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Low risk of complications with well-managed warfarin
Photo courtesy of NIGMS
Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).
However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.
Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.
The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.
So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.
The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.
Overall results
The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.
The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.
Aspirin and intracranial bleeding
When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).
But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).
Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).
In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).
INR and iTTR
Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.
This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).
Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).
This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).
The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).
For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability. 
Photo courtesy of NIGMS
Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).
However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.
Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.
The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.
So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.
The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.
Overall results
The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.
The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.
Aspirin and intracranial bleeding
When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).
But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).
Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).
In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).
INR and iTTR
Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.
This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).
Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).
This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).
The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).
For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.
Photo courtesy of NIGMS
Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).
However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.
Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.
The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.
So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.
The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.
Overall results
The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.
The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.
Aspirin and intracranial bleeding
When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).
But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).
Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).
In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).
INR and iTTR
Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.
This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).
Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).
This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).
The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).
For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.
Drug bests placebo in kids with chronic ITP
Photo by Bill Branson
The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.
Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.
Investigators said these results suggest romiplostim may be a treatment option for this patient population.
“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.
Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.
This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.
The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 109/L in the romiplostim arm and 17.7 x 109/L in the placebo arm.
Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.
The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).
The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).
The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).
Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.
In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.
Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.
Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).
One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.
There were no thrombotic events, none of the patients withdrew due to AEs, and none died.
“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.
“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”
Photo by Bill Branson
The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.
Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.
Investigators said these results suggest romiplostim may be a treatment option for this patient population.
“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.
Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.
This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.
The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 109/L in the romiplostim arm and 17.7 x 109/L in the placebo arm.
Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.
The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).
The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).
The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).
Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.
In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.
Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.
Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).
One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.
There were no thrombotic events, none of the patients withdrew due to AEs, and none died.
“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.
“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”
Photo by Bill Branson
The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.
Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.
Investigators said these results suggest romiplostim may be a treatment option for this patient population.
“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.
Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.
This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.
The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 109/L in the romiplostim arm and 17.7 x 109/L in the placebo arm.
Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.
The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).
The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).
The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).
Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.
In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.
Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.
Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).
One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.
There were no thrombotic events, none of the patients withdrew due to AEs, and none died.
“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.
“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”
Treatment can produce durable responses in NHL
2016 AACR Annual Meeting
© AACR/Todd Buchanan
NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.
The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.
In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.
The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.
In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.
These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.
Patients and study design
The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.
The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.
In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.
In Arm 1 (n=12), patients received rituximab (at 375 mg/m2) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).
In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).
The first patient treated on this trial received 250 mg/m2 of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.
The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.
Safety
Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.
In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).
Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).
The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.
The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.
All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.
Efficacy
Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.
The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.
Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.
For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.
*Information in the abstract differs from that presented at the meeting.
2016 AACR Annual Meeting
© AACR/Todd Buchanan
NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.
The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.
In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.
The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.
In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.
These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.
Patients and study design
The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.
The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.
In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.
In Arm 1 (n=12), patients received rituximab (at 375 mg/m2) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).
In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).
The first patient treated on this trial received 250 mg/m2 of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.
The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.
Safety
Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.
In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).
Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).
The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.
The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.
All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.
Efficacy
Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.
The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.
Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.
For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.
*Information in the abstract differs from that presented at the meeting.
2016 AACR Annual Meeting
© AACR/Todd Buchanan
NEW ORLEANS—Administering an antibody-radionuclide conjugate after B-cell depletion with rituximab can produce lasting responses in patients with relapsed non-Hodgkin lymphoma (NHL), according to a phase 1/2 study.
The conjugate, 177Lu-DOTA-HH1 (Betalutin), consists of the tumor-specific antibody HH1, which targets the CD37 antigen on the surface of NHL cells, conjugated to the β-emitting isotope lutetium-177 (Lu-177) via the chemical linker DOTA.
In an ongoing phase 1/2 study, Betalutin given after rituximab produced an overall response rate of 63.2%.
The median duration of response has not yet been reached, and 1 patient has maintained a response for more than 36 months.
In addition, the researchers said Betalutin was well tolerated, with a predictable and manageable safety profile. Most adverse events were hematologic, and all have been transient and reversible.
These results were presented at the 2016 AACR Annual Meeting (abstract LB-252*). The study is sponsored by Nordic Nanovector ASA.
