Lymphoma & Plasma Cell Disorders

LUGANO, SWITZERLAND – Copanlisib, an investigational intravenous inhibitor of phosphatidylinositol 3-kinase (PI3K), was associated with “promising” efficacy and a better safety profile than has been seen with oral PI3K inhibitors in patients with relapsed or refractory indolent lymphomas.

In a phase 2 trial of the drug as monotherapy in patients with indolent lymphomas, copanlisib was associated with an overall response rate of 58.6% among 104 patients with follicular lymphoma (FL), including 14.4% complete responses (CR) and 44.2% partial responses (PR), reported Martin Dreyling, MD, of the Universität München-Grosshadern in Munich, Germany.

“The favorable risk-benefit profile of this compound suggests further [need for] testing in follicular lymphoma. My personal interpretation is that the different safety profile is due to the intermittent dosing and the IV application, avoiding adverse cause-effect both in the gut and the liver,” he said at the 14th International Conference on Malignant Lymphoma.

Dr. Dreyling noted that the oral PI3K inhibitor idelalisib (Zydelig) is approved for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab and in patients with relapsed FL or small lymphocytic lymphomas (SLL) who have received at least two prior lines of systemic therapy. This agent, however, carries a black box warning about fatal and serious toxicities, including hepatic events, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation.

Copanlisib inhibits all isoforms of P13K but is predominantly active against the alpha and delta isoforms of the kinase. The alpha form, expressed in many cell types, is involved in insulin signaling and angiogenesis and in resistance mechanisms to lymphoma. The delta form, expressed in leukocytes, is involved in B-cell signaling, development, and survival, making PIK3 an attractive target, Dr. Dreyling explained.

The study included patients with indolent B-cell lymphomas, including FL grades 1-3a, marginal zone lymphoma, SLL, or lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) for whom at least two prior lines of therapy had failed.

The patients received copanlisib 60 mg IV on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.

Of 142 assigned to and started on treatment, 46 patients (32.3%) remained on treatment at the time of data cutoff. Of the 96 patients (67.7%) who discontinued, 35 did so because of adverse events, 36 discontinued for radiologic or clinical evidence of progression, 16 withdrew, 5 were discontinued on the treating physician’s decision, and 4 stopped for other, unspecified reasons.

Among all 142 patients, the median duration of therapy was 22 weeks and the median number of cycles was 5.5. In all, 26.1% of patients required a dosage reduction to 45 mg, and 5.6% required reduction to 30 mg.

As noted, the objective tumor response rate (ORR) among patients was 58.6% for 104 patients with FL. For the 23 patients with marginal zone lymphoma, the ORR was 69.6%, consisting of two complete and 14 partial responses. Among eight patients with SLL, there were six partial responses and no complete responses. For the six patients with LPL/WM, there was one partial response.

The overall median duration of response was 22.6 months. Among patients with refractory disease and in all patients with FL the median duration of response was 12.2 months.

The median progression-free survival after 24 months of follow-up was 11.2 months for all patients. The median overall survival has not been reached.

The most frequent adverse events of grade 3 or 4 were hyperglycemia in 40.1% (33.1% grade 3 and 7.0% grade 4) and hypertension in 22.5% (all grade 3).

Grade 3 diarrhea, a significant problem with idelalisib, occurred in 4.2% of patients, and there were no grade 4 events.

Grade 3 pneumonitis was seen in two patients, and one had grade 4 colitis. There were three drug related deaths, including one patient each from lung infection, respiratory failure, or thromboembolic event..

The study was supported by Bayer. Dr. Dreyling disclosed receiving honoraria from the company and serving on a scientific/advisory board for the company.

LUGANO, SWITZERLAND – Copanlisib, an investigational intravenous inhibitor of phosphatidylinositol 3-kinase (PI3K), was associated with “promising” efficacy and a better safety profile than has been seen with oral PI3K inhibitors in patients with relapsed or refractory indolent lymphomas.

In a phase 2 trial of the drug as monotherapy in patients with indolent lymphomas, copanlisib was associated with an overall response rate of 58.6% among 104 patients with follicular lymphoma (FL), including 14.4% complete responses (CR) and 44.2% partial responses (PR), reported Martin Dreyling, MD, of the Universität München-Grosshadern in Munich, Germany.

“The favorable risk-benefit profile of this compound suggests further [need for] testing in follicular lymphoma. My personal interpretation is that the different safety profile is due to the intermittent dosing and the IV application, avoiding adverse cause-effect both in the gut and the liver,” he said at the 14th International Conference on Malignant Lymphoma.

