Aggressive Lymphomas

Gilles Salles, MD, PhD

The chimeric antigen receptor (CAR) T-cell therapy CTL019 produced a high response rate in a phase 2 trial of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

An interim analysis of the JULIET trial revealed a 3-month overall response rate (ORR) of 45%.

Thirty-seven percent of patients had a complete response (CR), and all of the patients who were in CR at 3 months were still in CR at the data cutoff point.

This confirms the high response rates and durable responses observed in a previous single-center trial*, said JULIET investigator Gilles Salles, MD, PhD, of Hospices Civils de Lyon in Lyon, France.

Dr Salles presented results from JULIET at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain (abstract LB2604).

The results were also presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (abstract 007).

The study was sponsored by Novartis.

Patients

JULIET enrolled 141 patients age 18 and older with relapsed/refractory DLBCL.

Forty-three patients discontinued the study before receiving CTL019—28 due to progressive disease (including 16 deaths), 9 due to an inability to manufacture CTL019, 2 due to adverse events, 1 due to investigator decision, 1 due to study withdrawal, and 1 due to protocol deviation.

Eighty-five patients were infused. The remaining 13 patients were pending infusion at the data cutoff—December 20, 2016.

The median age of the 85 infused patients was 56 (range, 24-75). Ninety-six percent of patients had DLBCL not otherwise specified. Fifty-one percent had germinal center B-cell type DLBCL.

Fifty-four percent of patients had an ECOG performance status of 0, and 46% had a status of 1. Fifty-three percent of patients had stage IV disease, and 8% had bone marrow involvement.

Forty percent of patients had 2 prior lines of antineoplastic therapy, 29% had 3, and 31% had 4 to 7 prior lines.

Forty-one percent of patients were refractory to their last therapy, and 59% had relapsed after their last therapy. Fifty-one percent of patients had prior autologous stem cell transplant.

Treatment

Seventy-six patients (89%) received bridging chemotherapy to prevent disease progression during CTL019 manufacturing. This treatment was completed 2 to 14 days prior to CTL019 infusion.

The median CTL019 cell dose was 3.1 x 10⁸ (range, 0.1-6.0 x 10⁸).

Response

Fifty-one patients were evaluated for response. The median time from infusion to data cutoff was 3.7 months.

The best ORR was 59%, with a CR rate of 43% and a partial response rate of 16%. Twelve percent of patients had stable disease, and 24% progressed.

At 3 months, the ORR was 45%. The CR rate was 37%, and the partial response rate was 8%.

“All patients in CR at 3 months remained in CR at follow-up, and the median duration of response was not reached,” Dr Salles noted.

None of the responders went on to receive a transplant.

Safety

All 85 patients were evaluated for safety. Adverse events of special interest, occurring within 8 weeks of CTL019 infusion, were:

• Cytokine release syndrome—57% all grades, 17% grade 3, 9% grade 4
• Infections—27% all grades, 12% grade 3, 1% grade 4
• Cytopenias not resolved by day 28—26% all grades, 13% grade 3, 8% grade 4
• Neurologic events—21% all grades, 9% grade 3, 4% grade 4
• Febrile neutropenia—14% all grades, 13% grade 3, 1% grade 4
• Tumor lysis syndrome—1% grade 3.

“Adverse events were reversible and effectively managed at the different centers by appropriately trained study personnel,” Dr Salles noted. “There were no CTL019-related deaths and no cerebral edema.”

*SJ Schuster et al, 2016 ASH Annual Meeting, abstract 3026

Gilles Salles, MD, PhD

The chimeric antigen receptor (CAR) T-cell therapy CTL019 produced a high response rate in a phase 2 trial of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

An interim analysis of the JULIET trial revealed a 3-month overall response rate (ORR) of 45%.

Thirty-seven percent of patients had a complete response (CR), and all of the patients who were in CR at 3 months were still in CR at the data cutoff point.

This confirms the high response rates and durable responses observed in a previous single-center trial*, said JULIET investigator Gilles Salles, MD, PhD, of Hospices Civils de Lyon in Lyon, France.

Dr Salles presented results from JULIET at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain (abstract LB2604).

The results were also presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (abstract 007).

The study was sponsored by Novartis.

Patients

JULIET enrolled 141 patients age 18 and older with relapsed/refractory DLBCL.

Forty-three patients discontinued the study before receiving CTL019—28 due to progressive disease (including 16 deaths), 9 due to an inability to manufacture CTL019, 2 due to adverse events, 1 due to investigator decision, 1 due to study withdrawal, and 1 due to protocol deviation.

Eighty-five patients were infused. The remaining 13 patients were pending infusion at the data cutoff—December 20, 2016.

The median age of the 85 infused patients was 56 (range, 24-75). Ninety-six percent of patients had DLBCL not otherwise specified. Fifty-one percent had germinal center B-cell type DLBCL.

Fifty-four percent of patients had an ECOG performance status of 0, and 46% had a status of 1. Fifty-three percent of patients had stage IV disease, and 8% had bone marrow involvement.

Forty percent of patients had 2 prior lines of antineoplastic therapy, 29% had 3, and 31% had 4 to 7 prior lines.

Forty-one percent of patients were refractory to their last therapy, and 59% had relapsed after their last therapy. Fifty-one percent of patients had prior autologous stem cell transplant.

Treatment

Seventy-six patients (89%) received bridging chemotherapy to prevent disease progression during CTL019 manufacturing. This treatment was completed 2 to 14 days prior to CTL019 infusion.

The median CTL019 cell dose was 3.1 x 10⁸ (range, 0.1-6.0 x 10⁸).

Response

Fifty-one patients were evaluated for response. The median time from infusion to data cutoff was 3.7 months.

The best ORR was 59%, with a CR rate of 43% and a partial response rate of 16%. Twelve percent of patients had stable disease, and 24% progressed.

At 3 months, the ORR was 45%. The CR rate was 37%, and the partial response rate was 8%.

“All patients in CR at 3 months remained in CR at follow-up, and the median duration of response was not reached,” Dr Salles noted.

None of the responders went on to receive a transplant.

Safety

All 85 patients were evaluated for safety. Adverse events of special interest, occurring within 8 weeks of CTL019 infusion, were:

• Cytokine release syndrome—57% all grades, 17% grade 3, 9% grade 4
• Infections—27% all grades, 12% grade 3, 1% grade 4
• Cytopenias not resolved by day 28—26% all grades, 13% grade 3, 8% grade 4
• Neurologic events—21% all grades, 9% grade 3, 4% grade 4
• Febrile neutropenia—14% all grades, 13% grade 3, 1% grade 4
• Tumor lysis syndrome—1% grade 3.

“Adverse events were reversible and effectively managed at the different centers by appropriately trained study personnel,” Dr Salles noted. “There were no CTL019-related deaths and no cerebral edema.”

*SJ Schuster et al, 2016 ASH Annual Meeting, abstract 3026

Gilles Salles, MD, PhD

The chimeric antigen receptor (CAR) T-cell therapy CTL019 produced a high response rate in a phase 2 trial of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

An interim analysis of the JULIET trial revealed a 3-month overall response rate (ORR) of 45%.

Thirty-seven percent of patients had a complete response (CR), and all of the patients who were in CR at 3 months were still in CR at the data cutoff point.

This confirms the high response rates and durable responses observed in a previous single-center trial*, said JULIET investigator Gilles Salles, MD, PhD, of Hospices Civils de Lyon in Lyon, France.

Dr Salles presented results from JULIET at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain (abstract LB2604).

The results were also presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (abstract 007).

The study was sponsored by Novartis.

Patients

JULIET enrolled 141 patients age 18 and older with relapsed/refractory DLBCL.

Forty-three patients discontinued the study before receiving CTL019—28 due to progressive disease (including 16 deaths), 9 due to an inability to manufacture CTL019, 2 due to adverse events, 1 due to investigator decision, 1 due to study withdrawal, and 1 due to protocol deviation.

Eighty-five patients were infused. The remaining 13 patients were pending infusion at the data cutoff—December 20, 2016.

The median age of the 85 infused patients was 56 (range, 24-75). Ninety-six percent of patients had DLBCL not otherwise specified. Fifty-one percent had germinal center B-cell type DLBCL.

Fifty-four percent of patients had an ECOG performance status of 0, and 46% had a status of 1. Fifty-three percent of patients had stage IV disease, and 8% had bone marrow involvement.

Forty percent of patients had 2 prior lines of antineoplastic therapy, 29% had 3, and 31% had 4 to 7 prior lines.

Forty-one percent of patients were refractory to their last therapy, and 59% had relapsed after their last therapy. Fifty-one percent of patients had prior autologous stem cell transplant.

Treatment

Seventy-six patients (89%) received bridging chemotherapy to prevent disease progression during CTL019 manufacturing. This treatment was completed 2 to 14 days prior to CTL019 infusion.

The median CTL019 cell dose was 3.1 x 10⁸ (range, 0.1-6.0 x 10⁸).

Response

Fifty-one patients were evaluated for response. The median time from infusion to data cutoff was 3.7 months.