Patients and study design
The researchers presented data on 21 patients—19 with follicular lymphoma and 2 with mantle cell lymphoma. All tumors were positive for CD37.
The patients’ median age was 68 (range, 41-78). Sixty-seven percent were male, and they had received 1 to 8 prior treatment regimens.
In this dose-escalation study, patients received Betalutin at 3 different doses, but they were also divided into 2 arms according to predosing with cold HH1 antibody.
In Arm 1 (n=12), patients received rituximab (at 375 mg/m2) on day -28 and -21 to deplete circulating B cells. On day 0, predosing with 50 mg HH1 was given before Betalutin injection. Then, patients received Betalutin at 10 MBq/kg (n=3), 15 MBq/kg (n=6), or 20 MBq/kg (n=3).
In Arm 2 (n=4), patients received rituximab at the same dose and schedule as Arm 1, but Betalutin was administered without HH1 predosing on day 0 at either 10 MBq/kg (n=2) or 15 MBq/kg (n=2).
The first patient treated on this trial received 250 mg/m2 of rituximab on day -7 and day 0 prior to Betalutin administration and was included in the 10 MBq/kg group in Arm 2.
The 15 MBq/kg dose level of Arm 1 has been expanded into the phase 2 portion of the study, as dose-limiting toxicities occurred at the 20 MBq/kg dose. Five patients have been treated in the phase 2 portion.
Safety
Adverse events (AEs) from the phase 2 portion of the study were not reported, as the data are still being collected.
In the phase 1 portion, grade 3/4 AEs were hematologic in nature and included decreases in platelet counts (3 grade 3 and 6 grade 4) and neutrophil counts (5 grade 3 and 4 grade 4).
Serious AEs included decreases in platelet counts (n=2), atrial fibrillation (n=2), epistaxis (n=1), fractured sternum (n=1), decreased neutrophil count (n=1), pharyngitis (n=1), pneumonia (n=1), pulmonary embolism (n=1), and sepsis (n=1).
The pulmonary embolism was deemed unrelated to treatment, but the remaining events were considered possibly or probably related to Betalutin.
The researchers noted that 1 patient experienced pharyngitis, pneumonia, pulmonary embolism, epistaxis, sepsis, and a decrease in lymphocyte count.
All patients’ platelets and neutrophils recovered. Two patients required platelet transfusions—one patient in the 20 MBq/kg cohort of Arm 1 and one patient in the 15 MBq/kg cohort of Arm 2.
Efficacy
Nineteen patients were evaluable for response. The overall response rate was 63.2% (n=12) and included both complete (31.6%, n=6) and partial responses (31.6%, n=6). Progression occurred in 21.1% of patients (n=4), and 15.8% (n=3) had stable disease.
The researchers presented data on 9 patients treated at the recommended 15 MBq/kg dose level with 50 mg HH1 predosing. Five patients were treated in phase 1 and 4 in phase 2. One of these patients was excluded from the analysis due to transformed lymphoma.
Two patients in phase 1 responded—both complete responses—and 3 patients in phase 2 responded—2 complete and 1 partial response.
For the entire study cohort, the median duration of response has not yet been reached. Six responses are ongoing—2 for 3+ months, 1 for 6+ months, 1 for 18+ months, 1 for 24+ months, and 1 for 36+ months.
*Information in the abstract differs from that presented at the meeting.
Method detects SNVs better, group says
Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.
The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.
During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).
The researchers described Monovar in Nature Methods.
“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”
Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.
The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.
In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.
The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).
The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).
Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.
The researchers also believe Monovar could be used for studies in a range of biomedical fields.
“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.
“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”
Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.
The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.
During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).
The researchers described Monovar in Nature Methods.
“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”
Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.
The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.
In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.
The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).
The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).
Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.
The researchers also believe Monovar could be used for studies in a range of biomedical fields.
“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.
“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”
Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.
The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.
During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).
The researchers described Monovar in Nature Methods.
“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”
Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.
The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.
In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.
The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).
The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).
Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.
The researchers also believe Monovar could be used for studies in a range of biomedical fields.
“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.
“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”
Drug shows early promise for low-grade lymphoma
follicular lymphoma
NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.
In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.
This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.
In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.
“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.
Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.
The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.
Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).
At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.
In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).
“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”
Safety
All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.
The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.
