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HL survivors should be screened for CAD after chest irradiation
VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.
The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.
These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.
The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).
“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.
“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”
Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.
The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.
CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.
Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.
Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).
Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).
The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).
Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.
Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).
“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.
“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”
“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”
Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.
He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.
“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”
“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 
VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.
The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.
These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.
The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).
“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.
“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”
Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.
The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.
CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.
Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.
Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).
Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).
The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).
Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.
Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).
“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.
“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”
“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”
Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.
He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.
“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”
“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.”
VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.
The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.
These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.
The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).
“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.
“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”
Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.
The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.
CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.
Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.
Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).
Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).
The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).
Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.
Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).
“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.
“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”
“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”
Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.
He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.
“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”
“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.”
Novel inhibitor proves ‘potent’ in hematologic malignancies
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
IV and SC rituximab produce similar results in FL
In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).
Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.
Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.
Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.
Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.
The study was funded by Roche, which markets rituximab as Rituxan and MabThera.
The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.
Patients were randomized to receive IV rituximab at 375 mg/m2 (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.
Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.
Patients then received rituximab maintenance every 8 weeks.
The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.
Efficacy
In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between the treatment arms at cycle 7.
The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean Ctrough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).
In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.
At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.
At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.
At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).
Safety
The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.
Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).
Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.
Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.
The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL.
In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).
Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.
Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.
Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.
Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.
The study was funded by Roche, which markets rituximab as Rituxan and MabThera.
The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.
Patients were randomized to receive IV rituximab at 375 mg/m2 (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.
Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.
Patients then received rituximab maintenance every 8 weeks.
The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.
Efficacy
In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between the treatment arms at cycle 7.
The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean Ctrough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).
In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.
At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.
At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.
At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).
Safety
The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.
Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).
Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.
Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.
The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL.
In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).
Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.
Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.
Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.
Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.
The study was funded by Roche, which markets rituximab as Rituxan and MabThera.
The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.
Patients were randomized to receive IV rituximab at 375 mg/m2 (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.
Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.
Patients then received rituximab maintenance every 8 weeks.
The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.
Efficacy
In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between the treatment arms at cycle 7.
The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean Ctrough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).
In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.
At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.
At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.
At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).
Safety
The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.
Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).
Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.
Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.
The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL.
EC approves pembrolizumab for cHL patients
The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).
The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.
The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).
This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.
The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.
Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.
KEYNOTE-087
In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
- Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
- Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
- Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.
In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.
In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.
For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.
The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.
KEYNOTE-013
KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.
Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.
The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.
The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.
The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.
The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).
The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).
AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.
The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).
The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.
The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).
This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.
The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.
Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.
KEYNOTE-087
In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
- Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
- Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
- Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.
In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.
In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.
For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.
The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.
KEYNOTE-013
KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.
Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.
The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.
The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.
The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.
The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).
The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).
AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.
The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).
The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.
The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).
This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.
The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.
Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.
KEYNOTE-087
In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
- Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
- Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
- Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.
In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.
In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.
For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.
The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.
KEYNOTE-013
KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.
Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.
The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.
The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.
The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.
The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).
The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).
AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.
BTK inhibitor staves off progression in CLL
Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.
In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.
Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.
The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.
The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.
The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.
The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.
Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.
Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.
At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.
Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.
“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”
The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.
Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.
The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.
The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).
The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).
“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.”
Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.
In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.
Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.
The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.
The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.
The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.
The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.
Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.
Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.
At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.
Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.
“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”
The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.
Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.
The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.
The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).
The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).
“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.”
Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.
In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.
Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.
The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.
The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.
The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.
The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.
Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.
Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.
At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.
Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.
“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”
The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.
Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.
The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.
The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).
The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).
“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.”
Cord blood/placental cell combo induces rapid immune recovery
MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.
Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Augmenting cord blood
Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.
Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.
More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).
Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.
In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.
Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).
The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.
Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.
The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.
The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.
The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.
Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.
Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.
There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.
None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.
The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.
MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.
Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Augmenting cord blood
Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.
Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.
More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).
Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.
In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.
Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).
The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.
Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.
The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.
The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.
The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.
Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.
Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.
There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.
None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.
The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.
MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.
Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Augmenting cord blood
Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.
Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.
More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).
Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.
In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.
Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).
The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.
Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.
The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.
The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.
The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.
Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.
Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.
There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.
None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.
The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.
Key clinical point: A combination of donor cord blood and human placenta–derived stem cells induced more rapid engraftment than cord blood alone.
Major finding: The probability of 12-month overall survival was 81%.
Data source: Open-label single-arm study in 16 children with severe malignant and nonmalignant diseases requiring hematopoietic stem cell transplants.