Dr. Dreyling noted that the oral PI3K inhibitor idelalisib (Zydelig) is approved for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab and in patients with relapsed FL or small lymphocytic lymphomas (SLL) who have received at least two prior lines of systemic therapy. This agent, however, carries a black box warning about fatal and serious toxicities, including hepatic events, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation.

Copanlisib inhibits all isoforms of P13K but is predominantly active against the alpha and delta isoforms of the kinase. The alpha form, expressed in many cell types, is involved in insulin signaling and angiogenesis and in resistance mechanisms to lymphoma. The delta form, expressed in leukocytes, is involved in B-cell signaling, development, and survival, making PIK3 an attractive target, Dr. Dreyling explained.

The study included patients with indolent B-cell lymphomas, including FL grades 1-3a, marginal zone lymphoma, SLL, or lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) for whom at least two prior lines of therapy had failed.

The patients received copanlisib 60 mg IV on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.

Of 142 assigned to and started on treatment, 46 patients (32.3%) remained on treatment at the time of data cutoff. Of the 96 patients (67.7%) who discontinued, 35 did so because of adverse events, 36 discontinued for radiologic or clinical evidence of progression, 16 withdrew, 5 were discontinued on the treating physician’s decision, and 4 stopped for other, unspecified reasons.

Among all 142 patients, the median duration of therapy was 22 weeks and the median number of cycles was 5.5. In all, 26.1% of patients required a dosage reduction to 45 mg, and 5.6% required reduction to 30 mg.

As noted, the objective tumor response rate (ORR) among patients was 58.6% for 104 patients with FL. For the 23 patients with marginal zone lymphoma, the ORR was 69.6%, consisting of two complete and 14 partial responses. Among eight patients with SLL, there were six partial responses and no complete responses. For the six patients with LPL/WM, there was one partial response.

The overall median duration of response was 22.6 months. Among patients with refractory disease and in all patients with FL the median duration of response was 12.2 months.

The median progression-free survival after 24 months of follow-up was 11.2 months for all patients. The median overall survival has not been reached.

The most frequent adverse events of grade 3 or 4 were hyperglycemia in 40.1% (33.1% grade 3 and 7.0% grade 4) and hypertension in 22.5% (all grade 3).

Grade 3 diarrhea, a significant problem with idelalisib, occurred in 4.2% of patients, and there were no grade 4 events.

Grade 3 pneumonitis was seen in two patients, and one had grade 4 colitis. There were three drug related deaths, including one patient each from lung infection, respiratory failure, or thromboembolic event..

The study was supported by Bayer. Dr. Dreyling disclosed receiving honoraria from the company and serving on a scientific/advisory board for the company.

LUGANO, SWITZERLAND – Copanlisib, an investigational intravenous inhibitor of phosphatidylinositol 3-kinase (PI3K), was associated with “promising” efficacy and a better safety profile than has been seen with oral PI3K inhibitors in patients with relapsed or refractory indolent lymphomas.

In a phase 2 trial of the drug as monotherapy in patients with indolent lymphomas, copanlisib was associated with an overall response rate of 58.6% among 104 patients with follicular lymphoma (FL), including 14.4% complete responses (CR) and 44.2% partial responses (PR), reported Martin Dreyling, MD, of the Universität München-Grosshadern in Munich, Germany.

“The favorable risk-benefit profile of this compound suggests further [need for] testing in follicular lymphoma. My personal interpretation is that the different safety profile is due to the intermittent dosing and the IV application, avoiding adverse cause-effect both in the gut and the liver,” he said at the 14th International Conference on Malignant Lymphoma.

Dr. Dreyling noted that the oral PI3K inhibitor idelalisib (Zydelig) is approved for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab and in patients with relapsed FL or small lymphocytic lymphomas (SLL) who have received at least two prior lines of systemic therapy. This agent, however, carries a black box warning about fatal and serious toxicities, including hepatic events, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation.

Copanlisib inhibits all isoforms of P13K but is predominantly active against the alpha and delta isoforms of the kinase. The alpha form, expressed in many cell types, is involved in insulin signaling and angiogenesis and in resistance mechanisms to lymphoma. The delta form, expressed in leukocytes, is involved in B-cell signaling, development, and survival, making PIK3 an attractive target, Dr. Dreyling explained.

The study included patients with indolent B-cell lymphomas, including FL grades 1-3a, marginal zone lymphoma, SLL, or lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) for whom at least two prior lines of therapy had failed.

The patients received copanlisib 60 mg IV on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.

Of 142 assigned to and started on treatment, 46 patients (32.3%) remained on treatment at the time of data cutoff. Of the 96 patients (67.7%) who discontinued, 35 did so because of adverse events, 36 discontinued for radiologic or clinical evidence of progression, 16 withdrew, 5 were discontinued on the treating physician’s decision, and 4 stopped for other, unspecified reasons.