In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.
Efficacy
The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).
In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).
CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.
Furthermore, treated and untreated tumors decreased in volume across all dose groups.
At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).
In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.
However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).
Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).
The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.
follicular lymphoma
NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.
In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.
This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.
In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.
“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.
Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.
The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.
Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).
At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.
In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).
“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”
Safety
All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.
The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.
In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.
Efficacy
The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).
In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).
CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.
Furthermore, treated and untreated tumors decreased in volume across all dose groups.
At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).
In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.
However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).
Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).
The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.
follicular lymphoma
NEW ORLEANS—The TLR9 agonist SD-101 has produced encouraging early results in patients with low-grade B-cell lymphoma, according to researchers.
In an ongoing phase 1/2 study, patients received low-dose radiation, followed by an injection of SD-101 into one of their tumors.
This prompted changes in the tumor microenvironment that potentially induced a systemic antitumor response and decreased the volume of both treated and untreated tumors.
In addition, SD-101 was considered well tolerated, with no dose-limiting toxicities or maximum-tolerated dose.
“We are pleased to have already demonstrated a safety profile, pharmacodynamics, and preliminary efficacy in this study,” said Ronald Levy, MD, of Stanford University in California.
Dr Levy and his colleagues presented these results at the 2016 AACR Annual Meeting (abstract CT047). The study is sponsored by Dynavax Technologies Corporation, the company developing SD-101.
The researchers reported data for 13 patients with untreated, low-grade B-cell lymphoma. They had a mean age of 63.2, and 53.8% were male.
Patients had follicular lymphoma (n=9), small lymphocytic lymphoma (n=2), chronic lymphocytic leukemia (n=1), and nodal marginal zone lymphoma (n=1).
At least 2 sites of measurable disease were required for participation in this study. One site was treated with low-dose radiation (2 Gy) and injected with SD-101 on days 1, 8, 15, 22, and 29. Other lesions received no treatment.
In Part 1—the dose-escalation portion of the study—patients received SD-101 at 1 mg (n=3), 2 mg (n=3), 4 mg (n=3), or 8 mg (n=4). The phase 2 expansion portion of the study is ongoing, with enrollment in 2 dose cohorts (1 mg and 8 mg).
“This clinical trial design is unique and takes advantage of the fact that lymphoma patients have easily injectable sites of disease,” Dr Levy said. “The local injections are conveniently added to low-dose radiotherapy, a standard treatment for low-grade lymphoma.”
Safety
All 13 patients experienced at least 1 adverse event (AEs), although nearly all were grade 1 or 2.
The most common treatment-related AEs were local injection-site reactions and flu-like symptoms, including fever, chills, and myalgia (n=11 for all 3). However, the researchers said these AEs were primarily short-lived and controlled by over-the-counter acetaminophen in most cases.
In the 8 mg dosing cohort, 1 patient had grade 3 neutropenia and 2 had grade 3 malaise, all of which were considered treatment-related. In addition, there was a case of grade 3 asymptomatic pulmonary embolism in the 4 mg dose cohort, which was deemed serious but unrelated to treatment.
Efficacy
The researchers observed induction of interferon-responsive genes at all dose levels 24 hours after the second dose of SD-101 was given (Day 9).
In addition, T-cell numbers increased at the treated site by Day 8. The total T cells increased in 7 of 10 evaluable patients by Day 8 (range, >300% to 18%).
CD4+ and CD8+ T cells increased simultaneously in 5 of 7 evaluable patients, regulatory T cells decreased in 8 of 10 evaluable patients by Day 8, and follicular T helper cells decreased in 9 of 9 evaluable patients by Day 8.
Furthermore, treated and untreated tumors decreased in volume across all dose groups.
At Day 90, 12 patients had a reduction of the product of diameters in treated tumors (median -45.3%; range, -87 to +100), and 11 patients had a reduction in untreated tumors (median -8.1%; range, -48 to +45).
In 9 patients, these abscopal effects were sustained for at least 180 to 360 days.
However, 6 patients discontinued from the study due to progression. Three had radiographic progression—1 at Day 92 (in the 4 mg cohort) and 2 at 1 year (1 in the 1 mg cohort and 1 in the 2 mg cohort).