Disclosures: The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.
Maintenance lenalidomide prolongs progression-free survival in DLBCL
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Key clinical point:
Major finding: Median progression-free survival was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide.
Data source: A 5-year international, randomized double-blind placebo-controlled phase III trial involving 650 patients aged 60-80 years.
Disclosures: The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Pembrolizumab could change treatment paradigm, team says
The anti-PD-1 therapy pembrolizumab could change the treatment paradigm of relapsed or refractory classic Hodgkin lymphoma (cHL), according to researchers.
In a phase 2 trial, pembrolizumab produced an overall response rate (ORR) of 69% and a complete response (CR) rate of 22% in adults with cHL who had failed treatment with brentuximab vedotin (BV), autologous hematopoietic stem cell transplant (auto-HSCT), or both.
The researchers said the safety profile of pembrolizumab was “acceptable” and largely consistent with safety in previous studies of the drug.
Twelve percent of patients temporarily stopped taking pembrolizumab due to treatment-related adverse events (AEs), and 4% stopped taking the drug entirely as a result of AEs.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues reported these results, from the KEYNOTE-087 trial, in the Journal of Clinical Oncology.
The trial was sponsored by Merck, the company that markets pembrolizumab as Keytruda.
In KEYNOTE-087, the researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Efficacy
Across all 210 enrolled patients, the ORR was 69.0%, and the CR rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.
In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.
In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.
Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.
An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).
For the entire study cohort, the median duration of response was not reached, and the median overall survival was not reached. At 9 months, the overall survival rate was 97.5%, and the progression-free survival rate was 63.4%.
Safety
The most common AEs related to pembrolizumab were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
Nine patients (4.3%) stopped taking pembrolizumab due to treatment-related AEs, including myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, and cytokine release syndrome.
Twenty-six patients (12.4%) had treatment interruptions due to pembrolizumab-related AEs.
Two patients died during follow-up, but neither death was considered related to pembrolizumab. One patient died of septic shock and the other of acute graft-versus-host disease.
The anti-PD-1 therapy pembrolizumab could change the treatment paradigm of relapsed or refractory classic Hodgkin lymphoma (cHL), according to researchers.
In a phase 2 trial, pembrolizumab produced an overall response rate (ORR) of 69% and a complete response (CR) rate of 22% in adults with cHL who had failed treatment with brentuximab vedotin (BV), autologous hematopoietic stem cell transplant (auto-HSCT), or both.
The researchers said the safety profile of pembrolizumab was “acceptable” and largely consistent with safety in previous studies of the drug.
Twelve percent of patients temporarily stopped taking pembrolizumab due to treatment-related adverse events (AEs), and 4% stopped taking the drug entirely as a result of AEs.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues reported these results, from the KEYNOTE-087 trial, in the Journal of Clinical Oncology.
The trial was sponsored by Merck, the company that markets pembrolizumab as Keytruda.
In KEYNOTE-087, the researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Efficacy
Across all 210 enrolled patients, the ORR was 69.0%, and the CR rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.
In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.
In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.
Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.
An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).
For the entire study cohort, the median duration of response was not reached, and the median overall survival was not reached. At 9 months, the overall survival rate was 97.5%, and the progression-free survival rate was 63.4%.
Safety
The most common AEs related to pembrolizumab were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
Nine patients (4.3%) stopped taking pembrolizumab due to treatment-related AEs, including myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, and cytokine release syndrome.
Twenty-six patients (12.4%) had treatment interruptions due to pembrolizumab-related AEs.
Two patients died during follow-up, but neither death was considered related to pembrolizumab. One patient died of septic shock and the other of acute graft-versus-host disease.
The anti-PD-1 therapy pembrolizumab could change the treatment paradigm of relapsed or refractory classic Hodgkin lymphoma (cHL), according to researchers.
In a phase 2 trial, pembrolizumab produced an overall response rate (ORR) of 69% and a complete response (CR) rate of 22% in adults with cHL who had failed treatment with brentuximab vedotin (BV), autologous hematopoietic stem cell transplant (auto-HSCT), or both.
The researchers said the safety profile of pembrolizumab was “acceptable” and largely consistent with safety in previous studies of the drug.
Twelve percent of patients temporarily stopped taking pembrolizumab due to treatment-related adverse events (AEs), and 4% stopped taking the drug entirely as a result of AEs.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues reported these results, from the KEYNOTE-087 trial, in the Journal of Clinical Oncology.
