User login
Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Monalizumab-cetuximab combo shows promise in advanced head and neck SCC
WASHINGTON – and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.
As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.
Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.
“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.
A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.
Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m2 once weekly then 250 mg/m2 once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.
They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.
This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.
“Serious adverse events are in the single digits,” Dr. Cohen said.
Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.
“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”
Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.
“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”
Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.
“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.
“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.
Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.
SOURCE: Cohen R et al. SITC 2018, Abstract 051.
WASHINGTON – and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.
As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.
Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.
“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.
A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.
Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m2 once weekly then 250 mg/m2 once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.
They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.
This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.
“Serious adverse events are in the single digits,” Dr. Cohen said.
Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.
“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”
Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.
“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”
Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.
“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.
“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.
Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.
SOURCE: Cohen R et al. SITC 2018, Abstract 051.
WASHINGTON – and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.
As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.
Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.
“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.
A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.
Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m2 once weekly then 250 mg/m2 once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.
They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.
This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.
“Serious adverse events are in the single digits,” Dr. Cohen said.
Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.
“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”
Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.
“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”
Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.
“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.
“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.
Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.
SOURCE: Cohen R et al. SITC 2018, Abstract 051.
REPORTING FROM SITC 2018
Key clinical point: Monalizumab + cetuximab is safe, active in recurrent or metastatic SCC of the head and neck.
Major finding: Overall response rate in 40 evaluable patients was 27.5%,with 1 CR and 10 PRs at 8 weeks.
Study details: A cohort expansion of 40 patients in the single-arm, non-randomized phase 1/2 study.
Disclosures: Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.
Source: Cohen R et al. SITC 2018, Abstract 051.
Development of reversible B-cell inhibitor XmAb5871 for SLE moves forward
CHICAGO – The novel reversible B-cell inhibitor XmAb5871 showed promise for delaying loss of improvement after steroid therapy in patients with systemic lupus erythematosus in a randomized, placebo-controlled, phase 2 study.
Patients with moderate to severe nonorgan-threatening systemic lupus erythematosus (SLE) who underwent biweekly treatment with XmAb5871 after intramuscular glucocorticoid therapy more often achieved the trial’s primary endpoint of no loss of improvement through day 225 than did patients who took placebo. Overall, 21 (42%) of 50 patients who were randomized to receive active treatment reached this outcome, compared with 12 (29%) of 42 who received placebo based on the “efficacy-evaluable” patient population, defined as those who completed day 225, had a loss of improvement, or discontinued because of a drug-related adverse even. The difference between the treatment and placebo groups with respect to loss of improvement through day 225 reflected a positive trend, but did not reach statistical significance (P = .18), Debra J. Zack, MD, of Xencor in Monrovia, Calif., and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.
Of the patients who didn’t achieve the primary endpoint, 23 (46%) in the XmAb5871 arm versus 30 (71%) in the placebo arm experienced loss of improvement at any visit, the investigators noted. Six patients in the treatment arm discontinued for toxicity and were also considered nonresponders.
Treatment with XmAb5871 also led to a longer median time to loss of improvement of 230 days in comparison with the 130 days observed in placebo-treated patients. The difference was statistically significant in the efficacy-evaluable population (hazard ratio, 0.53; P = .025) and nearly statistically significant in the intent-to-treat (ITT) population of 52 patients in each group (HR, 0.59; P = .06), they noted.
Maintenance of improvement, which was another secondary endpoint, did not differ significantly between the groups in the efficacy-evaluable population (58.0% vs. 40.5%, respectively; P = .11), but did differ significantly with treatment versus placebo at both day 225 (response rates of 44.0% vs. 23.1%, respectively; P = .06) and at day 169 (57.7% vs. 34.6%; P = .02) in the ITT population, they said.
Of note, patients in the treatment group stayed in the study longer (median of 6.9 vs. 3.6 months) and received more infusions (median of 15.0 vs. 8.5).
“Antigen-activated B cells are down-regulated by engagement of immune complexes with the inhibitory Fcy receptor FcyRIIB on the B cell surface. XmAb5871 is an anti-CD19 monoclonal antibody engineered to enhance binding to FcyRIIB,” they explained, adding that the study was designed using unique methodology to minimize background medication and placebo responses to allow for better interpretation of the results in patients with complex, heterogeneous disease.
Participants were adults with a median age of 44.5 years; most (99 of 104) were women. All received an intramuscular glucocorticoid injection at the start of the screening period as background immunosuppressants were stopped, and those who experienced at least a 4-point decrease on the SLE disease activity index or at least a 1-grade decrease in at least one British Isles Lupus Activity Group A or B score were eligible for enrollment. Background immunosuppressants had to be stopped by the time of enrollment, but patients were allowed to remain on hydroxychloroquine and prednisone 10 mg or less daily or the equivalent.
Those enrolled were randomized to receive intravenous XmAb5871 at a dose of 5 mg/kg or placebo every 14 days for up to 16 doses until day 225 or loss of improvement (at which time patients could receive standard of care and withdraw from the study); all received intramuscular glucocorticoids (Depo-Medrol 80 mg [methylprednisolone acetate]) on days 1 and 15.
XmAb5871 was well tolerated in this study and had a safety profile consistent with that seen in previous SLE studies, with the exception of six withdrawals caused by infusion reactions, the investigators said. They noted that a subcutaneous formulation showed no infusion reactions or gastrointestinal-related infusion reactions in a bioavailability study of 40 healthy subjects, and so a formulation for subcutaneous injection will be used in future studies.
The vast majority of the 149 treatment-related adverse events that occurred in 41 patients in the current study (including 26% in placebo group patients) were mild or moderate in severity. A total of 13 serious adverse events (SAEs) occurred in 11 patients, and included fever, SLE flare (lung), atrial fibrillation, worsening hypertension, iron deficiency anemia, pneumonia (occurring 36 days, or 10 half-lives, after the last dose), infusion-related reaction, and vertigo in the XmAb5871 patients, and anemia SLE flare, SLE flare (enteritis), angioedema, and migraine headache in the placebo group.