The best ORR was 59%, with a CR rate of 43% and a partial response rate of 16%. Twelve percent of patients had stable disease, and 24% progressed.

At 3 months, the ORR was 45%. The CR rate was 37%, and the partial response rate was 8%.

“All patients in CR at 3 months remained in CR at follow-up, and the median duration of response was not reached,” Dr Salles noted.

None of the responders went on to receive a transplant.

Safety

All 85 patients were evaluated for safety. Adverse events of special interest, occurring within 8 weeks of CTL019 infusion, were:

• Cytokine release syndrome—57% all grades, 17% grade 3, 9% grade 4
• Infections—27% all grades, 12% grade 3, 1% grade 4
• Cytopenias not resolved by day 28—26% all grades, 13% grade 3, 8% grade 4
• Neurologic events—21% all grades, 9% grade 3, 4% grade 4
• Febrile neutropenia—14% all grades, 13% grade 3, 1% grade 4
• Tumor lysis syndrome—1% grade 3.

“Adverse events were reversible and effectively managed at the different centers by appropriately trained study personnel,” Dr Salles noted. “There were no CTL019-related deaths and no cerebral edema.”

*SJ Schuster et al, 2016 ASH Annual Meeting, abstract 3026

Micrograph showing CLL

LUGANO, SWITZERLAND—Results of a phase 1 study suggest a 2-drug combination may be safe and effective in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL).

The ongoing study is a test of the BTK inhibitor BGB-3111 and the anti-CD20 antibody obinutuzumab.

The overall response rate (ORR) with this combination was 81% in the entire study population, 89% in treatment-naïve CLL/SLL patients, 92% in relapsed/refractory CLL/SLL patients, and 73% in relapsed/refractory FL patients.

The rate of serious adverse events (AEs) was 24% in both CLL/SLL and FL patients.

These results were presented at the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by BeiGene, Ltd.

“This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase,” said study investigator Constantine Tam, MD, of St. Vincent’s Hospital in Melbourne, Australia.

“The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time.”

The trial consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include treatment-naive or relapsed/refractory CLL/SLL and relapsed/refractory FL.

The dose-escalation component is testing BGB-3111 at 320 mg once daily or 160 mg twice daily in 28-day cycles, in combination with obinutuzumab. Obinutuzumab is administered in line with standard CLL dosing (3 loading doses of 1000 mg weekly, followed by 1000 mg on day 1 of cycles 2 to 6).

The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg twice daily with the same obinutuzumab schedule.

As of the data cutoff (March 31, 2017), 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.

Patient characteristics

The median age was 68 (range, 28-82) in the CLL/SLL patients and 56 (range, 41-86) in the FL patients.

ECOG performance status was 0 in 42% of CLL/SLL patients, 1 in 56% of these patients, and 2 in 2%. ECOG performance status was 0 in 82% of FL patients, 1 in 12% of these patients, and 2 in 6%.

Twenty CLL/SLL patients were treatment-naïve, and 25 had relapsed/refractory disease. All 17 FL patients had relapsed/refractory disease.

The median number of prior therapies was 1 (range, 1-4) in the relapsed/refractory CLL/SLL patients and 3 (range, 1-7) in the FL patients.

Safety

At the time of the data cutoff, BGB-3111 was deemed well tolerated in patients with CLL/SLL and FL.

The most frequent AEs of any cause occurring in at least 15% of patients with CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%).

Most of these events were grade 1/2. The exceptions were grade 3/4 neutropenia (20%) and grade 3/4 thrombocytopenia (4%).

The most frequent AEs in FL patients were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%). All of these events were grade 1/2.

Serious AEs occurred in 24% of both the CLL/SLL patients and the FL patients.

Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients. Nearly all cases were grade 1/2. The exception was 1 grade 4 case in a CLL/SLL patient.

There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation.

One patient discontinued treatment due to an AE—squamous cell carcinoma. This patient had a prior history of squamous cell carcinoma.

Efficacy

At the time of the data cutoff, 43 patients with CLL/SLL (18 treatment-naive, 25 relapsed/refractory) and 15 patients with relapsed/refractory FL had greater than 12 weeks of follow-up and were evaluable for efficacy.

In treatment-naive CLL/SLL, after a median follow-up of 7.0 months (range, 2.8–11.8 months), the ORR was 89%. The complete response (CR) rate was 22%, the rate of partial response (PR) was 67%, and the rate of stable disease (SD) was 11%.

In relapsed/refractory CLL/SLL, at a median follow-up of 8.0 months (range, 3.8–14.0 months) the ORR was 92%. The CR rate was 16%, the PR rate was 76%, and 4% of patients had SD.

One patient (4%) with relapsed/refractory CLL/SLL had progressive disease (Richter’s transformation).

In relapsed/refractory FL, at a median follow-up of 6.2 months (range, 1.2–10.7 months), the ORR was 73%. The CR rate was 33%, the PR rate was 40%, and 13% of patients had SD.

Two patients (13%) with relapsed/refractory FL had progressive disease.

On the basis of these data, BeiGene plans to expand its global registrational program for BGB-3111 to include a phase 2 trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with relapsed/refractory FL.

The company is also planning a phase 3 trial comparing BGB-3111 with bendamustine plus rituximab in patients with treatment-naive CLL.

Micrograph showing CLL

LUGANO, SWITZERLAND—Results of a phase 1 study suggest a 2-drug combination may be safe and effective in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL).

The ongoing study is a test of the BTK inhibitor BGB-3111 and the anti-CD20 antibody obinutuzumab.

The overall response rate (ORR) with this combination was 81% in the entire study population, 89% in treatment-naïve CLL/SLL patients, 92% in relapsed/refractory CLL/SLL patients, and 73% in relapsed/refractory FL patients.

The rate of serious adverse events (AEs) was 24% in both CLL/SLL and FL patients.

These results were presented at the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by BeiGene, Ltd.

“This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase,” said study investigator Constantine Tam, MD, of St. Vincent’s Hospital in Melbourne, Australia.

“The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time.”

The trial consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include treatment-naive or relapsed/refractory CLL/SLL and relapsed/refractory FL.

The dose-escalation component is testing BGB-3111 at 320 mg once daily or 160 mg twice daily in 28-day cycles, in combination with obinutuzumab. Obinutuzumab is administered in line with standard CLL dosing (3 loading doses of 1000 mg weekly, followed by 1000 mg on day 1 of cycles 2 to 6).

The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg twice daily with the same obinutuzumab schedule.

As of the data cutoff (March 31, 2017), 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.

Patient characteristics

The median age was 68 (range, 28-82) in the CLL/SLL patients and 56 (range, 41-86) in the FL patients.

ECOG performance status was 0 in 42% of CLL/SLL patients, 1 in 56% of these patients, and 2 in 2%. ECOG performance status was 0 in 82% of FL patients, 1 in 12% of these patients, and 2 in 6%.

Twenty CLL/SLL patients were treatment-naïve, and 25 had relapsed/refractory disease. All 17 FL patients had relapsed/refractory disease.

The median number of prior therapies was 1 (range, 1-4) in the relapsed/refractory CLL/SLL patients and 3 (range, 1-7) in the FL patients.

Safety

At the time of the data cutoff, BGB-3111 was deemed well tolerated in patients with CLL/SLL and FL.

The most frequent AEs of any cause occurring in at least 15% of patients with CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%).

Most of these events were grade 1/2. The exceptions were grade 3/4 neutropenia (20%) and grade 3/4 thrombocytopenia (4%).

The most frequent AEs in FL patients were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%). All of these events were grade 1/2.

Serious AEs occurred in 24% of both the CLL/SLL patients and the FL patients.

Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients. Nearly all cases were grade 1/2. The exception was 1 grade 4 case in a CLL/SLL patient.

There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation.

One patient discontinued treatment due to an AE—squamous cell carcinoma. This patient had a prior history of squamous cell carcinoma.

Efficacy

At the time of the data cutoff, 43 patients with CLL/SLL (18 treatment-naive, 25 relapsed/refractory) and 15 patients with relapsed/refractory FL had greater than 12 weeks of follow-up and were evaluable for efficacy.

In treatment-naive CLL/SLL, after a median follow-up of 7.0 months (range, 2.8–11.8 months), the ORR was 89%. The complete response (CR) rate was 22%, the rate of partial response (PR) was 67%, and the rate of stable disease (SD) was 11%.

In relapsed/refractory CLL/SLL, at a median follow-up of 8.0 months (range, 3.8–14.0 months) the ORR was 92%. The CR rate was 16%, the PR rate was 76%, and 4% of patients had SD.

One patient (4%) with relapsed/refractory CLL/SLL had progressive disease (Richter’s transformation).

In relapsed/refractory FL, at a median follow-up of 6.2 months (range, 1.2–10.7 months), the ORR was 73%. The CR rate was 33%, the PR rate was 40%, and 13% of patients had SD.

Two patients (13%) with relapsed/refractory FL had progressive disease.