Two patients had clinical progression—1 at Day 197 (4 mg) and 1 at Day 273 (2 mg). And 1 patient discontinued at Day 203 due to a combination of clinical and radiographic progression (8 mg).
The researchers pointed out that there was no evidence of a dose response with SD-101, but the study included a limited number of patients.
Team explains CD8 Treg dysfunction
Image by Kathryn T. Iacono
Research published in The Journal of Clinical Investigation provides new insights regarding CD8 regulatory T cells (Tregs).
Investigators found that, in young, healthy individuals, CD8 Tregs suppress the activation and expansion of CD4 T cells.
However, older individuals and patients with a rare form of vasculitis exhibit CD8 Treg dysfunction, which is tied to a drop in production of an enzyme called NADPH oxidase 2 (NOX2).
Cornelia Weyand, MD, of Stanford University Medical Center in California, and her colleagues conducted this research.
First, the team found that CD8 Tregs preferentially take up residence in lymph nodes, the spleen, and other regions where there are huge “armies” of CD4 T cells. This proximity puts the CD8 Tregs in a position to stamp out CD4 T-cell activation early on.
Further experiments demonstrated that CD8 Tregs manufacture copious amounts of NOX2, which they package into tiny membrane-bound packets and transfer to the surfaces of abutting CD4 T cells.
These NOX2-laden packets are then taken up by the CD4 T cells. Inside their new home, the enzymes produce large volumes of highly reactive signaling substances that dial down CD4 T cells’ activation and proliferation.
The investigators noted that contact between CD8 Tregs and CD4 T cells in the early stages of activation shuts down the CD4 T cells’ activity and reduces their proliferation by half or more, even several days after the CD8 Tregs have been removed. Transferring NOX2 alone onto activated CD4 T cells also produces this effect.
Next, the team analyzed blood samples from healthy individuals and observed that CD8 Tregs were only about half as common in blood from people age 60 and older as in blood from 20- to 30-year-olds.
Both CD8 Treg numbers and their ability to suppress CD4 T-cell proliferation declined with advancing age. Experiments traced this to a drop in NOX2 production by older donors’ CD8 Tregs.
The investigators also discovered CD8 Treg failure in giant-cell arteritis (GCA). The team compared blood from GCA patients to blood from age-matched healthy control subjects and from patients with 2 other autoimmune diseases—psoriatic arthritis and small-vessel vasculitis. This revealed a severe deficit among GCA patients in NOX2-producing CD8 Tregs.
“This tells us that the deficit in NOX2-producing CD8 Tregs is specific to GCA, not just driving or driven by inflammation,” Dr Weyand said. “That’s good news for our patients who have this disease, which has been an enigma. Now we know something about what’s causing it.”
The discovery of NOX2 on the surface of CD8 Tregs—but not on other T-cell types—makes them much easier to identify and count, Dr Weyand added.
She and her colleagues are taking advantage of the new-found biomarker to tally CD8 Tregs in patients with age-associated disorders now understood to be driven by chronic inflammation to see if CD8 Treg deficits underlie some of these conditions’ pathology and whether they may be amenable to potential NOX2-restoring treatments.
Image by Kathryn T. Iacono
Research published in The Journal of Clinical Investigation provides new insights regarding CD8 regulatory T cells (Tregs).
Investigators found that, in young, healthy individuals, CD8 Tregs suppress the activation and expansion of CD4 T cells.
However, older individuals and patients with a rare form of vasculitis exhibit CD8 Treg dysfunction, which is tied to a drop in production of an enzyme called NADPH oxidase 2 (NOX2).
Cornelia Weyand, MD, of Stanford University Medical Center in California, and her colleagues conducted this research.
First, the team found that CD8 Tregs preferentially take up residence in lymph nodes, the spleen, and other regions where there are huge “armies” of CD4 T cells. This proximity puts the CD8 Tregs in a position to stamp out CD4 T-cell activation early on.
Further experiments demonstrated that CD8 Tregs manufacture copious amounts of NOX2, which they package into tiny membrane-bound packets and transfer to the surfaces of abutting CD4 T cells.
These NOX2-laden packets are then taken up by the CD4 T cells. Inside their new home, the enzymes produce large volumes of highly reactive signaling substances that dial down CD4 T cells’ activation and proliferation.