The trial was sponsored by Merck, the company that markets pembrolizumab as Keytruda.
In KEYNOTE-087, the researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Efficacy
Across all 210 enrolled patients, the ORR was 69.0%, and the CR rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.
In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.
In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.
Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.
An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).
For the entire study cohort, the median duration of response was not reached, and the median overall survival was not reached. At 9 months, the overall survival rate was 97.5%, and the progression-free survival rate was 63.4%.
Safety
The most common AEs related to pembrolizumab were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
Nine patients (4.3%) stopped taking pembrolizumab due to treatment-related AEs, including myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, and cytokine release syndrome.
Twenty-six patients (12.4%) had treatment interruptions due to pembrolizumab-related AEs.
Two patients died during follow-up, but neither death was considered related to pembrolizumab. One patient died of septic shock and the other of acute graft-versus-host disease.
EMA recommends orphan status for drug for DLBCL
The European Medicines Agency (EMA) has recommended that PQR309 receive orphan drug designation for the treatment of patients with diffuse large B-cell lymphoma (DLBCL).
PQR309, is an oral, brain-penetrant, dual inhibitor of the PI3K/mTOR pathway being developed by PIQUR Therapeutics AG.
PQR309 is currently being investigated in phase 1 and 2 studies in relapsed or refractory lymphoma (NCT02249429), relapsed or refractory primary central nervous system lymphoma (NCT02669511), and other malignancies.
Preclinical research of PQR309 in lymphomas was presented at the AACR Annual Meeting 2017 (abstract 2652).
Researchers tested the drug in 40 cell lines—27 DLBCL, 10 mantle cell lymphoma, and 3 splenic marginal zone lymphoma.
The researchers reported that PQR309 had “potent antiproliferative activity” in most of the cell lines.
The median IC50 was 166 nM in DLBCL cell lines, 235 nM in mantle cell lymphoma cell lines, and 214 nM in splenic marginal zone lymphoma cell lines.
In addition, PQR309 demonstrated similar activity in activated B-cell like DLBCL and germinal center B-cell like DLBCL.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.
The European Medicines Agency (EMA) has recommended that PQR309 receive orphan drug designation for the treatment of patients with diffuse large B-cell lymphoma (DLBCL).
PQR309, is an oral, brain-penetrant, dual inhibitor of the PI3K/mTOR pathway being developed by PIQUR Therapeutics AG.
PQR309 is currently being investigated in phase 1 and 2 studies in relapsed or refractory lymphoma (NCT02249429), relapsed or refractory primary central nervous system lymphoma (NCT02669511), and other malignancies.
Preclinical research of PQR309 in lymphomas was presented at the AACR Annual Meeting 2017 (abstract 2652).
Researchers tested the drug in 40 cell lines—27 DLBCL, 10 mantle cell lymphoma, and 3 splenic marginal zone lymphoma.
The researchers reported that PQR309 had “potent antiproliferative activity” in most of the cell lines.
The median IC50 was 166 nM in DLBCL cell lines, 235 nM in mantle cell lymphoma cell lines, and 214 nM in splenic marginal zone lymphoma cell lines.
In addition, PQR309 demonstrated similar activity in activated B-cell like DLBCL and germinal center B-cell like DLBCL.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.
The European Medicines Agency (EMA) has recommended that PQR309 receive orphan drug designation for the treatment of patients with diffuse large B-cell lymphoma (DLBCL).
PQR309, is an oral, brain-penetrant, dual inhibitor of the PI3K/mTOR pathway being developed by PIQUR Therapeutics AG.
PQR309 is currently being investigated in phase 1 and 2 studies in relapsed or refractory lymphoma (NCT02249429), relapsed or refractory primary central nervous system lymphoma (NCT02669511), and other malignancies.
Preclinical research of PQR309 in lymphomas was presented at the AACR Annual Meeting 2017 (abstract 2652).
Researchers tested the drug in 40 cell lines—27 DLBCL, 10 mantle cell lymphoma, and 3 splenic marginal zone lymphoma.
The researchers reported that PQR309 had “potent antiproliferative activity” in most of the cell lines.
The median IC50 was 166 nM in DLBCL cell lines, 235 nM in mantle cell lymphoma cell lines, and 214 nM in splenic marginal zone lymphoma cell lines.
In addition, PQR309 demonstrated similar activity in activated B-cell like DLBCL and germinal center B-cell like DLBCL.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.
Drug receives fast track designation for follicular lymphoma
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.