On the basis of these data, BeiGene plans to expand its global registrational program for BGB-3111 to include a phase 2 trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with relapsed/refractory FL.

The company is also planning a phase 3 trial comparing BGB-3111 with bendamustine plus rituximab in patients with treatment-naive CLL.

Micrograph showing CLL

LUGANO, SWITZERLAND—Results of a phase 1 study suggest a 2-drug combination may be safe and effective in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL).

The ongoing study is a test of the BTK inhibitor BGB-3111 and the anti-CD20 antibody obinutuzumab.

The overall response rate (ORR) with this combination was 81% in the entire study population, 89% in treatment-naïve CLL/SLL patients, 92% in relapsed/refractory CLL/SLL patients, and 73% in relapsed/refractory FL patients.

The rate of serious adverse events (AEs) was 24% in both CLL/SLL and FL patients.

These results were presented at the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by BeiGene, Ltd.

“This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase,” said study investigator Constantine Tam, MD, of St. Vincent’s Hospital in Melbourne, Australia.

“The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time.”

The trial consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include treatment-naive or relapsed/refractory CLL/SLL and relapsed/refractory FL.

The dose-escalation component is testing BGB-3111 at 320 mg once daily or 160 mg twice daily in 28-day cycles, in combination with obinutuzumab. Obinutuzumab is administered in line with standard CLL dosing (3 loading doses of 1000 mg weekly, followed by 1000 mg on day 1 of cycles 2 to 6).

The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg twice daily with the same obinutuzumab schedule.

As of the data cutoff (March 31, 2017), 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.

Patient characteristics

The median age was 68 (range, 28-82) in the CLL/SLL patients and 56 (range, 41-86) in the FL patients.

ECOG performance status was 0 in 42% of CLL/SLL patients, 1 in 56% of these patients, and 2 in 2%. ECOG performance status was 0 in 82% of FL patients, 1 in 12% of these patients, and 2 in 6%.

Twenty CLL/SLL patients were treatment-naïve, and 25 had relapsed/refractory disease. All 17 FL patients had relapsed/refractory disease.

The median number of prior therapies was 1 (range, 1-4) in the relapsed/refractory CLL/SLL patients and 3 (range, 1-7) in the FL patients.

Safety

At the time of the data cutoff, BGB-3111 was deemed well tolerated in patients with CLL/SLL and FL.

The most frequent AEs of any cause occurring in at least 15% of patients with CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%).

Most of these events were grade 1/2. The exceptions were grade 3/4 neutropenia (20%) and grade 3/4 thrombocytopenia (4%).

The most frequent AEs in FL patients were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%). All of these events were grade 1/2.

Serious AEs occurred in 24% of both the CLL/SLL patients and the FL patients.

Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients. Nearly all cases were grade 1/2. The exception was 1 grade 4 case in a CLL/SLL patient.

There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation.

One patient discontinued treatment due to an AE—squamous cell carcinoma. This patient had a prior history of squamous cell carcinoma.

Efficacy

At the time of the data cutoff, 43 patients with CLL/SLL (18 treatment-naive, 25 relapsed/refractory) and 15 patients with relapsed/refractory FL had greater than 12 weeks of follow-up and were evaluable for efficacy.

In treatment-naive CLL/SLL, after a median follow-up of 7.0 months (range, 2.8–11.8 months), the ORR was 89%. The complete response (CR) rate was 22%, the rate of partial response (PR) was 67%, and the rate of stable disease (SD) was 11%.

In relapsed/refractory CLL/SLL, at a median follow-up of 8.0 months (range, 3.8–14.0 months) the ORR was 92%. The CR rate was 16%, the PR rate was 76%, and 4% of patients had SD.

One patient (4%) with relapsed/refractory CLL/SLL had progressive disease (Richter’s transformation).

In relapsed/refractory FL, at a median follow-up of 6.2 months (range, 1.2–10.7 months), the ORR was 73%. The CR rate was 33%, the PR rate was 40%, and 13% of patients had SD.

Two patients (13%) with relapsed/refractory FL had progressive disease.

On the basis of these data, BeiGene plans to expand its global registrational program for BGB-3111 to include a phase 2 trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with relapsed/refractory FL.

The company is also planning a phase 3 trial comparing BGB-3111 with bendamustine plus rituximab in patients with treatment-naive CLL.

High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.

Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.

[email protected]

High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.

Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.

[email protected]

High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.

Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.

[email protected]

LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.

Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.

Neil Osterweil/Frontline Medical News

Large multicenter study

Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.

In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.

The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.

Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.

Among the patients with FL, 75% had significant reduction in tumor burden.

The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.

The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.

The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.

In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.

Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.

“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.

The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.

The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.

LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.

Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.

Neil Osterweil/Frontline Medical News

Large multicenter study

Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.

In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.

The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.

Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.

Among the patients with FL, 75% had significant reduction in tumor burden.

The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.

The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.

The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.

In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.

Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.

“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.

The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.

The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.

LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.

Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.

Neil Osterweil/Frontline Medical News

Large multicenter study

Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.

In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.

The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.

Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.

Among the patients with FL, 75% had significant reduction in tumor burden.

The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.

The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.

The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.

In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.

Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.

“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.

The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.

The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.

Micrograph showing HL

LUGANO, SWITZERLAND—Nivolumab can provide long-term treatment for a broad range of adults who have relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous hematopoietic stem cell transplant (auto-HSCT), according to a presentation at the 14th International Conference on Malignant Lymphoma (ICML).

In the phase 2 CheckMate-205 study, cHL patients achieved durable responses regardless of the depth of response, previous exposure to brentuximab vedotin (BV), and refractoriness to prior therapies.

Researchers observed sustained progression-free survival (PFS) in patients with stable disease (SD) or better, and the safety profile of nivolumab was considered acceptable.

“Nivolumab offers a favorable treatment outcome for patients who have relapsed disease after autologous stem cell transplant,” said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Fanale presented results from CheckMate-205 at 14-ICML. The study was sponsored by Bristol-Myers Squibb Company.

CheckMate-205 enrolled 243 adults with relapsed or refractory cHL who had undergone auto-HSCT. Patients were divided into 3 cohorts:

• Cohort A included patients who were naïve to BV (n=63)
• Cohort B included patients who received BV only after auto-HSCT (n=80)
• Cohort C included patients who received BV before and/or after auto-HSCT (n=100).

All patients received nivolumab at 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

In cohort C, patients who were in complete response (CR) for 1 year were to discontinue nivolumab, but they could resume treatment with the drug if they relapsed within 2 years.

Patient characteristics

The median age was 33 (range, 18-65) in cohort A, 37 (range, 18-72) in cohort B, and 32 (range, 19-69) in cohort C.

ECOG performance status was 0 for 62% of patients in cohort A, 53% in cohort B, and 50% in cohort C. The remaining patients had a performance status of 1.

The percentage of patients with stage IV disease was 38% in cohort A, 68% in cohort B, and 61% in cohort C.

The median number of prior therapies was 2 (range, 2-8) in cohort A, 4 (range, 3-15) in cohort B, and 4 (range, 2-9) in cohort C. Fifty-nine percent, 74%, and 69% of patients, respectively, had received prior radiotherapy.

The median time from diagnosis to the first dose of nivolumab was 3.1 years (range, 1.0-30.6) in cohort A, 6.2 years (range, 1.3-25.1) in cohort B, and 3.5 years (range, 1.0-24.9) in cohort C.

The median time from auto-HSCT to the first dose of nivolumab was 1.0 years (range, 0.3-18.2) in cohort A, 3.4 years (range, 0.2-19.0) in cohort B, and 1.7 years (range, 0.2-17.0) in cohort C.

Safety

The most common drug-related adverse events (AEs) were fatigue (23% any grade, 1% grade 3/4), diarrhea (15% any grade, 1% grade 3/4), infusion-related reactions (14% any grade, <1% grade 3/4), rash (12% any grade, 1% grade 3/4), nausea (10% grade 1/2), and pruritus (10% grade 1/2).

The most common drug-related serious AEs were infusion-related reactions (2% any grade, <1% grade 3/4) and pneumonitis (1% grade 1/2).

Drug-related AEs leading to treatment discontinuation were pneumonitis (2% grade 1/2) and autoimmune hepatitis (1% grade 3/4).

There were no deaths due to drug-related AEs.

Response

The objective response rate was 69% overall, 65% in cohort A, 68% in cohort B, and 73% in cohort C.

CR was the best response for 16% of all patients, 29% of cohort A, 13% of cohort B, and 12% of cohort C.

Partial response (PR) was the best response for 53% of all patients, 37% of patients in cohort A, 55% in cohort B, and 61% in cohort C.

SD was the best response for 19% of all patients, 24% of patients in cohort A, 21% in cohort B, and 15% in cohort C.

In post-hoc analyses, responses were similar irrespective of BV treatment sequence.

The median duration of response was 17 months overall, 20 months for cohort A, 16 months for cohort B, and 15 months for cohort C.

The median duration of response in patients with a CR was 20 months overall and for cohorts A and B, but it was 15 months for cohort C.