“All SAEs were considered not or unlikely related except the infusion-related reaction. There were no deaths and no opportunistic infections,” they wrote.
Although the primary endpoint of loss of improvement by day 225 was not significantly better in the treatment group in this study, a positive trend was noted, the median time to loss of improvement was extended by 76%, and the risk of increased SLE disease activity was reduced by 47% in those who received XmAb5871, they said, concluding that the findings support further evaluation of the agent in patients with SLE.
The study was supported by Xencor.
SOURCE: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
CHICAGO – The novel reversible B-cell inhibitor XmAb5871 showed promise for delaying loss of improvement after steroid therapy in patients with systemic lupus erythematosus in a randomized, placebo-controlled, phase 2 study.
Patients with moderate to severe nonorgan-threatening systemic lupus erythematosus (SLE) who underwent biweekly treatment with XmAb5871 after intramuscular glucocorticoid therapy more often achieved the trial’s primary endpoint of no loss of improvement through day 225 than did patients who took placebo. Overall, 21 (42%) of 50 patients who were randomized to receive active treatment reached this outcome, compared with 12 (29%) of 42 who received placebo based on the “efficacy-evaluable” patient population, defined as those who completed day 225, had a loss of improvement, or discontinued because of a drug-related adverse even. The difference between the treatment and placebo groups with respect to loss of improvement through day 225 reflected a positive trend, but did not reach statistical significance (P = .18), Debra J. Zack, MD, of Xencor in Monrovia, Calif., and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.
Of the patients who didn’t achieve the primary endpoint, 23 (46%) in the XmAb5871 arm versus 30 (71%) in the placebo arm experienced loss of improvement at any visit, the investigators noted. Six patients in the treatment arm discontinued for toxicity and were also considered nonresponders.
Treatment with XmAb5871 also led to a longer median time to loss of improvement of 230 days in comparison with the 130 days observed in placebo-treated patients. The difference was statistically significant in the efficacy-evaluable population (hazard ratio, 0.53; P = .025) and nearly statistically significant in the intent-to-treat (ITT) population of 52 patients in each group (HR, 0.59; P = .06), they noted.
Maintenance of improvement, which was another secondary endpoint, did not differ significantly between the groups in the efficacy-evaluable population (58.0% vs. 40.5%, respectively; P = .11), but did differ significantly with treatment versus placebo at both day 225 (response rates of 44.0% vs. 23.1%, respectively; P = .06) and at day 169 (57.7% vs. 34.6%; P = .02) in the ITT population, they said.
Of note, patients in the treatment group stayed in the study longer (median of 6.9 vs. 3.6 months) and received more infusions (median of 15.0 vs. 8.5).
“Antigen-activated B cells are down-regulated by engagement of immune complexes with the inhibitory Fcy receptor FcyRIIB on the B cell surface. XmAb5871 is an anti-CD19 monoclonal antibody engineered to enhance binding to FcyRIIB,” they explained, adding that the study was designed using unique methodology to minimize background medication and placebo responses to allow for better interpretation of the results in patients with complex, heterogeneous disease.
Participants were adults with a median age of 44.5 years; most (99 of 104) were women. All received an intramuscular glucocorticoid injection at the start of the screening period as background immunosuppressants were stopped, and those who experienced at least a 4-point decrease on the SLE disease activity index or at least a 1-grade decrease in at least one British Isles Lupus Activity Group A or B score were eligible for enrollment. Background immunosuppressants had to be stopped by the time of enrollment, but patients were allowed to remain on hydroxychloroquine and prednisone 10 mg or less daily or the equivalent.
Those enrolled were randomized to receive intravenous XmAb5871 at a dose of 5 mg/kg or placebo every 14 days for up to 16 doses until day 225 or loss of improvement (at which time patients could receive standard of care and withdraw from the study); all received intramuscular glucocorticoids (Depo-Medrol 80 mg [methylprednisolone acetate]) on days 1 and 15.
XmAb5871 was well tolerated in this study and had a safety profile consistent with that seen in previous SLE studies, with the exception of six withdrawals caused by infusion reactions, the investigators said. They noted that a subcutaneous formulation showed no infusion reactions or gastrointestinal-related infusion reactions in a bioavailability study of 40 healthy subjects, and so a formulation for subcutaneous injection will be used in future studies.
The vast majority of the 149 treatment-related adverse events that occurred in 41 patients in the current study (including 26% in placebo group patients) were mild or moderate in severity. A total of 13 serious adverse events (SAEs) occurred in 11 patients, and included fever, SLE flare (lung), atrial fibrillation, worsening hypertension, iron deficiency anemia, pneumonia (occurring 36 days, or 10 half-lives, after the last dose), infusion-related reaction, and vertigo in the XmAb5871 patients, and anemia SLE flare, SLE flare (enteritis), angioedema, and migraine headache in the placebo group.
“All SAEs were considered not or unlikely related except the infusion-related reaction. There were no deaths and no opportunistic infections,” they wrote.
Although the primary endpoint of loss of improvement by day 225 was not significantly better in the treatment group in this study, a positive trend was noted, the median time to loss of improvement was extended by 76%, and the risk of increased SLE disease activity was reduced by 47% in those who received XmAb5871, they said, concluding that the findings support further evaluation of the agent in patients with SLE.
The study was supported by Xencor.
SOURCE: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
CHICAGO – The novel reversible B-cell inhibitor XmAb5871 showed promise for delaying loss of improvement after steroid therapy in patients with systemic lupus erythematosus in a randomized, placebo-controlled, phase 2 study.
Patients with moderate to severe nonorgan-threatening systemic lupus erythematosus (SLE) who underwent biweekly treatment with XmAb5871 after intramuscular glucocorticoid therapy more often achieved the trial’s primary endpoint of no loss of improvement through day 225 than did patients who took placebo. Overall, 21 (42%) of 50 patients who were randomized to receive active treatment reached this outcome, compared with 12 (29%) of 42 who received placebo based on the “efficacy-evaluable” patient population, defined as those who completed day 225, had a loss of improvement, or discontinued because of a drug-related adverse even. The difference between the treatment and placebo groups with respect to loss of improvement through day 225 reflected a positive trend, but did not reach statistical significance (P = .18), Debra J. Zack, MD, of Xencor in Monrovia, Calif., and her colleagues reported in a poster at the annual meeting of the American College of Rheumatology.