The investigators noted that contact between CD8 Tregs and CD4 T cells in the early stages of activation shuts down the CD4 T cells’ activity and reduces their proliferation by half or more, even several days after the CD8 Tregs have been removed. Transferring NOX2 alone onto activated CD4 T cells also produces this effect.
Next, the team analyzed blood samples from healthy individuals and observed that CD8 Tregs were only about half as common in blood from people age 60 and older as in blood from 20- to 30-year-olds.
Both CD8 Treg numbers and their ability to suppress CD4 T-cell proliferation declined with advancing age. Experiments traced this to a drop in NOX2 production by older donors’ CD8 Tregs.
The investigators also discovered CD8 Treg failure in giant-cell arteritis (GCA). The team compared blood from GCA patients to blood from age-matched healthy control subjects and from patients with 2 other autoimmune diseases—psoriatic arthritis and small-vessel vasculitis. This revealed a severe deficit among GCA patients in NOX2-producing CD8 Tregs.
“This tells us that the deficit in NOX2-producing CD8 Tregs is specific to GCA, not just driving or driven by inflammation,” Dr Weyand said. “That’s good news for our patients who have this disease, which has been an enigma. Now we know something about what’s causing it.”
The discovery of NOX2 on the surface of CD8 Tregs—but not on other T-cell types—makes them much easier to identify and count, Dr Weyand added.
She and her colleagues are taking advantage of the new-found biomarker to tally CD8 Tregs in patients with age-associated disorders now understood to be driven by chronic inflammation to see if CD8 Treg deficits underlie some of these conditions’ pathology and whether they may be amenable to potential NOX2-restoring treatments.
Image by Kathryn T. Iacono
Research published in The Journal of Clinical Investigation provides new insights regarding CD8 regulatory T cells (Tregs).
Investigators found that, in young, healthy individuals, CD8 Tregs suppress the activation and expansion of CD4 T cells.
However, older individuals and patients with a rare form of vasculitis exhibit CD8 Treg dysfunction, which is tied to a drop in production of an enzyme called NADPH oxidase 2 (NOX2).
Cornelia Weyand, MD, of Stanford University Medical Center in California, and her colleagues conducted this research.
First, the team found that CD8 Tregs preferentially take up residence in lymph nodes, the spleen, and other regions where there are huge “armies” of CD4 T cells. This proximity puts the CD8 Tregs in a position to stamp out CD4 T-cell activation early on.
Further experiments demonstrated that CD8 Tregs manufacture copious amounts of NOX2, which they package into tiny membrane-bound packets and transfer to the surfaces of abutting CD4 T cells.
These NOX2-laden packets are then taken up by the CD4 T cells. Inside their new home, the enzymes produce large volumes of highly reactive signaling substances that dial down CD4 T cells’ activation and proliferation.
The investigators noted that contact between CD8 Tregs and CD4 T cells in the early stages of activation shuts down the CD4 T cells’ activity and reduces their proliferation by half or more, even several days after the CD8 Tregs have been removed. Transferring NOX2 alone onto activated CD4 T cells also produces this effect.
Next, the team analyzed blood samples from healthy individuals and observed that CD8 Tregs were only about half as common in blood from people age 60 and older as in blood from 20- to 30-year-olds.
Both CD8 Treg numbers and their ability to suppress CD4 T-cell proliferation declined with advancing age. Experiments traced this to a drop in NOX2 production by older donors’ CD8 Tregs.
The investigators also discovered CD8 Treg failure in giant-cell arteritis (GCA). The team compared blood from GCA patients to blood from age-matched healthy control subjects and from patients with 2 other autoimmune diseases—psoriatic arthritis and small-vessel vasculitis. This revealed a severe deficit among GCA patients in NOX2-producing CD8 Tregs.
“This tells us that the deficit in NOX2-producing CD8 Tregs is specific to GCA, not just driving or driven by inflammation,” Dr Weyand said. “That’s good news for our patients who have this disease, which has been an enigma. Now we know something about what’s causing it.”
The discovery of NOX2 on the surface of CD8 Tregs—but not on other T-cell types—makes them much easier to identify and count, Dr Weyand added.
