtagene ciloleucel is EC-approved to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. Additionally, the cost of axicabtagene ciloleucel is too high for it to be considered a cost-effective use of NHS resources, and the therapy does not meet criteria for inclusion in the Cancer Drugs Fund.

1. Borchmann P et al. AN UPDATED ANALYSIS OF JULIET, A GLOBAL PIVOTAL PHASE 2 TRIAL OF TISAGENLECLEUCEL IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). EHA 2018. Abstract S799.

Photo from Penn Medicine

Proton therapy can help mitigate toxicity in adults with mediastinal lymphomas, but the treatment should only be used in patients expected to derive the most benefit, according to new guidelines from the International Lymphoma Radiation Oncology Group.

The guidelines note that proton therapy reduces the radiation dose to organs at risk in certain clinical presentations, such as when the mediastinal target is on both sides of the heart.

However, the advantages of proton therapy are not always clear in other situations, such as when the target spans the right side of the heart or when the target is above the heart with no axillary involvement.

“The limited availability of proton therapy calls for case selection based on a clear understanding of which cases will derive most benefit from proton therapy as compared to advanced photon techniques,” said guideline author Bouthaina Dabaja, MD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues.

The group’s guidelines were published in Blood.

The guidelines note that proton therapy—like intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy—presents an opportunity for more conformal dose distribution and better sparing of organs at risk.

Proton therapy can greatly benefit certain patients with mediastinal disease, including:

• Young female patients in whom proton therapy would reduce the breast dose and decrease the risk of secondary breast cancer
• Patients at high risk of radiation-related toxicity due to previous treatment
• Patients with disease spanning below the origin of the left main stem coronary artery that is anterior to, posterior to, or on the left side of the heart.

“The relation of disease to organs at risk determines the situations in which proton therapy is most beneficial,” the experts said in the guidelines.

However, the consideration of proton therapy needs to factor in the complexities of proton therapy planning, the need to manage uncertainties, and the “evolving nature of the technology,” which includes the development of pencil beam scanning.

While passive scattering proton therapy is the least complex delivery technique, it is challenging because beams can conform only to one side of the target. In contrast, active mode pencil beam scanning proton therapy potentially provides better conformality and sparing of organs at risk.

“Because treatment involves delivery of individual controlled spots, inhomogenous doses can be created deliberately,” the guideline authors said.

However, “motion management is of prime importance” with pencil beam scanning proton therapy, which is more sensitive to density changes in the beam path than is passive scattering proton therapy.

To that end, physicians should pay close attention to evaluating intrafractional movement, which is frequently tied to the breathing cycle.

Dr. Dabaja and her coauthors reported no funding or conflicts of interest.

Photo from Penn Medicine

Proton therapy can help mitigate toxicity in adults with mediastinal lymphomas, but the treatment should only be used in patients expected to derive the most benefit, according to new guidelines from the International Lymphoma Radiation Oncology Group.

The guidelines note that proton therapy reduces the radiation dose to organs at risk in certain clinical presentations, such as when the mediastinal target is on both sides of the heart.

However, the advantages of proton therapy are not always clear in other situations, such as when the target spans the right side of the heart or when the target is above the heart with no axillary involvement.

“The limited availability of proton therapy calls for case selection based on a clear understanding of which cases will derive most benefit from proton therapy as compared to advanced photon techniques,” said guideline author Bouthaina Dabaja, MD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues.

The group’s guidelines were published in Blood.

The guidelines note that proton therapy—like intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy—presents an opportunity for more conformal dose distribution and better sparing of organs at risk.

Proton therapy can greatly benefit certain patients with mediastinal disease, including:

• Young female patients in whom proton therapy would reduce the breast dose and decrease the risk of secondary breast cancer
• Patients at high risk of radiation-related toxicity due to previous treatment
• Patients with disease spanning below the origin of the left main stem coronary artery that is anterior to, posterior to, or on the left side of the heart.

“The relation of disease to organs at risk determines the situations in which proton therapy is most beneficial,” the experts said in the guidelines.

However, the consideration of proton therapy needs to factor in the complexities of proton therapy planning, the need to manage uncertainties, and the “evolving nature of the technology,” which includes the development of pencil beam scanning.

While passive scattering proton therapy is the least complex delivery technique, it is challenging because beams can conform only to one side of the target. In contrast, active mode pencil beam scanning proton therapy potentially provides better conformality and sparing of organs at risk.

“Because treatment involves delivery of individual controlled spots, inhomogenous doses can be created deliberately,” the guideline authors said.

However, “motion management is of prime importance” with pencil beam scanning proton therapy, which is more sensitive to density changes in the beam path than is passive scattering proton therapy.

To that end, physicians should pay close attention to evaluating intrafractional movement, which is frequently tied to the breathing cycle.

Dr. Dabaja and her coauthors reported no funding or conflicts of interest.

Photo from Penn Medicine

Proton therapy can help mitigate toxicity in adults with mediastinal lymphomas, but the treatment should only be used in patients expected to derive the most benefit, according to new guidelines from the International Lymphoma Radiation Oncology Group.

The guidelines note that proton therapy reduces the radiation dose to organs at risk in certain clinical presentations, such as when the mediastinal target is on both sides of the heart.

However, the advantages of proton therapy are not always clear in other situations, such as when the target spans the right side of the heart or when the target is above the heart with no axillary involvement.

“The limited availability of proton therapy calls for case selection based on a clear understanding of which cases will derive most benefit from proton therapy as compared to advanced photon techniques,” said guideline author Bouthaina Dabaja, MD, of the University of Texas MD Anderson Cancer Center in Houston, and her colleagues.

The group’s guidelines were published in Blood.

The guidelines note that proton therapy—like intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy—presents an opportunity for more conformal dose distribution and better sparing of organs at risk.

Proton therapy can greatly benefit certain patients with mediastinal disease, including:

• Young female patients in whom proton therapy would reduce the breast dose and decrease the risk of secondary breast cancer
• Patients at high risk of radiation-related toxicity due to previous treatment
• Patients with disease spanning below the origin of the left main stem coronary artery that is anterior to, posterior to, or on the left side of the heart.

“The relation of disease to organs at risk determines the situations in which proton therapy is most beneficial,” the experts said in the guidelines.

However, the consideration of proton therapy needs to factor in the complexities of proton therapy planning, the need to manage uncertainties, and the “evolving nature of the technology,” which includes the development of pencil beam scanning.

While passive scattering proton therapy is the least complex delivery technique, it is challenging because beams can conform only to one side of the target. In contrast, active mode pencil beam scanning proton therapy potentially provides better conformality and sparing of organs at risk.

“Because treatment involves delivery of individual controlled spots, inhomogenous doses can be created deliberately,” the guideline authors said.

However, “motion management is of prime importance” with pencil beam scanning proton therapy, which is more sensitive to density changes in the beam path than is passive scattering proton therapy.

To that end, physicians should pay close attention to evaluating intrafractional movement, which is frequently tied to the breathing cycle.

Dr. Dabaja and her coauthors reported no funding or conflicts of interest.