Of the patients who didn’t achieve the primary endpoint, 23 (46%) in the XmAb5871 arm versus 30 (71%) in the placebo arm experienced loss of improvement at any visit, the investigators noted. Six patients in the treatment arm discontinued for toxicity and were also considered nonresponders.
Treatment with XmAb5871 also led to a longer median time to loss of improvement of 230 days in comparison with the 130 days observed in placebo-treated patients. The difference was statistically significant in the efficacy-evaluable population (hazard ratio, 0.53; P = .025) and nearly statistically significant in the intent-to-treat (ITT) population of 52 patients in each group (HR, 0.59; P = .06), they noted.
Maintenance of improvement, which was another secondary endpoint, did not differ significantly between the groups in the efficacy-evaluable population (58.0% vs. 40.5%, respectively; P = .11), but did differ significantly with treatment versus placebo at both day 225 (response rates of 44.0% vs. 23.1%, respectively; P = .06) and at day 169 (57.7% vs. 34.6%; P = .02) in the ITT population, they said.
Of note, patients in the treatment group stayed in the study longer (median of 6.9 vs. 3.6 months) and received more infusions (median of 15.0 vs. 8.5).
“Antigen-activated B cells are down-regulated by engagement of immune complexes with the inhibitory Fcy receptor FcyRIIB on the B cell surface. XmAb5871 is an anti-CD19 monoclonal antibody engineered to enhance binding to FcyRIIB,” they explained, adding that the study was designed using unique methodology to minimize background medication and placebo responses to allow for better interpretation of the results in patients with complex, heterogeneous disease.
Participants were adults with a median age of 44.5 years; most (99 of 104) were women. All received an intramuscular glucocorticoid injection at the start of the screening period as background immunosuppressants were stopped, and those who experienced at least a 4-point decrease on the SLE disease activity index or at least a 1-grade decrease in at least one British Isles Lupus Activity Group A or B score were eligible for enrollment. Background immunosuppressants had to be stopped by the time of enrollment, but patients were allowed to remain on hydroxychloroquine and prednisone 10 mg or less daily or the equivalent.
Those enrolled were randomized to receive intravenous XmAb5871 at a dose of 5 mg/kg or placebo every 14 days for up to 16 doses until day 225 or loss of improvement (at which time patients could receive standard of care and withdraw from the study); all received intramuscular glucocorticoids (Depo-Medrol 80 mg [methylprednisolone acetate]) on days 1 and 15.
XmAb5871 was well tolerated in this study and had a safety profile consistent with that seen in previous SLE studies, with the exception of six withdrawals caused by infusion reactions, the investigators said. They noted that a subcutaneous formulation showed no infusion reactions or gastrointestinal-related infusion reactions in a bioavailability study of 40 healthy subjects, and so a formulation for subcutaneous injection will be used in future studies.
The vast majority of the 149 treatment-related adverse events that occurred in 41 patients in the current study (including 26% in placebo group patients) were mild or moderate in severity. A total of 13 serious adverse events (SAEs) occurred in 11 patients, and included fever, SLE flare (lung), atrial fibrillation, worsening hypertension, iron deficiency anemia, pneumonia (occurring 36 days, or 10 half-lives, after the last dose), infusion-related reaction, and vertigo in the XmAb5871 patients, and anemia SLE flare, SLE flare (enteritis), angioedema, and migraine headache in the placebo group.
“All SAEs were considered not or unlikely related except the infusion-related reaction. There were no deaths and no opportunistic infections,” they wrote.
Although the primary endpoint of loss of improvement by day 225 was not significantly better in the treatment group in this study, a positive trend was noted, the median time to loss of improvement was extended by 76%, and the risk of increased SLE disease activity was reduced by 47% in those who received XmAb5871, they said, concluding that the findings support further evaluation of the agent in patients with SLE.
The study was supported by Xencor.
SOURCE: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: XmAb5871 shows promise in systemic lupus erythematosus.
Major finding: There was no loss of improvement through day 225 in 42% of patients treated with XmAb5871 versus 29% with placebo.
Study details: A randomized, placebo-controlled, phase 2 study.
Disclosures: The study was supported by Xencor. Dr. Zack is an employee of Xencor.
Source: Zack DJ et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L14.
FDA expands approval of brentuximab vedotin to PTCL
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
Relapsed MCL: Options for treatment
CHICAGO – according to Kristie A. Blum, MD.
Venetoclax and lenalidomide can also be considered in the relapsed mantle cell lymphoma (MCL) setting, Dr. Blum, a professor in the department of hematology and medical oncology at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“I tend to favor BTK inhibitors as my first line of therapy,” she said, later qualifying that this applies when clinical trial enrollment is unavailable.
Ibrutinib
The BTK inhibitor ibrutinib is well established as a treatment for MCL and for use in the relapsed setting, she said, noting that pooled data from the phase 2 CYC-1104 trial, the phase 2 MCL 2001 (SPARK) trial, and the phase 3 MCL3001 (RAY) trial showed an overall response (OR) rate of 66% in 370 patients and a complete response (CR) rate of 20%.
The median duration of response (DOR) was 18.6 months, median progression-free survival (PFS) was 12.8 months, and median overall survival (OS) was 25 months (Br J Haematol. 2017 Nov;179[3]:430-8).
Adding rituximab to ibrutinib (R-ibrutinib) improved outcomes, at least in one single center phase 2 trial of 50 relapsed patients with a median of three prior therapies, she said. The OR rate in that study was 88%, and the CR rate was 58% (Br J Haematol. 2018 May;182[3]:404-11).
“What was really impressive to me was that the median duration of response was about 46 months. PFS was 43 months, and patients were on [treatment] as long as 56 cycles,” she said.
Acalabrutinib
The newer BTK inhibitor acalabrutinib also shows benefit in the relapsed MCL setting, Dr. Blum said.