Among all 142 patients, the median duration of therapy was 22 weeks and the median number of cycles was 5.5. In all, 26.1% of patients required a dosage reduction to 45 mg, and 5.6% required reduction to 30 mg.

As noted, the objective tumor response rate (ORR) among patients was 58.6% for 104 patients with FL. For the 23 patients with marginal zone lymphoma, the ORR was 69.6%, consisting of two complete and 14 partial responses. Among eight patients with SLL, there were six partial responses and no complete responses. For the six patients with LPL/WM, there was one partial response.

The overall median duration of response was 22.6 months. Among patients with refractory disease and in all patients with FL the median duration of response was 12.2 months.

The median progression-free survival after 24 months of follow-up was 11.2 months for all patients. The median overall survival has not been reached.

The most frequent adverse events of grade 3 or 4 were hyperglycemia in 40.1% (33.1% grade 3 and 7.0% grade 4) and hypertension in 22.5% (all grade 3).

Grade 3 diarrhea, a significant problem with idelalisib, occurred in 4.2% of patients, and there were no grade 4 events.

Grade 3 pneumonitis was seen in two patients, and one had grade 4 colitis. There were three drug related deaths, including one patient each from lung infection, respiratory failure, or thromboembolic event..

The study was supported by Bayer. Dr. Dreyling disclosed receiving honoraria from the company and serving on a scientific/advisory board for the company.

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.

hematologynews@frontlinemedcom.com

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.

hematologynews@frontlinemedcom.com

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.

hematologynews@frontlinemedcom.com

Photo by Rhoda Baer

Narrow insurance plan coverage may prevent US cancer patients from receiving care at “high-quality” cancer centers, according to research published in the Journal of Clinical Oncology.

Researchers found that “narrow network” insurance plans—lower-premium plans with reduced access to certain providers—are more likely to exclude doctors associated with National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN) cancer centers.

These centers are recognized for their scientific and research leadership, quality and safety initiatives, and access to expert physicians and clinical trials.

NCCN member institutions are particularly recognized for higher-quality care, and treatment at NCI-designated cancer centers is associated with lower mortality than other hospitals, particularly among more severely ill patients and those with more advanced disease.

For this study, researchers examined cancer provider networks offered on the 2014 individual health insurance exchanges and then determined which oncologists were affiliated with NCI-designated and NCCN cancer centers.

The researchers found that narrower networks were less likely to include physicians associated with NCI-designated and NCCN member institutions.

“To see such a robust result was surprising,” said study author Laura Yasaitis, PhD, of the University of Pennsylvania in Philadelphia.

“The finding that narrower networks were more likely to exclude NCI and NCCN oncologists was consistent no matter how we looked at it. This is not just a few networks. It’s a clear trend.”

The researchers said the results point to 2 major problems—transparency and access.

“Patients should be able to easily figure out whether the physicians they might need will be covered under a given plan,” said study author Justin E. Bekelman, MD, of the University of Pennsylvania.

The researchers suggested that insurers report doctor’s affiliations with NCI and NCCN cancer centers so that consumers can make more informed choices.

The team also suggested that insurers offer mechanisms that would allow patients to seek care out of network without incurring penalties in exceptional circumstances.

“If patients have narrow network plans and absolutely need the kind of complex cancer care that they can only receive from one of these providers, there should be a standard exception process to allow patients to access the care they need,” Dr Bekelman said. 

Photo by Rhoda Baer

Narrow insurance plan coverage may prevent US cancer patients from receiving care at “high-quality” cancer centers, according to research published in the Journal of Clinical Oncology.

Researchers found that “narrow network” insurance plans—lower-premium plans with reduced access to certain providers—are more likely to exclude doctors associated with National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN) cancer centers.

These centers are recognized for their scientific and research leadership, quality and safety initiatives, and access to expert physicians and clinical trials.

NCCN member institutions are particularly recognized for higher-quality care, and treatment at NCI-designated cancer centers is associated with lower mortality than other hospitals, particularly among more severely ill patients and those with more advanced disease.

For this study, researchers examined cancer provider networks offered on the 2014 individual health insurance exchanges and then determined which oncologists were affiliated with NCI-designated and NCCN cancer centers.

The researchers found that narrower networks were less likely to include physicians associated with NCI-designated and NCCN member institutions.

“To see such a robust result was surprising,” said study author Laura Yasaitis, PhD, of the University of Pennsylvania in Philadelphia.