The median duration of response in patients with a PR was 13 months overall, 17 months for cohort A, 11 months for cohort B, and 13 months for cohort C.

Survival

The median PFS for all patients was 15 months (range, 11-19). The median PFS was 22 months (range, 19-not reached) for patients who achieved a CR, 15 months (range, 11-19) for those who achieved a PR, and 11 months (range, 6-18) for those who had SD.

The median PFS was 18 months (range, 11-22) for patients in cohort A, 15 months (range, 11-20) for cohort B, and 12 months (range, 11-18) for cohort C.

The median overall survival (OS) has not been reached in any of the cohorts. The 12-months OS is 92% overall, 93% in cohort A, 95% in cohort B, and 90% in cohort C.

Patient status after extended follow-up

Forty percent of all patients were still on treatment after extended follow-up, as were 48% of patients in cohort A, 40% in cohort B, and 35% in cohort C.

The most common reason for stopping treatment was disease progression—25% of cohort A, 28% of cohort B, and 24% of cohort C.

Patients also stopped treatment due to nivolumab-related toxicity—5% in cohort A, 11% in cohort B, and 7% in cohort C. Three percent, 1%, and 1%, respectively, stopped due to AEs unrelated to nivolumab.

Three percent of patients in cohort C stopped because they had attained the maximum clinical benefit, and 8% in cohort C completed treatment. This includes 7 patients who discontinued treatment because they were in CR for 1 year.

None of the patients in cohort A or B discontinued because they attained the maximum clinical benefit or because they completed treatment.

Eight percent of patients in cohort A, 10% in cohort B, and 17% in cohort C discontinued so they could proceed to HSCT.

Outcomes after allo-HSCT

Forty-four patients received allogeneic (allo-) HSCT after nivolumab. The median post-HSCT follow-up was 5.5 months (range, 0-19), and the median time from last dose of nivolumab to allo-HSCT was 1.6 months (range, 0.5-13.5).

At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 27%. The rate of grade 3-4 acute GVHD was 17%, and the rate of chronic GVHD was 10%.  At 6 months, the rates were 30%, 20%, and 15%, respectively.

The incidence of transplant-related mortality was 13% at 100 days and at 6 months.

“While there are risks, potentially, for acute GVHD and transplant-related mortality, these aren’t necessarily significantly different from what we’ve seen from other historical publications,” Dr Fanale said.

She cited data showing that the 100-day incidence of acute GVHD in cHL patients who underwent allo-HSCT ranges from 26% to 60%, and the incidence of transplant-related mortality in these patients ranges from 6% to 28%.

Micrograph showing HL

LUGANO, SWITZERLAND—Nivolumab can provide long-term treatment for a broad range of adults who have relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous hematopoietic stem cell transplant (auto-HSCT), according to a presentation at the 14th International Conference on Malignant Lymphoma (ICML).

In the phase 2 CheckMate-205 study, cHL patients achieved durable responses regardless of the depth of response, previous exposure to brentuximab vedotin (BV), and refractoriness to prior therapies.

Researchers observed sustained progression-free survival (PFS) in patients with stable disease (SD) or better, and the safety profile of nivolumab was considered acceptable.

“Nivolumab offers a favorable treatment outcome for patients who have relapsed disease after autologous stem cell transplant,” said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Fanale presented results from CheckMate-205 at 14-ICML. The study was sponsored by Bristol-Myers Squibb Company.

CheckMate-205 enrolled 243 adults with relapsed or refractory cHL who had undergone auto-HSCT. Patients were divided into 3 cohorts:

• Cohort A included patients who were naïve to BV (n=63)
• Cohort B included patients who received BV only after auto-HSCT (n=80)
• Cohort C included patients who received BV before and/or after auto-HSCT (n=100).

All patients received nivolumab at 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

In cohort C, patients who were in complete response (CR) for 1 year were to discontinue nivolumab, but they could resume treatment with the drug if they relapsed within 2 years.

Patient characteristics

The median age was 33 (range, 18-65) in cohort A, 37 (range, 18-72) in cohort B, and 32 (range, 19-69) in cohort C.

ECOG performance status was 0 for 62% of patients in cohort A, 53% in cohort B, and 50% in cohort C. The remaining patients had a performance status of 1.

The percentage of patients with stage IV disease was 38% in cohort A, 68% in cohort B, and 61% in cohort C.

The median number of prior therapies was 2 (range, 2-8) in cohort A, 4 (range, 3-15) in cohort B, and 4 (range, 2-9) in cohort C. Fifty-nine percent, 74%, and 69% of patients, respectively, had received prior radiotherapy.

The median time from diagnosis to the first dose of nivolumab was 3.1 years (range, 1.0-30.6) in cohort A, 6.2 years (range, 1.3-25.1) in cohort B, and 3.5 years (range, 1.0-24.9) in cohort C.

The median time from auto-HSCT to the first dose of nivolumab was 1.0 years (range, 0.3-18.2) in cohort A, 3.4 years (range, 0.2-19.0) in cohort B, and 1.7 years (range, 0.2-17.0) in cohort C.

Safety

The most common drug-related adverse events (AEs) were fatigue (23% any grade, 1% grade 3/4), diarrhea (15% any grade, 1% grade 3/4), infusion-related reactions (14% any grade, <1% grade 3/4), rash (12% any grade, 1% grade 3/4), nausea (10% grade 1/2), and pruritus (10% grade 1/2).

The most common drug-related serious AEs were infusion-related reactions (2% any grade, <1% grade 3/4) and pneumonitis (1% grade 1/2).

Drug-related AEs leading to treatment discontinuation were pneumonitis (2% grade 1/2) and autoimmune hepatitis (1% grade 3/4).

There were no deaths due to drug-related AEs.

Response

The objective response rate was 69% overall, 65% in cohort A, 68% in cohort B, and 73% in cohort C.

CR was the best response for 16% of all patients, 29% of cohort A, 13% of cohort B, and 12% of cohort C.

Partial response (PR) was the best response for 53% of all patients, 37% of patients in cohort A, 55% in cohort B, and 61% in cohort C.

SD was the best response for 19% of all patients, 24% of patients in cohort A, 21% in cohort B, and 15% in cohort C.

In post-hoc analyses, responses were similar irrespective of BV treatment sequence.

The median duration of response was 17 months overall, 20 months for cohort A, 16 months for cohort B, and 15 months for cohort C.

The median duration of response in patients with a CR was 20 months overall and for cohorts A and B, but it was 15 months for cohort C.

The median duration of response in patients with a PR was 13 months overall, 17 months for cohort A, 11 months for cohort B, and 13 months for cohort C.

Survival

The median PFS for all patients was 15 months (range, 11-19). The median PFS was 22 months (range, 19-not reached) for patients who achieved a CR, 15 months (range, 11-19) for those who achieved a PR, and 11 months (range, 6-18) for those who had SD.

The median PFS was 18 months (range, 11-22) for patients in cohort A, 15 months (range, 11-20) for cohort B, and 12 months (range, 11-18) for cohort C.

The median overall survival (OS) has not been reached in any of the cohorts. The 12-months OS is 92% overall, 93% in cohort A, 95% in cohort B, and 90% in cohort C.

Patient status after extended follow-up

Forty percent of all patients were still on treatment after extended follow-up, as were 48% of patients in cohort A, 40% in cohort B, and 35% in cohort C.

The most common reason for stopping treatment was disease progression—25% of cohort A, 28% of cohort B, and 24% of cohort C.

Patients also stopped treatment due to nivolumab-related toxicity—5% in cohort A, 11% in cohort B, and 7% in cohort C. Three percent, 1%, and 1%, respectively, stopped due to AEs unrelated to nivolumab.

Three percent of patients in cohort C stopped because they had attained the maximum clinical benefit, and 8% in cohort C completed treatment. This includes 7 patients who discontinued treatment because they were in CR for 1 year.

None of the patients in cohort A or B discontinued because they attained the maximum clinical benefit or because they completed treatment.

Eight percent of patients in cohort A, 10% in cohort B, and 17% in cohort C discontinued so they could proceed to HSCT.

Outcomes after allo-HSCT

Forty-four patients received allogeneic (allo-) HSCT after nivolumab. The median post-HSCT follow-up was 5.5 months (range, 0-19), and the median time from last dose of nivolumab to allo-HSCT was 1.6 months (range, 0.5-13.5).

At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 27%. The rate of grade 3-4 acute GVHD was 17%, and the rate of chronic GVHD was 10%.  At 6 months, the rates were 30%, 20%, and 15%, respectively.

The incidence of transplant-related mortality was 13% at 100 days and at 6 months.

“While there are risks, potentially, for acute GVHD and transplant-related mortality, these aren’t necessarily significantly different from what we’ve seen from other historical publications,” Dr Fanale said.

She cited data showing that the 100-day incidence of acute GVHD in cHL patients who underwent allo-HSCT ranges from 26% to 60%, and the incidence of transplant-related mortality in these patients ranges from 6% to 28%.