In a recent multicenter, open-label, phase 2 study of 124 patients with a median age of 68 years and a median of two prior therapies, acalabrutinib at a dose of 100 mg twice daily was associated with an OR rate of 81% and a CR rate of 40% (Lancet. 2018 Feb 17;391:659-67).
“Seems a little better than what you’d expect with single agent ibrutinib,” she said, noting that median DOR and PFS have not been reached in that study.
The main toxicities have been “headache and some diarrhea,” but follow-up is currently only about 15 months, she added.
Venetoclax
Another option in this setting is the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, which was shown in a recent phase 1 study of patients with various lymphoma subtypes to have activity in relapsed MCL, Dr. Blum said.
The OR rate in 28 relapsed MCL patients in that study was 75%, and the median PFS was 14 months (J Clin Oncol. 2017 Mar;35:826-33).
Additionally, an “intriguing combination study of venetoclax and ibrutinib” was recently published in the New England Journal of Medicine, she noted.
That study included only 23 patients with relapsed MCL, but they were a “pretty high-risk” group with a median age of 68 years, about half having a TP53 abnormality, and 30% having a prior transplant.
The OR and CR rates at 16 weeks by positron emission tomography were 71% and 62%, respectively (N Engl J Med. 2018 Mar 29;378:1211-23).
“Actually, about 40% achieved [minimal residual disease] negativity, but this was only checked in about half the patients,” she said. “So this is an intriguing combination and hopefully something we’ll see more of in the upcoming years.”
Lenalidomide
In the randomized phase 2 SPRINT study, patients received either single-agent lenolidamine or the investigator’s choice of single-agent rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine.
The expected OR rate in 170 patients treated with lenalidomide was 40% versus 11% in 84 patients treated with investigator’s choice of treatment, and the respective CR rates were 5% and 0% (Lancet Oncol. 2016 Mar 1;17(3):319-31).
Median DOR was 16 months versus 10.4 months, PFS was 8.7 versus 5.2 months, and median OS was 27.9 versus 21.1 months in the groups, respectively.
Other options
Combination regimens, such as R-CHOP and R-bendamustine, are also options for the treatment of relapsed MCL patients who haven’t received combination therapy in the past, Dr. Blum said. Transplant is another option in some patients.
“I will consider transplants for younger patients if they come to me and they actually hadn’t had one in [their] first CR,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – according to Kristie A. Blum, MD.
Venetoclax and lenalidomide can also be considered in the relapsed mantle cell lymphoma (MCL) setting, Dr. Blum, a professor in the department of hematology and medical oncology at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“I tend to favor BTK inhibitors as my first line of therapy,” she said, later qualifying that this applies when clinical trial enrollment is unavailable.
Ibrutinib
The BTK inhibitor ibrutinib is well established as a treatment for MCL and for use in the relapsed setting, she said, noting that pooled data from the phase 2 CYC-1104 trial, the phase 2 MCL 2001 (SPARK) trial, and the phase 3 MCL3001 (RAY) trial showed an overall response (OR) rate of 66% in 370 patients and a complete response (CR) rate of 20%.
The median duration of response (DOR) was 18.6 months, median progression-free survival (PFS) was 12.8 months, and median overall survival (OS) was 25 months (Br J Haematol. 2017 Nov;179[3]:430-8).
Adding rituximab to ibrutinib (R-ibrutinib) improved outcomes, at least in one single center phase 2 trial of 50 relapsed patients with a median of three prior therapies, she said. The OR rate in that study was 88%, and the CR rate was 58% (Br J Haematol. 2018 May;182[3]:404-11).
“What was really impressive to me was that the median duration of response was about 46 months. PFS was 43 months, and patients were on [treatment] as long as 56 cycles,” she said.
Acalabrutinib
The newer BTK inhibitor acalabrutinib also shows benefit in the relapsed MCL setting, Dr. Blum said.
In a recent multicenter, open-label, phase 2 study of 124 patients with a median age of 68 years and a median of two prior therapies, acalabrutinib at a dose of 100 mg twice daily was associated with an OR rate of 81% and a CR rate of 40% (Lancet. 2018 Feb 17;391:659-67).
“Seems a little better than what you’d expect with single agent ibrutinib,” she said, noting that median DOR and PFS have not been reached in that study.
The main toxicities have been “headache and some diarrhea,” but follow-up is currently only about 15 months, she added.
Venetoclax
Another option in this setting is the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, which was shown in a recent phase 1 study of patients with various lymphoma subtypes to have activity in relapsed MCL, Dr. Blum said.
The OR rate in 28 relapsed MCL patients in that study was 75%, and the median PFS was 14 months (J Clin Oncol. 2017 Mar;35:826-33).
Additionally, an “intriguing combination study of venetoclax and ibrutinib” was recently published in the New England Journal of Medicine, she noted.
That study included only 23 patients with relapsed MCL, but they were a “pretty high-risk” group with a median age of 68 years, about half having a TP53 abnormality, and 30% having a prior transplant.
The OR and CR rates at 16 weeks by positron emission tomography were 71% and 62%, respectively (N Engl J Med. 2018 Mar 29;378:1211-23).
“Actually, about 40% achieved [minimal residual disease] negativity, but this was only checked in about half the patients,” she said. “So this is an intriguing combination and hopefully something we’ll see more of in the upcoming years.”
Lenalidomide
In the randomized phase 2 SPRINT study, patients received either single-agent lenolidamine or the investigator’s choice of single-agent rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine.
The expected OR rate in 170 patients treated with lenalidomide was 40% versus 11% in 84 patients treated with investigator’s choice of treatment, and the respective CR rates were 5% and 0% (Lancet Oncol. 2016 Mar 1;17(3):319-31).
Median DOR was 16 months versus 10.4 months, PFS was 8.7 versus 5.2 months, and median OS was 27.9 versus 21.1 months in the groups, respectively.
Other options
Combination regimens, such as R-CHOP and R-bendamustine, are also options for the treatment of relapsed MCL patients who haven’t received combination therapy in the past, Dr. Blum said. Transplant is another option in some patients.