“The finding that narrower networks were more likely to exclude NCI and NCCN oncologists was consistent no matter how we looked at it. This is not just a few networks. It’s a clear trend.”

The researchers said the results point to 2 major problems—transparency and access.

“Patients should be able to easily figure out whether the physicians they might need will be covered under a given plan,” said study author Justin E. Bekelman, MD, of the University of Pennsylvania.

The researchers suggested that insurers report doctor’s affiliations with NCI and NCCN cancer centers so that consumers can make more informed choices.

The team also suggested that insurers offer mechanisms that would allow patients to seek care out of network without incurring penalties in exceptional circumstances.

“If patients have narrow network plans and absolutely need the kind of complex cancer care that they can only receive from one of these providers, there should be a standard exception process to allow patients to access the care they need,” Dr Bekelman said. 

Photo by Rhoda Baer

Narrow insurance plan coverage may prevent US cancer patients from receiving care at “high-quality” cancer centers, according to research published in the Journal of Clinical Oncology.

Researchers found that “narrow network” insurance plans—lower-premium plans with reduced access to certain providers—are more likely to exclude doctors associated with National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN) cancer centers.

These centers are recognized for their scientific and research leadership, quality and safety initiatives, and access to expert physicians and clinical trials.

NCCN member institutions are particularly recognized for higher-quality care, and treatment at NCI-designated cancer centers is associated with lower mortality than other hospitals, particularly among more severely ill patients and those with more advanced disease.

For this study, researchers examined cancer provider networks offered on the 2014 individual health insurance exchanges and then determined which oncologists were affiliated with NCI-designated and NCCN cancer centers.

The researchers found that narrower networks were less likely to include physicians associated with NCI-designated and NCCN member institutions.

“To see such a robust result was surprising,” said study author Laura Yasaitis, PhD, of the University of Pennsylvania in Philadelphia.

“The finding that narrower networks were more likely to exclude NCI and NCCN oncologists was consistent no matter how we looked at it. This is not just a few networks. It’s a clear trend.”

The researchers said the results point to 2 major problems—transparency and access.

“Patients should be able to easily figure out whether the physicians they might need will be covered under a given plan,” said study author Justin E. Bekelman, MD, of the University of Pennsylvania.

The researchers suggested that insurers report doctor’s affiliations with NCI and NCCN cancer centers so that consumers can make more informed choices.

The team also suggested that insurers offer mechanisms that would allow patients to seek care out of network without incurring penalties in exceptional circumstances.

“If patients have narrow network plans and absolutely need the kind of complex cancer care that they can only receive from one of these providers, there should be a standard exception process to allow patients to access the care they need,” Dr Bekelman said. 

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%.

As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.

The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.

While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.

Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.

Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.

Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.

Source:

Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.

As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.

The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.

While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.

Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.

Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.

Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.

Source:

Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.

As more people are surviving breast cancer, more will be given bisphosphonate (BP) for bone metastases—and may be at risk for treatment adverse effects, such as atypical femoral fracture (AFF). Clinicians from Royal Victoria Hospital, Belfast, United Kingdom, describe what they learned in the first reported case of AFF caused by daily ibandronate.

The patient, a 55-year-old woman, had been diagnosed and treated for breast cancer. Twelve years later, she began having hip and lower back pain and was diagnosed with bony metastatic spread. She was started on hormone-suppressing therapy as well as daily ibandronic acid. Four years later, she began having new lower limb and groin pain. Radiography, bone scans and other tests indicated further metastatic spread to her left femur.

While she was waiting for scheduled radiotherapy, she fell, fracturing her left femur. Radiographs revealed AFF, presumed secondary to her BP therapy rather than metastasis. She underwent intramedullary nail fixation.

Evidence suggests that AFFs are stress fractures, the clinicians say. Repetitive loading on bone can lead to micro cracks, which are even more vulnerable to stress when BPs suppress the normal bone repair process.

Atypical femoral fracture is rare. Most cases have been patients receiving intravenous BP; to the clinicians’ knowledge this is the first report of AFF with an oral BP prescribed for bone metastatic breast cancer. But incidence of AFF grows with prolonged treatment, and the risk is raised with oral dosing, which is much higher in cancer cases, the clinicians note, compared with osteoporosis.

Because patients often have prodromal pain before an overt break, the clinicians suggest asking all oncology patients on BP about pain in thigh, hip, or groin. Bone scans and magnetic resonance imaging may reveal an imminent fracture. The clinicians caution that AFFs can be bilateral, so the opposite side also should be imaged.

Source:

Espey R, Grimes S, Heyburn G, Kealey WD. BMJ Case Rep. 2017;2017. pii: bcr-2016-217489.
doi: 10.1136/bcr-2016-217489.

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.