Micrograph showing HL

LUGANO, SWITZERLAND—Nivolumab can provide long-term treatment for a broad range of adults who have relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous hematopoietic stem cell transplant (auto-HSCT), according to a presentation at the 14th International Conference on Malignant Lymphoma (ICML).

In the phase 2 CheckMate-205 study, cHL patients achieved durable responses regardless of the depth of response, previous exposure to brentuximab vedotin (BV), and refractoriness to prior therapies.

Researchers observed sustained progression-free survival (PFS) in patients with stable disease (SD) or better, and the safety profile of nivolumab was considered acceptable.

“Nivolumab offers a favorable treatment outcome for patients who have relapsed disease after autologous stem cell transplant,” said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Fanale presented results from CheckMate-205 at 14-ICML. The study was sponsored by Bristol-Myers Squibb Company.

CheckMate-205 enrolled 243 adults with relapsed or refractory cHL who had undergone auto-HSCT. Patients were divided into 3 cohorts:

• Cohort A included patients who were naïve to BV (n=63)
• Cohort B included patients who received BV only after auto-HSCT (n=80)
• Cohort C included patients who received BV before and/or after auto-HSCT (n=100).

All patients received nivolumab at 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

In cohort C, patients who were in complete response (CR) for 1 year were to discontinue nivolumab, but they could resume treatment with the drug if they relapsed within 2 years.

Patient characteristics

The median age was 33 (range, 18-65) in cohort A, 37 (range, 18-72) in cohort B, and 32 (range, 19-69) in cohort C.

ECOG performance status was 0 for 62% of patients in cohort A, 53% in cohort B, and 50% in cohort C. The remaining patients had a performance status of 1.

The percentage of patients with stage IV disease was 38% in cohort A, 68% in cohort B, and 61% in cohort C.

The median number of prior therapies was 2 (range, 2-8) in cohort A, 4 (range, 3-15) in cohort B, and 4 (range, 2-9) in cohort C. Fifty-nine percent, 74%, and 69% of patients, respectively, had received prior radiotherapy.

The median time from diagnosis to the first dose of nivolumab was 3.1 years (range, 1.0-30.6) in cohort A, 6.2 years (range, 1.3-25.1) in cohort B, and 3.5 years (range, 1.0-24.9) in cohort C.

The median time from auto-HSCT to the first dose of nivolumab was 1.0 years (range, 0.3-18.2) in cohort A, 3.4 years (range, 0.2-19.0) in cohort B, and 1.7 years (range, 0.2-17.0) in cohort C.

Safety

The most common drug-related adverse events (AEs) were fatigue (23% any grade, 1% grade 3/4), diarrhea (15% any grade, 1% grade 3/4), infusion-related reactions (14% any grade, <1% grade 3/4), rash (12% any grade, 1% grade 3/4), nausea (10% grade 1/2), and pruritus (10% grade 1/2).

The most common drug-related serious AEs were infusion-related reactions (2% any grade, <1% grade 3/4) and pneumonitis (1% grade 1/2).

Drug-related AEs leading to treatment discontinuation were pneumonitis (2% grade 1/2) and autoimmune hepatitis (1% grade 3/4).

There were no deaths due to drug-related AEs.

Response

The objective response rate was 69% overall, 65% in cohort A, 68% in cohort B, and 73% in cohort C.

CR was the best response for 16% of all patients, 29% of cohort A, 13% of cohort B, and 12% of cohort C.

Partial response (PR) was the best response for 53% of all patients, 37% of patients in cohort A, 55% in cohort B, and 61% in cohort C.

SD was the best response for 19% of all patients, 24% of patients in cohort A, 21% in cohort B, and 15% in cohort C.

In post-hoc analyses, responses were similar irrespective of BV treatment sequence.

The median duration of response was 17 months overall, 20 months for cohort A, 16 months for cohort B, and 15 months for cohort C.

The median duration of response in patients with a CR was 20 months overall and for cohorts A and B, but it was 15 months for cohort C.

The median duration of response in patients with a PR was 13 months overall, 17 months for cohort A, 11 months for cohort B, and 13 months for cohort C.

Survival

The median PFS for all patients was 15 months (range, 11-19). The median PFS was 22 months (range, 19-not reached) for patients who achieved a CR, 15 months (range, 11-19) for those who achieved a PR, and 11 months (range, 6-18) for those who had SD.

The median PFS was 18 months (range, 11-22) for patients in cohort A, 15 months (range, 11-20) for cohort B, and 12 months (range, 11-18) for cohort C.

The median overall survival (OS) has not been reached in any of the cohorts. The 12-months OS is 92% overall, 93% in cohort A, 95% in cohort B, and 90% in cohort C.

Patient status after extended follow-up

Forty percent of all patients were still on treatment after extended follow-up, as were 48% of patients in cohort A, 40% in cohort B, and 35% in cohort C.

The most common reason for stopping treatment was disease progression—25% of cohort A, 28% of cohort B, and 24% of cohort C.

Patients also stopped treatment due to nivolumab-related toxicity—5% in cohort A, 11% in cohort B, and 7% in cohort C. Three percent, 1%, and 1%, respectively, stopped due to AEs unrelated to nivolumab.

Three percent of patients in cohort C stopped because they had attained the maximum clinical benefit, and 8% in cohort C completed treatment. This includes 7 patients who discontinued treatment because they were in CR for 1 year.

None of the patients in cohort A or B discontinued because they attained the maximum clinical benefit or because they completed treatment.

Eight percent of patients in cohort A, 10% in cohort B, and 17% in cohort C discontinued so they could proceed to HSCT.

Outcomes after allo-HSCT

Forty-four patients received allogeneic (allo-) HSCT after nivolumab. The median post-HSCT follow-up was 5.5 months (range, 0-19), and the median time from last dose of nivolumab to allo-HSCT was 1.6 months (range, 0.5-13.5).

At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 27%. The rate of grade 3-4 acute GVHD was 17%, and the rate of chronic GVHD was 10%.  At 6 months, the rates were 30%, 20%, and 15%, respectively.

The incidence of transplant-related mortality was 13% at 100 days and at 6 months.

“While there are risks, potentially, for acute GVHD and transplant-related mortality, these aren’t necessarily significantly different from what we’ve seen from other historical publications,” Dr Fanale said.

She cited data showing that the 100-day incidence of acute GVHD in cHL patients who underwent allo-HSCT ranges from 26% to 60%, and the incidence of transplant-related mortality in these patients ranges from 6% to 28%.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Micrograph showing DLBCL

The European Medicines Agency (EMA) has granted polatuzumab vedotin access to the agency’s PRIority MEdicines (PRIME) program.

The access is for polatuzumab vedotin when used in combination with rituximab and bendamustine for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Polatuzumab vedotin is an anti-CD79b antibody drug conjugate consisting of an anti-CD79b monoclonal antibody that is linked to a microtubule-disrupting agent.

Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics’ technology.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

The acceptance of polatuzumab vedotin in the PRIME program was supported by results from the phase 2 component of the GO29365 study.

Results from this trial were recently presented at the 22nd Congress of the European Hematology Association (EHA) as abstract S468.

Micrograph showing DLBCL

The European Medicines Agency (EMA) has granted polatuzumab vedotin access to the agency’s PRIority MEdicines (PRIME) program.

The access is for polatuzumab vedotin when used in combination with rituximab and bendamustine for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Polatuzumab vedotin is an anti-CD79b antibody drug conjugate consisting of an anti-CD79b monoclonal antibody that is linked to a microtubule-disrupting agent.

Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics’ technology.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

The acceptance of polatuzumab vedotin in the PRIME program was supported by results from the phase 2 component of the GO29365 study.

Results from this trial were recently presented at the 22nd Congress of the European Hematology Association (EHA) as abstract S468.

Micrograph showing DLBCL

The European Medicines Agency (EMA) has granted polatuzumab vedotin access to the agency’s PRIority MEdicines (PRIME) program.

The access is for polatuzumab vedotin when used in combination with rituximab and bendamustine for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Polatuzumab vedotin is an anti-CD79b antibody drug conjugate consisting of an anti-CD79b monoclonal antibody that is linked to a microtubule-disrupting agent.

Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics’ technology.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

The acceptance of polatuzumab vedotin in the PRIME program was supported by results from the phase 2 component of the GO29365 study.

Results from this trial were recently presented at the 22nd Congress of the European Hematology Association (EHA) as abstract S468.

Diffuse large B-cell lymphoma

LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.

In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.

At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.

He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.

Patients

Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.

The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.

The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.

Treatment

Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.

Thirty patients received a single dose of JCAR017 at 5 x 10⁷ CAR cells (dose-level 1, single [DL1S]).

Six patients received 2 doses of 5 x 10⁷ CAR cells (dose-level 1, double [DL1D]).

Nineteen patients received a single dose of 1 x 10⁸ CAR cells (dose-level 2, single [DL2S]).

Safety

More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.

Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.

One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.

Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.

The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).

There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).

“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.

Response

Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

Dr Abramson noted that there was a dose-response relationship.

Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.

At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.

Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.

At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.