“I will consider transplants for younger patients if they come to me and they actually hadn’t had one in [their] first CR,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – according to Kristie A. Blum, MD.
Venetoclax and lenalidomide can also be considered in the relapsed mantle cell lymphoma (MCL) setting, Dr. Blum, a professor in the department of hematology and medical oncology at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“I tend to favor BTK inhibitors as my first line of therapy,” she said, later qualifying that this applies when clinical trial enrollment is unavailable.
Ibrutinib
The BTK inhibitor ibrutinib is well established as a treatment for MCL and for use in the relapsed setting, she said, noting that pooled data from the phase 2 CYC-1104 trial, the phase 2 MCL 2001 (SPARK) trial, and the phase 3 MCL3001 (RAY) trial showed an overall response (OR) rate of 66% in 370 patients and a complete response (CR) rate of 20%.
The median duration of response (DOR) was 18.6 months, median progression-free survival (PFS) was 12.8 months, and median overall survival (OS) was 25 months (Br J Haematol. 2017 Nov;179[3]:430-8).
Adding rituximab to ibrutinib (R-ibrutinib) improved outcomes, at least in one single center phase 2 trial of 50 relapsed patients with a median of three prior therapies, she said. The OR rate in that study was 88%, and the CR rate was 58% (Br J Haematol. 2018 May;182[3]:404-11).
“What was really impressive to me was that the median duration of response was about 46 months. PFS was 43 months, and patients were on [treatment] as long as 56 cycles,” she said.
Acalabrutinib
The newer BTK inhibitor acalabrutinib also shows benefit in the relapsed MCL setting, Dr. Blum said.
In a recent multicenter, open-label, phase 2 study of 124 patients with a median age of 68 years and a median of two prior therapies, acalabrutinib at a dose of 100 mg twice daily was associated with an OR rate of 81% and a CR rate of 40% (Lancet. 2018 Feb 17;391:659-67).
“Seems a little better than what you’d expect with single agent ibrutinib,” she said, noting that median DOR and PFS have not been reached in that study.
The main toxicities have been “headache and some diarrhea,” but follow-up is currently only about 15 months, she added.
Venetoclax
Another option in this setting is the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax, which was shown in a recent phase 1 study of patients with various lymphoma subtypes to have activity in relapsed MCL, Dr. Blum said.
The OR rate in 28 relapsed MCL patients in that study was 75%, and the median PFS was 14 months (J Clin Oncol. 2017 Mar;35:826-33).
Additionally, an “intriguing combination study of venetoclax and ibrutinib” was recently published in the New England Journal of Medicine, she noted.
That study included only 23 patients with relapsed MCL, but they were a “pretty high-risk” group with a median age of 68 years, about half having a TP53 abnormality, and 30% having a prior transplant.
The OR and CR rates at 16 weeks by positron emission tomography were 71% and 62%, respectively (N Engl J Med. 2018 Mar 29;378:1211-23).
“Actually, about 40% achieved [minimal residual disease] negativity, but this was only checked in about half the patients,” she said. “So this is an intriguing combination and hopefully something we’ll see more of in the upcoming years.”
Lenalidomide
In the randomized phase 2 SPRINT study, patients received either single-agent lenolidamine or the investigator’s choice of single-agent rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine.
The expected OR rate in 170 patients treated with lenalidomide was 40% versus 11% in 84 patients treated with investigator’s choice of treatment, and the respective CR rates were 5% and 0% (Lancet Oncol. 2016 Mar 1;17(3):319-31).
Median DOR was 16 months versus 10.4 months, PFS was 8.7 versus 5.2 months, and median OS was 27.9 versus 21.1 months in the groups, respectively.
Other options
Combination regimens, such as R-CHOP and R-bendamustine, are also options for the treatment of relapsed MCL patients who haven’t received combination therapy in the past, Dr. Blum said. Transplant is another option in some patients.
“I will consider transplants for younger patients if they come to me and they actually hadn’t had one in [their] first CR,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
EXPERT ANALYSIS FROM MHM 2018
Early phase 2 data: Mocetinostat/durvalumab combo shows promise in mNSCLC
WASHINGTON, D.C. – (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.
Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.
Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.
Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.
Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.
“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.
Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.
“So I think this is likely to be related to mocetinostat,” Dr. Patel said.
Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.
For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.
“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.
In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.
Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.
The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.
Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
SOURCE: Patel M et al. SITC 2018, Abstract 027.
WASHINGTON, D.C. – (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.
Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.
Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.
Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.
Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.
“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.
Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.
“So I think this is likely to be related to mocetinostat,” Dr. Patel said.
Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.
For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.
“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.
In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.
Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.
The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.
Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
SOURCE: Patel M et al. SITC 2018, Abstract 027.
WASHINGTON, D.C. – (mNSCLC) – including patients who progressed on prior checkpoint inhibitor therapy (CIT), according to preliminary findings from a phase 2 trial.
Of 29 evaluable patients who progressed on prior checkpoint blockade, 12 had “some degree of tumor regression” and 5 achieved a confirmed partial response, Manish Patel, DO, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“Some of these responses were quite durable. The longest response ... was a little over 1 year,” said Dr. Patel, of the University of Minnesota Masonic Cancer Center, Minneapolis.
Several patients continue to show objective responses, and the initial estimate of response duration is a median of more than 5 months, he added.
Of note, no differences have been seen to date with respect to clinical benefit in patients who did and did not have prior clinical benefit on checkpoint blockade, Dr. Patel said.
Overall, the combination was very well tolerated. The most common adverse events were fatigue, nausea, and diarrhea, with more than 10% of patients experiencing grade 3 or higher fatigue.
“Otherwise the toxicities were relatively minor,” he said, noting, however, that 8% of patients had cardiac events during the study, including atrial fibrillation, pericardial effusion, and a few cases of pericardial tamponade.
Such effects have been described in prior mocetinostat monotherapy trials, and all patients in the current study underwent pretreatment echocardiograms and did not have evidence of pericardial effusion at the start.