She and her colleagues are taking advantage of the new-found biomarker to tally CD8 Tregs in patients with age-associated disorders now understood to be driven by chronic inflammation to see if CD8 Treg deficits underlie some of these conditions’ pathology and whether they may be amenable to potential NOX2-restoring treatments.
mAb can reduce CSCs in newly diagnosed MM
Photo by Linda Bartlett
NEW ORLEANS—A small study suggests that treatment with lenalidomide and dexamethasone (len-dex) prompts an increase in cancer stem cells (CSCs) for patients with newly diagnosed multiple myeloma (MM).
However, adding an anti-CD19 monoclonal antibody (mAb) to the regimen can reduce CSCs.
Most patients who received the mAb, MEDI-551, experienced a decrease in CSCs, but the cells rebounded after the patients stopped receiving MEDI-551.
And those patients who did not see a decrease in CSCs progressed. However, some patients are still in response and remain on treatment with len-dex.
The investigators believe these early results suggest prolonged treatment with len-dex and MED-551 may be safe and clinically beneficial for MM patients.
The results were presented at the 2016 AACR Annual Meeting (abstract CT102).
The study included 17 patients with newly diagnosed MM. They had a median age of 65 (range, 34-73). Most had ISS stage I (n=11), 2 had stage II, and 4 had stage III. Seven patients had t(4;14).
“We chose to carry out this clinical trial in newly diagnosed patients because our original data showed that CD19 was almost always expressed by myeloma stem cells in these patients, whereas we don’t know if that is the case in more advanced patients,” said investigator William Matsui, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.
The patients received 28-day cycles of len-dex (len at 25 mg PO, days 1-21, and dex at 40 mg PO, weekly). Patients received MEDI-551 (at 4 mg/kg IV) in cycle 3 (day 1, 8) and cycle 4 (day 1). Responding patients continued on len-dex.
The investigators measured MM CSCs by quantifying the growth of MM colonies (CFU-MM) from marrow aspirates at baseline and at the end of cycles 2 and 4.
The team quantified peripheral blood CSCs by flow cytometry (CD19+CD27+ALDH+) at baseline and the end of cycles 2, 4, 5, and 7.
“We wanted to see if these 2 assays gave similar results, and, in this clinical trial, they were almost identical,” said investigator Carol Ann Huff, MD, also of Johns Hopkins.
“Since it is much easier to draw blood than bone marrow from our patients, we think that we can primarily use blood to track multiple myeloma stem cells in the future.”
Response
Two patients did not receive MEDI-551 due to progressive disease and noncompliance. So the investigators assessed responses in 15 patients.
After cycle 2 (len-dex alone), there were 3 very good partial responses (VGPRs), 10 partial responses (PRs), 1 molecular response, and 1 case of stable disease.
After cycle 4 (len-dex plus MEDI-551), there were 6 VGPRs, 8 PRs, and 1 molecular response.
Ten patients who completed treatment with MED-551 remain on len-dex. At the end of cycle 7, there was 1 complete response, 8 VGPRs, and 1 PR.
CFU-MM
When compared to baseline, bone-marrow-derived CFU-MM increased a median of 2.5-fold (range, 0.4-7.4) after cycle 2 but decreased a median of 0.48-fold (range, 0.14-0.85) in 14 patients after cycle 4.
The investigators compared these results to 5 newly diagnosed MM patients who only received standard treatment with len-dex.
In these patients, CFU-MM increased a median of 9.3-fold (range, 4-14) at a median of 4 months (range, 2-4). This is in spite of the fact that all of these patients had a PR or better.
Circulating CSCs
Compared to baseline, circulating MM CSCs increased a median of 1.6-fold (range, 0.4-8.6) in 14 patients after cycle 2 but decreased a median of 0.6-fold (range, 0.01-7.4) in 13 patients after cycle 4.
At the end of cycle 5, MM CSCs had increased in 4 of the 10 patients who were still on len-dex. By the end of cycle 7, MM CSCs had increased in 8 of the patients.
Circulating MM CSCs increased by the end of cycle 4 in 2 patients, and both had progressed by end of cycle 7.
Safety and next steps
The investigators said there were no serious adverse events in this trial, but 2 patients experienced grade 2 infusion reactions after the first MEDI-551 dose.
The team plans to conduct further studies to assess the long-term impact of MED-551 in MM patients and determine how the mAb might work in combination with other treatments, particularly transplant.