Diffuse large B-cell lymphoma

LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.

In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.

At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.

He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.

Patients

Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.

The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.

The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.

Treatment

Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.

Thirty patients received a single dose of JCAR017 at 5 x 10⁷ CAR cells (dose-level 1, single [DL1S]).

Six patients received 2 doses of 5 x 10⁷ CAR cells (dose-level 1, double [DL1D]).

Nineteen patients received a single dose of 1 x 10⁸ CAR cells (dose-level 2, single [DL2S]).

Safety

More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.

Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.

One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.

Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.

The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).

There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).

“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.

Response

Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

Dr Abramson noted that there was a dose-response relationship.

Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.

At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.

Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.

At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.

Diffuse large B-cell lymphoma

LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.

In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.

At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.

He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.

Patients

Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.

The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.

The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.

Treatment

Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.

Thirty patients received a single dose of JCAR017 at 5 x 10⁷ CAR cells (dose-level 1, single [DL1S]).

Six patients received 2 doses of 5 x 10⁷ CAR cells (dose-level 1, double [DL1D]).

Nineteen patients received a single dose of 1 x 10⁸ CAR cells (dose-level 2, single [DL2S]).

Safety

More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.

Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.

One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.

Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.

The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).

There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).

“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.

Response

Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

Dr Abramson noted that there was a dose-response relationship.

Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.

At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.

Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.

At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.

Photo by Rhoda Baer

MADRID—Patients with advanced Hodgkin lymphoma (HL) who are PET-negative after initial treatment with 2 cycles of eBEACOPP* should only receive 2 additional cycles of the therapy, new research suggests.

In the HD18 trial, PET-2-negative patients who received 4 cycles of eBEACOPP had non-inferior progression-free survival (PFS) and significantly better overall survival (OS) than PET-2-negative patients who received 6 or 8 cycles of the treatment.

Patients who received 4 cycles also had less severe toxicity and fewer second neoplasms than patients who received more cycles of eBEACOPP.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far,” said Peter Borchmann, MD, of University Hospital of Cologne in Germany.

“That’s why we recommend treatment with PET-2-guided eBEACOPP for patients with newly diagnosed, advanced-stage Hodgkin lymphoma.”

Dr Borchmann presented results from HD18 at the 22nd Congress of the European Hematology Association (EHA) as abstract S150.

Patients and treatment

Dr Borchmann and his colleagues set out to determine if they could decrease the number of eBEACOPP cycles in patients with negative PET-2 without compromising treatment efficacy.

From May 2008 to July 2014, the researchers recruited 2101 patients with newly diagnosed, advanced-stage HL.

Patients who were PET-negative after 2 cycles of eBEACOPP (n=1005) were initially randomized to receive 6 additional cycles of eBEACOPP or 2 additional cycles—a total of 8 cycles or 4 cycles, respectively. The protocol was later amended (in June 2011), and the total number of cycles in the standard therapy arm was reduced to 6.

There were 504 patients in the standard therapy arm—288 who received 8 cycles of eBEACOPP and 216 who received 6 cycles. There were 501 patients who received 4 cycles of eBEACOPP.

Sixteen patients in the standard therapy arm and 17 in the 4-cycle arm also received radiotherapy.

The median age was 32 (range, 18-60) in the standard therapy arm and 33 (range, 18-60) in the 4-cycle arm. Sixty-three percent and 62% of patients, respectively, were male.

Eight percent of patients in both arms had Ann Arbor stage IIB disease. Fifty-seven percent in the standard therapy arm and 55% in the 4-cycle arm had stage IIIA/B. And 35% and 36%, respectively, had stage IVA/B disease.

Thirty-five percent of patients in both arms had an IPS stage of 0-1. Fifty-one percent in the standard therapy arm and 52% in the 4-cycle arm had an IPS stage of 2-3. And 14% in both arms had an IPS stage of 4-7.

The median duration of therapy was 173 days (range, 41-266) for patients randomized to receive 8 cycles of eBEACOPP, 129 days (range, 35-178) in patients randomized to receive 6 cycles, and 85 days (range, 42-133) in patients randomized to receive 4 cycles.

One patient in the 6-cycle group received more than 6 cycles, and 6 patients in the 4-cycle arm received more than 4 cycles.

PFS and OS

The median follow-up was 55 months. The estimated 3-year PFS was 92.3% in the standard therapy arm and 94.8% in the 4-cycle arm. The estimated 5-year PFS was 91.2% and 91.8%, respectively. The hazard ratio was 0.88.

“[Based on these data,] we can conclude that 4 cycles are as effective as 6 or 8 cycles,” Dr Borchmann said.

The estimated 3-year OS was 95.9% in the standard therapy arm and 98.7% in the 4-cycle arm. The estimated 5-year OS was 95.4% and 97.6%, respectively. The hazard ratio was 0.36 (P=0.006).

Toxicity and second neoplasms

Grade 3/4 organ toxicity occurred in 22% of patients in the 8-cycle group, 13% in the 6-cycle group, and 8% in the 4-cycle group. Grade 4 anemia, thrombocytopenia, or infection occurred in 59%, 53%, and 38%, respectively.

Treatment-related morbidity occurred in 66% of patients in the 8-cycle group, 61% in the 6-cycle group, and 41% in the 4-cycle group.

Eighteen patients in the standard therapy arm had second neoplasms—8 with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 5 with non-Hodgkin lymphoma (NHL), and 5 with solid tumors.

Thirteen patients in the 4-cycle arm had second neoplasms—2 with AML/MDS, 8 with NHL, and 3 with solid tumors.

Causes of death

The cause of death was HL for 0.6% of patients (n=3) in the standard therapy arm and for 0.8% of patients (n=4) in the 4-cycle arm.

The cause of death was second malignancy for 2.2% of patients (n=11) in the standard therapy arm. Five patients died of AML, 3 of NHL, and 3 of solid tumor malignancies.

One patient (0.2%) in the 4-cycle arm died as a result of a second malignancy, which was AML.

Toxicity related to study treatment was the cause of death for 1.2% (n=6) of patients in the standard therapy arm. Five of the patients died of infection, and the sixth died of ischemic stroke.

None of the patients in the 4-cycle arm died of toxicity related to study treatment.

Other causes of death included toxicity of salvage treatment (0.4%, n=2 in both arms), other disease (0.2%, n=1 in both arms), accident (1 patient [0.2%] in the 4-cycle arm), and unknown cause (2 patients [0.4%] in the standard arm).

“[With 4 cycles of therapy,] we had a significant and very relevant reduction of severe, acute hematological and non-hematological toxicities, and this was accompanied by a relevant reduction of mortality for other reasons than HL,” Dr Borchmann said. “And we’ve almost eliminated HL as a cause of death in this trial.” 

*dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone

Photo by Rhoda Baer

MADRID—Patients with advanced Hodgkin lymphoma (HL) who are PET-negative after initial treatment with 2 cycles of eBEACOPP* should only receive 2 additional cycles of the therapy, new research suggests.

In the HD18 trial, PET-2-negative patients who received 4 cycles of eBEACOPP had non-inferior progression-free survival (PFS) and significantly better overall survival (OS) than PET-2-negative patients who received 6 or 8 cycles of the treatment.

Patients who received 4 cycles also had less severe toxicity and fewer second neoplasms than patients who received more cycles of eBEACOPP.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far,” said Peter Borchmann, MD, of University Hospital of Cologne in Germany.

“That’s why we recommend treatment with PET-2-guided eBEACOPP for patients with newly diagnosed, advanced-stage Hodgkin lymphoma.”

Dr Borchmann presented results from HD18 at the 22nd Congress of the European Hematology Association (EHA) as abstract S150.

Patients and treatment

Dr Borchmann and his colleagues set out to determine if they could decrease the number of eBEACOPP cycles in patients with negative PET-2 without compromising treatment efficacy.

From May 2008 to July 2014, the researchers recruited 2101 patients with newly diagnosed, advanced-stage HL.

Patients who were PET-negative after 2 cycles of eBEACOPP (n=1005) were initially randomized to receive 6 additional cycles of eBEACOPP or 2 additional cycles—a total of 8 cycles or 4 cycles, respectively. The protocol was later amended (in June 2011), and the total number of cycles in the standard therapy arm was reduced to 6.

There were 504 patients in the standard therapy arm—288 who received 8 cycles of eBEACOPP and 216 who received 6 cycles. There were 501 patients who received 4 cycles of eBEACOPP.

Sixteen patients in the standard therapy arm and 17 in the 4-cycle arm also received radiotherapy.

The median age was 32 (range, 18-60) in the standard therapy arm and 33 (range, 18-60) in the 4-cycle arm. Sixty-three percent and 62% of patients, respectively, were male.

Eight percent of patients in both arms had Ann Arbor stage IIB disease. Fifty-seven percent in the standard therapy arm and 55% in the 4-cycle arm had stage IIIA/B. And 35% and 36%, respectively, had stage IVA/B disease.

Thirty-five percent of patients in both arms had an IPS stage of 0-1. Fifty-one percent in the standard therapy arm and 52% in the 4-cycle arm had an IPS stage of 2-3. And 14% in both arms had an IPS stage of 4-7.