“So I think this is likely to be related to mocetinostat,” Dr. Patel said.
Mocetinostat is a spectrum-selective class I and class IV histone deacetylase inhibitor with multiple potential immunomodulatory features.
For example, the agent induces major histocompatibility complex Class I and Class II expression on tumor cells, enhances the function of T effector cells, and decreases the function of immunosuppressive cell subsets, including regulatory T cells and myeloid derived suppressor cells, Dr. Patel noted.
“It was hypothesized that because of these pleiotropic immune-supportive effects, that the combination of mocetinostat and checkpoint blockade might be a successful strategy for patients with non–small cell lung cancer,” he said.
In phase 1, doses of 50 mg, 70 mg, or 90 mg given three times weekly in combination with 1,500 mg of durvalumab were studied in patients with advanced solid tumors. Based on the safety data from that phase of the study, the recommended phase 2 dose of mocetinostat was 70 mg three times weekly with 1,500 mg of durvalumab on day 1 of each 28-day cycle.
Study subjects were patients with mNSCLC who had received at least one platinum-based doublet and whose most recent treatment prior to enrollment was with a checkpoint inhibitor, or who were immunotherapy naive.
The findings show promising clinical efficacy and safety, and enrollment in the study, which began in June 2016, is currently ongoing in the United States, he said.
Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
SOURCE: Patel M et al. SITC 2018, Abstract 027.
REPORTING FROM SITC 2018
Key clinical point: Mocetinostat/durvalumab shows clinical activity and manageable side effects in metastatic NSCLC.
Major finding: Five patients achieved a confirmed partial response.
Study details: A phase 2 study including 29 NSCLC patients.
Disclosures: Dr. Patel is an advisory board member for Nektar Therapeutics and has received research funding from Merck.
Source: Patel M et al. SITC 2018, Abstract 027.
Scleroderma SCOT trial findings hold similar in lung disease
CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.
The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).
In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.
Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.
Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.
“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.
Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.
CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.
“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”
Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.
“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.
The investigators reported having no relevant disclosures.
SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.
The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).
In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.
Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.
Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.
“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.
Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.
CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.
“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”
Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.
“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.
The investigators reported having no relevant disclosures.
SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.
The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).
In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.
Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.
Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.
“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.
Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.
CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.
“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”
Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.
“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.
The investigators reported having no relevant disclosures.
SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: Lung CT scores remain stable or improve following hematopoietic stem cell transplantation in patients with scleroderma-related interstitial lung disease when compared against monthly cyclophosphamide treatments.
Major finding: Quantitative interstitial lung disease scores decreased by 7% at 54 months in hematopoietic stem cell transplant patients versus no change in those who received cyclophosphamide (P = .024).
Study details: A study of 75 patients from the SCOT trial.
Disclosures: The investigators reported having no relevant disclosures.
Source: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.
Consider treatment, testing when CLL symptoms emerge
CHICAGO – said Paul M. Barr, MD.
He described a patient who had been observed for 7 years when he began to complain of increasing fatigue and lost work time. A complete blood count (CBC) showed thrombocytopenia.
The recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines state that assessments before treatment in this type of patient should include history and physical, evaluation of infectious disease status, and routine laboratory testing – including CBC and differential, chemistry, serum immunoglobulin, and direct antiglobulin test.
“Bone marrow biopsies and [computed tomography] scans are listed as ‘not necessarily required,’ ” Dr. Barr, medical director of the Clinical Trials Office for Wilmot Cancer Institute at the University of Rochester (N.Y.) said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
He added that he opts for CT scans prior to therapy “to understand the patient’s disease burden and potentially to compare to later” and that bone marrow biopsy is “still very reasonable” for understanding the source of a patient’s cytopenias.
“Is it marrow failure or [immune thrombocytopenia]? Could the patient have [myelodysplastic syndrome]? All important considerations,” he said.
Positron emission tomography (PET) scans, however, are only considered when there is concern about transformation, he noted.
Predictive tests that should be conducted before initiating therapy, and that could help in guiding therapy decisions, include TP53 mutation testing and immunoglobulin heavy chain variable region gene (IGHV) mutational status testing (although this doesn’t need to be repeated if it was done at diagnosis because mutational status doesn’t change). Another helpful test is molecular cytogenetics using fluorescence in situ hybridization (FISH) for del(13q), del(17p), and trisomy 12 in peripheral blood lymphocytes. This should be repeated even it was done at diagnosis because patients can acquire additional molecular aberrations over time, Dr. Barr said.
Among the data that justify this advice for predictive testing are studies showing the curative potential of fludarabine/cyclophosphamide/rituximab (FCR) in mutated IGHV CLL, the progression-free survival (PFS) benefits of ibrutinib for patients with del(17p), and the activity of idelalisib in relapsed/refractory CLL patients, including those with TP53 dysfunction.
“The IGHV mutation status is useful to know what to expect from chemoimmunotherapy over time,” Dr. Barr said, explaining that several analyses demonstrate that patients with mutated IGHV genes (patients with low-risk disease) respond exceptionally well to chemoimmunotherapy, especially FCR.
In fact, studies, including a 2016 study by Philip A. Thompson and his colleagues and another by Kirsten Fischer and her colleagues, show that nearly 60% of patients with IGHV mutation remain in remission 10 years after FCR treatment, he said. However, the same is not necessarily true for bendamustine/rituximab (BR); the CLL10 study showed a significantly greater PFS with FCR, compared with that seen with BR.
Unmutated patients in that study had lower PFS, but the outcomes were still better with FCR than with BR, he said.
Studies of novel agents, including ibrutinib and idelalisib, suggest they may have particular benefit in higher-risk patients.
Ibrutinib was shown in a phase 2 study to be of benefit regardless of IGHV status, and this was replicated in the first-line RESONATE 2 study, which compared ibrutinib with chlorambucil and showed it had better PFS than that seen in unmutated patients treated with FCR in other studies, said Dr. Barr, the first author on that study.
“So you can see how the treatment paradigms are starting to evolve. It does look like ... comparing across trials, that ibrutinib leads to better remission durations, compared to chemoimmunotherapy, so far,” he said.