“In other studies at Johns Hopkins, we have found that antibody therapies can work much better after a bone marrow transplant, especially allogeneic transplants,” Dr Matsui said.
Funding and drugs for this study were provided by MedImmune Inc., the developers of MEDI-551. Drs Huff and Matsui served as a paid scientific advisory board member and a consultant to MedImmune Inc., respectively.
Photo by Linda Bartlett
NEW ORLEANS—A small study suggests that treatment with lenalidomide and dexamethasone (len-dex) prompts an increase in cancer stem cells (CSCs) for patients with newly diagnosed multiple myeloma (MM).
However, adding an anti-CD19 monoclonal antibody (mAb) to the regimen can reduce CSCs.
Most patients who received the mAb, MEDI-551, experienced a decrease in CSCs, but the cells rebounded after the patients stopped receiving MEDI-551.
And those patients who did not see a decrease in CSCs progressed. However, some patients are still in response and remain on treatment with len-dex.
The investigators believe these early results suggest prolonged treatment with len-dex and MED-551 may be safe and clinically beneficial for MM patients.
The results were presented at the 2016 AACR Annual Meeting (abstract CT102).
The study included 17 patients with newly diagnosed MM. They had a median age of 65 (range, 34-73). Most had ISS stage I (n=11), 2 had stage II, and 4 had stage III. Seven patients had t(4;14).
“We chose to carry out this clinical trial in newly diagnosed patients because our original data showed that CD19 was almost always expressed by myeloma stem cells in these patients, whereas we don’t know if that is the case in more advanced patients,” said investigator William Matsui, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.
The patients received 28-day cycles of len-dex (len at 25 mg PO, days 1-21, and dex at 40 mg PO, weekly). Patients received MEDI-551 (at 4 mg/kg IV) in cycle 3 (day 1, 8) and cycle 4 (day 1). Responding patients continued on len-dex.
The investigators measured MM CSCs by quantifying the growth of MM colonies (CFU-MM) from marrow aspirates at baseline and at the end of cycles 2 and 4.
The team quantified peripheral blood CSCs by flow cytometry (CD19+CD27+ALDH+) at baseline and the end of cycles 2, 4, 5, and 7.
“We wanted to see if these 2 assays gave similar results, and, in this clinical trial, they were almost identical,” said investigator Carol Ann Huff, MD, also of Johns Hopkins.
“Since it is much easier to draw blood than bone marrow from our patients, we think that we can primarily use blood to track multiple myeloma stem cells in the future.”
Response
Two patients did not receive MEDI-551 due to progressive disease and noncompliance. So the investigators assessed responses in 15 patients.
After cycle 2 (len-dex alone), there were 3 very good partial responses (VGPRs), 10 partial responses (PRs), 1 molecular response, and 1 case of stable disease.
After cycle 4 (len-dex plus MEDI-551), there were 6 VGPRs, 8 PRs, and 1 molecular response.
Ten patients who completed treatment with MED-551 remain on len-dex. At the end of cycle 7, there was 1 complete response, 8 VGPRs, and 1 PR.
CFU-MM
When compared to baseline, bone-marrow-derived CFU-MM increased a median of 2.5-fold (range, 0.4-7.4) after cycle 2 but decreased a median of 0.48-fold (range, 0.14-0.85) in 14 patients after cycle 4.
The investigators compared these results to 5 newly diagnosed MM patients who only received standard treatment with len-dex.
In these patients, CFU-MM increased a median of 9.3-fold (range, 4-14) at a median of 4 months (range, 2-4). This is in spite of the fact that all of these patients had a PR or better.
Circulating CSCs
Compared to baseline, circulating MM CSCs increased a median of 1.6-fold (range, 0.4-8.6) in 14 patients after cycle 2 but decreased a median of 0.6-fold (range, 0.01-7.4) in 13 patients after cycle 4.
At the end of cycle 5, MM CSCs had increased in 4 of the 10 patients who were still on len-dex. By the end of cycle 7, MM CSCs had increased in 8 of the patients.
Circulating MM CSCs increased by the end of cycle 4 in 2 patients, and both had progressed by end of cycle 7.
Safety and next steps
The investigators said there were no serious adverse events in this trial, but 2 patients experienced grade 2 infusion reactions after the first MEDI-551 dose.