The median duration of therapy was 173 days (range, 41-266) for patients randomized to receive 8 cycles of eBEACOPP, 129 days (range, 35-178) in patients randomized to receive 6 cycles, and 85 days (range, 42-133) in patients randomized to receive 4 cycles.

One patient in the 6-cycle group received more than 6 cycles, and 6 patients in the 4-cycle arm received more than 4 cycles.

PFS and OS

The median follow-up was 55 months. The estimated 3-year PFS was 92.3% in the standard therapy arm and 94.8% in the 4-cycle arm. The estimated 5-year PFS was 91.2% and 91.8%, respectively. The hazard ratio was 0.88.

“[Based on these data,] we can conclude that 4 cycles are as effective as 6 or 8 cycles,” Dr Borchmann said.

The estimated 3-year OS was 95.9% in the standard therapy arm and 98.7% in the 4-cycle arm. The estimated 5-year OS was 95.4% and 97.6%, respectively. The hazard ratio was 0.36 (P=0.006).

Toxicity and second neoplasms

Grade 3/4 organ toxicity occurred in 22% of patients in the 8-cycle group, 13% in the 6-cycle group, and 8% in the 4-cycle group. Grade 4 anemia, thrombocytopenia, or infection occurred in 59%, 53%, and 38%, respectively.

Treatment-related morbidity occurred in 66% of patients in the 8-cycle group, 61% in the 6-cycle group, and 41% in the 4-cycle group.

Eighteen patients in the standard therapy arm had second neoplasms—8 with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 5 with non-Hodgkin lymphoma (NHL), and 5 with solid tumors.

Thirteen patients in the 4-cycle arm had second neoplasms—2 with AML/MDS, 8 with NHL, and 3 with solid tumors.

Causes of death

The cause of death was HL for 0.6% of patients (n=3) in the standard therapy arm and for 0.8% of patients (n=4) in the 4-cycle arm.

The cause of death was second malignancy for 2.2% of patients (n=11) in the standard therapy arm. Five patients died of AML, 3 of NHL, and 3 of solid tumor malignancies.

One patient (0.2%) in the 4-cycle arm died as a result of a second malignancy, which was AML.

Toxicity related to study treatment was the cause of death for 1.2% (n=6) of patients in the standard therapy arm. Five of the patients died of infection, and the sixth died of ischemic stroke.

None of the patients in the 4-cycle arm died of toxicity related to study treatment.

Other causes of death included toxicity of salvage treatment (0.4%, n=2 in both arms), other disease (0.2%, n=1 in both arms), accident (1 patient [0.2%] in the 4-cycle arm), and unknown cause (2 patients [0.4%] in the standard arm).

“[With 4 cycles of therapy,] we had a significant and very relevant reduction of severe, acute hematological and non-hematological toxicities, and this was accompanied by a relevant reduction of mortality for other reasons than HL,” Dr Borchmann said. “And we’ve almost eliminated HL as a cause of death in this trial.” 

*dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone

Photo by Rhoda Baer

MADRID—Patients with advanced Hodgkin lymphoma (HL) who are PET-negative after initial treatment with 2 cycles of eBEACOPP* should only receive 2 additional cycles of the therapy, new research suggests.

In the HD18 trial, PET-2-negative patients who received 4 cycles of eBEACOPP had non-inferior progression-free survival (PFS) and significantly better overall survival (OS) than PET-2-negative patients who received 6 or 8 cycles of the treatment.

Patients who received 4 cycles also had less severe toxicity and fewer second neoplasms than patients who received more cycles of eBEACOPP.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far,” said Peter Borchmann, MD, of University Hospital of Cologne in Germany.

“That’s why we recommend treatment with PET-2-guided eBEACOPP for patients with newly diagnosed, advanced-stage Hodgkin lymphoma.”

Dr Borchmann presented results from HD18 at the 22nd Congress of the European Hematology Association (EHA) as abstract S150.

Patients and treatment

Dr Borchmann and his colleagues set out to determine if they could decrease the number of eBEACOPP cycles in patients with negative PET-2 without compromising treatment efficacy.

From May 2008 to July 2014, the researchers recruited 2101 patients with newly diagnosed, advanced-stage HL.

Patients who were PET-negative after 2 cycles of eBEACOPP (n=1005) were initially randomized to receive 6 additional cycles of eBEACOPP or 2 additional cycles—a total of 8 cycles or 4 cycles, respectively. The protocol was later amended (in June 2011), and the total number of cycles in the standard therapy arm was reduced to 6.

There were 504 patients in the standard therapy arm—288 who received 8 cycles of eBEACOPP and 216 who received 6 cycles. There were 501 patients who received 4 cycles of eBEACOPP.

Sixteen patients in the standard therapy arm and 17 in the 4-cycle arm also received radiotherapy.

The median age was 32 (range, 18-60) in the standard therapy arm and 33 (range, 18-60) in the 4-cycle arm. Sixty-three percent and 62% of patients, respectively, were male.

Eight percent of patients in both arms had Ann Arbor stage IIB disease. Fifty-seven percent in the standard therapy arm and 55% in the 4-cycle arm had stage IIIA/B. And 35% and 36%, respectively, had stage IVA/B disease.

Thirty-five percent of patients in both arms had an IPS stage of 0-1. Fifty-one percent in the standard therapy arm and 52% in the 4-cycle arm had an IPS stage of 2-3. And 14% in both arms had an IPS stage of 4-7.

The median duration of therapy was 173 days (range, 41-266) for patients randomized to receive 8 cycles of eBEACOPP, 129 days (range, 35-178) in patients randomized to receive 6 cycles, and 85 days (range, 42-133) in patients randomized to receive 4 cycles.

One patient in the 6-cycle group received more than 6 cycles, and 6 patients in the 4-cycle arm received more than 4 cycles.

PFS and OS

The median follow-up was 55 months. The estimated 3-year PFS was 92.3% in the standard therapy arm and 94.8% in the 4-cycle arm. The estimated 5-year PFS was 91.2% and 91.8%, respectively. The hazard ratio was 0.88.

“[Based on these data,] we can conclude that 4 cycles are as effective as 6 or 8 cycles,” Dr Borchmann said.

The estimated 3-year OS was 95.9% in the standard therapy arm and 98.7% in the 4-cycle arm. The estimated 5-year OS was 95.4% and 97.6%, respectively. The hazard ratio was 0.36 (P=0.006).

Toxicity and second neoplasms

Grade 3/4 organ toxicity occurred in 22% of patients in the 8-cycle group, 13% in the 6-cycle group, and 8% in the 4-cycle group. Grade 4 anemia, thrombocytopenia, or infection occurred in 59%, 53%, and 38%, respectively.

Treatment-related morbidity occurred in 66% of patients in the 8-cycle group, 61% in the 6-cycle group, and 41% in the 4-cycle group.

Eighteen patients in the standard therapy arm had second neoplasms—8 with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 5 with non-Hodgkin lymphoma (NHL), and 5 with solid tumors.

Thirteen patients in the 4-cycle arm had second neoplasms—2 with AML/MDS, 8 with NHL, and 3 with solid tumors.

Causes of death

The cause of death was HL for 0.6% of patients (n=3) in the standard therapy arm and for 0.8% of patients (n=4) in the 4-cycle arm.

The cause of death was second malignancy for 2.2% of patients (n=11) in the standard therapy arm. Five patients died of AML, 3 of NHL, and 3 of solid tumor malignancies.

One patient (0.2%) in the 4-cycle arm died as a result of a second malignancy, which was AML.

Toxicity related to study treatment was the cause of death for 1.2% (n=6) of patients in the standard therapy arm. Five of the patients died of infection, and the sixth died of ischemic stroke.

None of the patients in the 4-cycle arm died of toxicity related to study treatment.

Other causes of death included toxicity of salvage treatment (0.4%, n=2 in both arms), other disease (0.2%, n=1 in both arms), accident (1 patient [0.2%] in the 4-cycle arm), and unknown cause (2 patients [0.4%] in the standard arm).

“[With 4 cycles of therapy,] we had a significant and very relevant reduction of severe, acute hematological and non-hematological toxicities, and this was accompanied by a relevant reduction of mortality for other reasons than HL,” Dr Borchmann said. “And we’ve almost eliminated HL as a cause of death in this trial.” 

*dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone

Photo courtesy of Columbia University

A small retrospective study of survivors of childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) has found that phosphorylated Tau (p-Tau) in patients’ cerebrospinal fluid (CSF) is a predictor of late neurocognitive consequences.

Investigators compared intellectual performance, memory, and executive functioning between survivors and control subjects and observed that CSF levels of p-Tau during treatment and total intrathecal methotrexate dose negatively correlated with intellectual performance.

They suggest that identifying at-risk children early “could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.”

The investigators enrolled 31 nonirradiated adults, 27 who had had ALL and 4 NHL. They compared the survivors to 35 age-matched controls.