Ibrutinib has also been shown to be of benefit for patients with del(17p). A single-arm phase 2 study showed 79% PFS in relapsed, high-risk patients, which is much better than has been seen with chemoimmunotherapy, he noted.
“Venetoclax is also a very good option for this patient population in the relapse setting,” he said, adding that the PFS with venetoclax has been shown to be very similar to that with ibrutinib.
Similarly, idelalisib has been shown to provide comparable benefit in relapsed/refractory CLL patients, with and without del(17p)/TP53 mutation, he said.
Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.
CHICAGO – said Paul M. Barr, MD.
He described a patient who had been observed for 7 years when he began to complain of increasing fatigue and lost work time. A complete blood count (CBC) showed thrombocytopenia.
The recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines state that assessments before treatment in this type of patient should include history and physical, evaluation of infectious disease status, and routine laboratory testing – including CBC and differential, chemistry, serum immunoglobulin, and direct antiglobulin test.
“Bone marrow biopsies and [computed tomography] scans are listed as ‘not necessarily required,’ ” Dr. Barr, medical director of the Clinical Trials Office for Wilmot Cancer Institute at the University of Rochester (N.Y.) said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
He added that he opts for CT scans prior to therapy “to understand the patient’s disease burden and potentially to compare to later” and that bone marrow biopsy is “still very reasonable” for understanding the source of a patient’s cytopenias.
“Is it marrow failure or [immune thrombocytopenia]? Could the patient have [myelodysplastic syndrome]? All important considerations,” he said.
Positron emission tomography (PET) scans, however, are only considered when there is concern about transformation, he noted.
Predictive tests that should be conducted before initiating therapy, and that could help in guiding therapy decisions, include TP53 mutation testing and immunoglobulin heavy chain variable region gene (IGHV) mutational status testing (although this doesn’t need to be repeated if it was done at diagnosis because mutational status doesn’t change). Another helpful test is molecular cytogenetics using fluorescence in situ hybridization (FISH) for del(13q), del(17p), and trisomy 12 in peripheral blood lymphocytes. This should be repeated even it was done at diagnosis because patients can acquire additional molecular aberrations over time, Dr. Barr said.
Among the data that justify this advice for predictive testing are studies showing the curative potential of fludarabine/cyclophosphamide/rituximab (FCR) in mutated IGHV CLL, the progression-free survival (PFS) benefits of ibrutinib for patients with del(17p), and the activity of idelalisib in relapsed/refractory CLL patients, including those with TP53 dysfunction.
“The IGHV mutation status is useful to know what to expect from chemoimmunotherapy over time,” Dr. Barr said, explaining that several analyses demonstrate that patients with mutated IGHV genes (patients with low-risk disease) respond exceptionally well to chemoimmunotherapy, especially FCR.
In fact, studies, including a 2016 study by Philip A. Thompson and his colleagues and another by Kirsten Fischer and her colleagues, show that nearly 60% of patients with IGHV mutation remain in remission 10 years after FCR treatment, he said. However, the same is not necessarily true for bendamustine/rituximab (BR); the CLL10 study showed a significantly greater PFS with FCR, compared with that seen with BR.
Unmutated patients in that study had lower PFS, but the outcomes were still better with FCR than with BR, he said.
Studies of novel agents, including ibrutinib and idelalisib, suggest they may have particular benefit in higher-risk patients.
Ibrutinib was shown in a phase 2 study to be of benefit regardless of IGHV status, and this was replicated in the first-line RESONATE 2 study, which compared ibrutinib with chlorambucil and showed it had better PFS than that seen in unmutated patients treated with FCR in other studies, said Dr. Barr, the first author on that study.
“So you can see how the treatment paradigms are starting to evolve. It does look like ... comparing across trials, that ibrutinib leads to better remission durations, compared to chemoimmunotherapy, so far,” he said.
Ibrutinib has also been shown to be of benefit for patients with del(17p). A single-arm phase 2 study showed 79% PFS in relapsed, high-risk patients, which is much better than has been seen with chemoimmunotherapy, he noted.
“Venetoclax is also a very good option for this patient population in the relapse setting,” he said, adding that the PFS with venetoclax has been shown to be very similar to that with ibrutinib.
Similarly, idelalisib has been shown to provide comparable benefit in relapsed/refractory CLL patients, with and without del(17p)/TP53 mutation, he said.
Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.
CHICAGO – said Paul M. Barr, MD.
He described a patient who had been observed for 7 years when he began to complain of increasing fatigue and lost work time. A complete blood count (CBC) showed thrombocytopenia.
The recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines state that assessments before treatment in this type of patient should include history and physical, evaluation of infectious disease status, and routine laboratory testing – including CBC and differential, chemistry, serum immunoglobulin, and direct antiglobulin test.
“Bone marrow biopsies and [computed tomography] scans are listed as ‘not necessarily required,’ ” Dr. Barr, medical director of the Clinical Trials Office for Wilmot Cancer Institute at the University of Rochester (N.Y.) said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
He added that he opts for CT scans prior to therapy “to understand the patient’s disease burden and potentially to compare to later” and that bone marrow biopsy is “still very reasonable” for understanding the source of a patient’s cytopenias.
“Is it marrow failure or [immune thrombocytopenia]? Could the patient have [myelodysplastic syndrome]? All important considerations,” he said.
Positron emission tomography (PET) scans, however, are only considered when there is concern about transformation, he noted.
Predictive tests that should be conducted before initiating therapy, and that could help in guiding therapy decisions, include TP53 mutation testing and immunoglobulin heavy chain variable region gene (IGHV) mutational status testing (although this doesn’t need to be repeated if it was done at diagnosis because mutational status doesn’t change). Another helpful test is molecular cytogenetics using fluorescence in situ hybridization (FISH) for del(13q), del(17p), and trisomy 12 in peripheral blood lymphocytes. This should be repeated even it was done at diagnosis because patients can acquire additional molecular aberrations over time, Dr. Barr said.
Among the data that justify this advice for predictive testing are studies showing the curative potential of fludarabine/cyclophosphamide/rituximab (FCR) in mutated IGHV CLL, the progression-free survival (PFS) benefits of ibrutinib for patients with del(17p), and the activity of idelalisib in relapsed/refractory CLL patients, including those with TP53 dysfunction.
“The IGHV mutation status is useful to know what to expect from chemoimmunotherapy over time,” Dr. Barr said, explaining that several analyses demonstrate that patients with mutated IGHV genes (patients with low-risk disease) respond exceptionally well to chemoimmunotherapy, especially FCR.
In fact, studies, including a 2016 study by Philip A. Thompson and his colleagues and another by Kirsten Fischer and her colleagues, show that nearly 60% of patients with IGHV mutation remain in remission 10 years after FCR treatment, he said. However, the same is not necessarily true for bendamustine/rituximab (BR); the CLL10 study showed a significantly greater PFS with FCR, compared with that seen with BR.
Unmutated patients in that study had lower PFS, but the outcomes were still better with FCR than with BR, he said.
Studies of novel agents, including ibrutinib and idelalisib, suggest they may have particular benefit in higher-risk patients.
Ibrutinib was shown in a phase 2 study to be of benefit regardless of IGHV status, and this was replicated in the first-line RESONATE 2 study, which compared ibrutinib with chlorambucil and showed it had better PFS than that seen in unmutated patients treated with FCR in other studies, said Dr. Barr, the first author on that study.
“So you can see how the treatment paradigms are starting to evolve. It does look like ... comparing across trials, that ibrutinib leads to better remission durations, compared to chemoimmunotherapy, so far,” he said.
Ibrutinib has also been shown to be of benefit for patients with del(17p). A single-arm phase 2 study showed 79% PFS in relapsed, high-risk patients, which is much better than has been seen with chemoimmunotherapy, he noted.
“Venetoclax is also a very good option for this patient population in the relapse setting,” he said, adding that the PFS with venetoclax has been shown to be very similar to that with ibrutinib.
Similarly, idelalisib has been shown to provide comparable benefit in relapsed/refractory CLL patients, with and without del(17p)/TP53 mutation, he said.
Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.
EXPERT ANALYSIS FROM MHM 2018
CLL: The initial work-up
CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 109/Land absolute lymphocyte count of 19 x 109/L and normal hemoglobin and platelets.
Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.
“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 109/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.
Immunophenotype
As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.
A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”
“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.
Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).
“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 109/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.
Staging
It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.
“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.
The stages include:
- Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
- Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
- Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
- Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
- Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).
Prognostic testing
Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.
There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.
“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.
Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.
For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.
“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.
However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.
Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.
Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.
CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 109/Land absolute lymphocyte count of 19 x 109/L and normal hemoglobin and platelets.
Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.
“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 109/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.
Immunophenotype
As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.
A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”
“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.
Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).
“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 109/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.
Staging
It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.
“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.
The stages include:
- Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
- Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
- Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
- Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
- Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).
Prognostic testing
Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.
There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.
“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.
Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.
For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.
“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.
However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.
Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.
Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.
CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 109/Land absolute lymphocyte count of 19 x 109/L and normal hemoglobin and platelets.
Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.
“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 109/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.
Immunophenotype
As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.
A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”
“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.
Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).
“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 109/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.
Staging
It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.
“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.
The stages include:
- Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
- Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
- Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
- Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
- Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).
Prognostic testing
Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.
There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.
“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.
Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.
For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.
“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.
However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.
Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.
Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.
EXPERT ANALYSIS FROM MHM 2018
Prognostic features could improve ALL outcomes
CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.
CD20
About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.
Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.
“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.
In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).
While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
MRD
Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.
Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.
In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).
Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”
In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”
Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.
The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.
In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).
“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”
One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.
Ph-like signature
Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.
“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.
Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.
The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.
Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.
Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.
“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”
As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.
“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.
“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.
CD20
About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.
Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.
“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.
In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).
While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
MRD
Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.
Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.
In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).
Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”
In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”
Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.
The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.
In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).
“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”
One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.
Ph-like signature
Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.
“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.
Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.
The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.
Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.
Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.
“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”
As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.
“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.
“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.
CD20
About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.
“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.
Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.
“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.
In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).
While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
MRD
Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.
Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.
In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).
Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”
In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”
Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.
The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.
In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).
“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”
One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.
Ph-like signature
Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.
“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.
Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.
The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.
Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.
Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.
“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”
As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.
“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.
“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
EXPERT ANALYSIS FROM MHM 2018
Adding pembrolizumab to cisplatin-based CRT shows promise in HPV+ head and neck cancers
WASHINGTON – according to Steven F. Powell, MD.
Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.
About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.
“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.
Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.
Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.
Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.
It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.
“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.
As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”
The patient who progressed developed distant metastases and died from their disease, he said.
Treatment in this study included 40 mg/m2 of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).
“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.
Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.
“So adding CRT did not impact the safety of giving standard therapy,” he said.
Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.
The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.
“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.
“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.
The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.
WASHINGTON – according to Steven F. Powell, MD.
Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.
About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.
“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.
Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.
Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.
Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.
It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.
“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.
As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”
The patient who progressed developed distant metastases and died from their disease, he said.
Treatment in this study included 40 mg/m2 of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).
“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.
Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.
“So adding CRT did not impact the safety of giving standard therapy,” he said.
Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.
The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.
“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.
“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.
The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.
WASHINGTON – according to Steven F. Powell, MD.
Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.
About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.
“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.
Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.
Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.
Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.
It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.
“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.
As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”
The patient who progressed developed distant metastases and died from their disease, he said.
Treatment in this study included 40 mg/m2 of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).
“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.
Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.
“So adding CRT did not impact the safety of giving standard therapy,” he said.
Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.
The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.
“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.
“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.
The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.
REPORTING FROM SITC 2018
Key clinical point: Adding pembrolizumab to weekly low-dose cisplatin-based chemoradiotherapy shows promise in human papillomavirus–associated head and neck squamous cell carcinoma.
Major finding: A total of 85% of patients had a complete response at the 21-month follow-up; progression-free survival was 97.1%.
Study details: An expansion cohort of 34 patients.
Disclosures: The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.