All study participants were a mean age of 21.5 years (range, 16.1–29.8). The mean age of the survivors at diagnosis was 6.4 years.

"Our team collected samples of brain fluid during the cancer treatment,” Rudi D’Hooge, PhD, of KU Leuven in Belgium, said. “We analyzed the p-Tau levels to measure the damage to the brain cells."

Investigators assessed intelligence, memory, and executive function using Wechsler Adult Intelligence Scale (WAIS IV), Rey Auditory Verbal Learning Test (AVLT), and Amsterdam Neuropsychological Tasks (ANT), respectively.

Statistical analysis included two-sided, one-way analysis of covariance (ANCOVA) with survivor group vs control group as an independent factor.  Parental socioeconomic status was a covariate.

Dr D’Hooge and colleagues published their findings in JNCI, the Journal of the National Cancer Institute.

Findings

Investigators found that survivors had statistically significant lower total intelligence (P=0.001), verbal intelligence (P=0.02), and performance intelligence (P=0.007) quotients than controls.

They also found a negative correlation between CSF p-Tau, but not CSF Tau, levels and total intelligence (P=0.02), verbal intelligence (P=0.001), and performance intelligence (P=0.04) quotients.

Only performance intelligence was negatively correlated with total intrathecal methotrexate (P=0.007).

And because total intrathecal methotrexate dose and CSF p-Tau were not significantly correlated (P=0.29), the investigators believe intervening factors increase CSF p-Tau independently from methotrexate dose.

Results of subset tests revealed that cognitive flexibility (set-shifting and working memory), and processing speed were affected (P<0.05).

However, long-term memory, focused and sustained attention, and inhibition appeared unaffected (P>0.05).

The investigators believe these differences in vulnerability of cognitive functions parallel patient age at time of development.

For example, long-term memory, focused and sustained attention, and inhibition develop before children reach 6 years, the mean age at which the survivor cohort was diagnosed.

But set-shifting, working memory, and processing speed mature during adolescence, after the patients were diagnosed and treated.

Limitations of the study, according to the investigators, include its retrospective and cross-sectional design, the relatively small sample size, and the lack of pretreatment neurocognitive data.

Nevertheless, they believe the study should encourage the use of the CSF biomarker, intrathecal methotrexate dose, and age at therapy initiation in neurotoxicity assessments to identify children at risk for long-term sequelae.

"If we systematically measure these p-Tau levels in the future," Iris Elens, MD, also of KU Leuven, said, "we can offer specific help to children with high values. With early coaching aimed at the most relevant functions we can prevent problems that would otherwise manifest 10 to 15 years after the treatment."

The Olivia Hendrickx Research Fund supported the study. 

Photo courtesy of Columbia University

A small retrospective study of survivors of childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) has found that phosphorylated Tau (p-Tau) in patients’ cerebrospinal fluid (CSF) is a predictor of late neurocognitive consequences.

Investigators compared intellectual performance, memory, and executive functioning between survivors and control subjects and observed that CSF levels of p-Tau during treatment and total intrathecal methotrexate dose negatively correlated with intellectual performance.

They suggest that identifying at-risk children early “could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.”

The investigators enrolled 31 nonirradiated adults, 27 who had had ALL and 4 NHL. They compared the survivors to 35 age-matched controls.

All study participants were a mean age of 21.5 years (range, 16.1–29.8). The mean age of the survivors at diagnosis was 6.4 years.

"Our team collected samples of brain fluid during the cancer treatment,” Rudi D’Hooge, PhD, of KU Leuven in Belgium, said. “We analyzed the p-Tau levels to measure the damage to the brain cells."

Investigators assessed intelligence, memory, and executive function using Wechsler Adult Intelligence Scale (WAIS IV), Rey Auditory Verbal Learning Test (AVLT), and Amsterdam Neuropsychological Tasks (ANT), respectively.

Statistical analysis included two-sided, one-way analysis of covariance (ANCOVA) with survivor group vs control group as an independent factor.  Parental socioeconomic status was a covariate.

Dr D’Hooge and colleagues published their findings in JNCI, the Journal of the National Cancer Institute.

Findings

Investigators found that survivors had statistically significant lower total intelligence (P=0.001), verbal intelligence (P=0.02), and performance intelligence (P=0.007) quotients than controls.

They also found a negative correlation between CSF p-Tau, but not CSF Tau, levels and total intelligence (P=0.02), verbal intelligence (P=0.001), and performance intelligence (P=0.04) quotients.

Only performance intelligence was negatively correlated with total intrathecal methotrexate (P=0.007).

And because total intrathecal methotrexate dose and CSF p-Tau were not significantly correlated (P=0.29), the investigators believe intervening factors increase CSF p-Tau independently from methotrexate dose.

Results of subset tests revealed that cognitive flexibility (set-shifting and working memory), and processing speed were affected (P<0.05).

However, long-term memory, focused and sustained attention, and inhibition appeared unaffected (P>0.05).

The investigators believe these differences in vulnerability of cognitive functions parallel patient age at time of development.

For example, long-term memory, focused and sustained attention, and inhibition develop before children reach 6 years, the mean age at which the survivor cohort was diagnosed.

But set-shifting, working memory, and processing speed mature during adolescence, after the patients were diagnosed and treated.

Limitations of the study, according to the investigators, include its retrospective and cross-sectional design, the relatively small sample size, and the lack of pretreatment neurocognitive data.

Nevertheless, they believe the study should encourage the use of the CSF biomarker, intrathecal methotrexate dose, and age at therapy initiation in neurotoxicity assessments to identify children at risk for long-term sequelae.

"If we systematically measure these p-Tau levels in the future," Iris Elens, MD, also of KU Leuven, said, "we can offer specific help to children with high values. With early coaching aimed at the most relevant functions we can prevent problems that would otherwise manifest 10 to 15 years after the treatment."

The Olivia Hendrickx Research Fund supported the study. 

Photo courtesy of Columbia University

A small retrospective study of survivors of childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) has found that phosphorylated Tau (p-Tau) in patients’ cerebrospinal fluid (CSF) is a predictor of late neurocognitive consequences.

Investigators compared intellectual performance, memory, and executive functioning between survivors and control subjects and observed that CSF levels of p-Tau during treatment and total intrathecal methotrexate dose negatively correlated with intellectual performance.

They suggest that identifying at-risk children early “could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.”

The investigators enrolled 31 nonirradiated adults, 27 who had had ALL and 4 NHL. They compared the survivors to 35 age-matched controls.

All study participants were a mean age of 21.5 years (range, 16.1–29.8). The mean age of the survivors at diagnosis was 6.4 years.

"Our team collected samples of brain fluid during the cancer treatment,” Rudi D’Hooge, PhD, of KU Leuven in Belgium, said. “We analyzed the p-Tau levels to measure the damage to the brain cells."

Investigators assessed intelligence, memory, and executive function using Wechsler Adult Intelligence Scale (WAIS IV), Rey Auditory Verbal Learning Test (AVLT), and Amsterdam Neuropsychological Tasks (ANT), respectively.

Statistical analysis included two-sided, one-way analysis of covariance (ANCOVA) with survivor group vs control group as an independent factor.  Parental socioeconomic status was a covariate.

Dr D’Hooge and colleagues published their findings in JNCI, the Journal of the National Cancer Institute.

Findings

Investigators found that survivors had statistically significant lower total intelligence (P=0.001), verbal intelligence (P=0.02), and performance intelligence (P=0.007) quotients than controls.

They also found a negative correlation between CSF p-Tau, but not CSF Tau, levels and total intelligence (P=0.02), verbal intelligence (P=0.001), and performance intelligence (P=0.04) quotients.

Only performance intelligence was negatively correlated with total intrathecal methotrexate (P=0.007).

And because total intrathecal methotrexate dose and CSF p-Tau were not significantly correlated (P=0.29), the investigators believe intervening factors increase CSF p-Tau independently from methotrexate dose.

Results of subset tests revealed that cognitive flexibility (set-shifting and working memory), and processing speed were affected (P<0.05).

However, long-term memory, focused and sustained attention, and inhibition appeared unaffected (P>0.05).

The investigators believe these differences in vulnerability of cognitive functions parallel patient age at time of development.

For example, long-term memory, focused and sustained attention, and inhibition develop before children reach 6 years, the mean age at which the survivor cohort was diagnosed.

But set-shifting, working memory, and processing speed mature during adolescence, after the patients were diagnosed and treated.

Limitations of the study, according to the investigators, include its retrospective and cross-sectional design, the relatively small sample size, and the lack of pretreatment neurocognitive data.

Nevertheless, they believe the study should encourage the use of the CSF biomarker, intrathecal methotrexate dose, and age at therapy initiation in neurotoxicity assessments to identify children at risk for long-term sequelae.

"If we systematically measure these p-Tau levels in the future," Iris Elens, MD, also of KU Leuven, said, "we can offer specific help to children with high values. With early coaching aimed at the most relevant functions we can prevent problems that would otherwise manifest 10 to 15 years after the treatment."

The Olivia Hendrickx Research Fund supported the study.