The team plans to conduct further studies to assess the long-term impact of MED-551 in MM patients and determine how the mAb might work in combination with other treatments, particularly transplant.
“In other studies at Johns Hopkins, we have found that antibody therapies can work much better after a bone marrow transplant, especially allogeneic transplants,” Dr Matsui said.
Funding and drugs for this study were provided by MedImmune Inc., the developers of MEDI-551. Drs Huff and Matsui served as a paid scientific advisory board member and a consultant to MedImmune Inc., respectively.
Photo by Linda Bartlett
NEW ORLEANS—A small study suggests that treatment with lenalidomide and dexamethasone (len-dex) prompts an increase in cancer stem cells (CSCs) for patients with newly diagnosed multiple myeloma (MM).
However, adding an anti-CD19 monoclonal antibody (mAb) to the regimen can reduce CSCs.
Most patients who received the mAb, MEDI-551, experienced a decrease in CSCs, but the cells rebounded after the patients stopped receiving MEDI-551.
And those patients who did not see a decrease in CSCs progressed. However, some patients are still in response and remain on treatment with len-dex.
The investigators believe these early results suggest prolonged treatment with len-dex and MED-551 may be safe and clinically beneficial for MM patients.
The results were presented at the 2016 AACR Annual Meeting (abstract CT102).
The study included 17 patients with newly diagnosed MM. They had a median age of 65 (range, 34-73). Most had ISS stage I (n=11), 2 had stage II, and 4 had stage III. Seven patients had t(4;14).
“We chose to carry out this clinical trial in newly diagnosed patients because our original data showed that CD19 was almost always expressed by myeloma stem cells in these patients, whereas we don’t know if that is the case in more advanced patients,” said investigator William Matsui, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland.
The patients received 28-day cycles of len-dex (len at 25 mg PO, days 1-21, and dex at 40 mg PO, weekly). Patients received MEDI-551 (at 4 mg/kg IV) in cycle 3 (day 1, 8) and cycle 4 (day 1). Responding patients continued on len-dex.
The investigators measured MM CSCs by quantifying the growth of MM colonies (CFU-MM) from marrow aspirates at baseline and at the end of cycles 2 and 4.
The team quantified peripheral blood CSCs by flow cytometry (CD19+CD27+ALDH+) at baseline and the end of cycles 2, 4, 5, and 7.
“We wanted to see if these 2 assays gave similar results, and, in this clinical trial, they were almost identical,” said investigator Carol Ann Huff, MD, also of Johns Hopkins.
“Since it is much easier to draw blood than bone marrow from our patients, we think that we can primarily use blood to track multiple myeloma stem cells in the future.”
Response
Two patients did not receive MEDI-551 due to progressive disease and noncompliance. So the investigators assessed responses in 15 patients.
After cycle 2 (len-dex alone), there were 3 very good partial responses (VGPRs), 10 partial responses (PRs), 1 molecular response, and 1 case of stable disease.
After cycle 4 (len-dex plus MEDI-551), there were 6 VGPRs, 8 PRs, and 1 molecular response.
Ten patients who completed treatment with MED-551 remain on len-dex. At the end of cycle 7, there was 1 complete response, 8 VGPRs, and 1 PR.
CFU-MM
When compared to baseline, bone-marrow-derived CFU-MM increased a median of 2.5-fold (range, 0.4-7.4) after cycle 2 but decreased a median of 0.48-fold (range, 0.14-0.85) in 14 patients after cycle 4.
The investigators compared these results to 5 newly diagnosed MM patients who only received standard treatment with len-dex.
In these patients, CFU-MM increased a median of 9.3-fold (range, 4-14) at a median of 4 months (range, 2-4). This is in spite of the fact that all of these patients had a PR or better.
Circulating CSCs
Compared to baseline, circulating MM CSCs increased a median of 1.6-fold (range, 0.4-8.6) in 14 patients after cycle 2 but decreased a median of 0.6-fold (range, 0.01-7.4) in 13 patients after cycle 4.
At the end of cycle 5, MM CSCs had increased in 4 of the 10 patients who were still on len-dex. By the end of cycle 7, MM CSCs had increased in 8 of the patients.
Circulating MM CSCs increased by the end of cycle 4 in 2 patients, and both had progressed by end of cycle 7.
Safety and next steps
The investigators said there were no serious adverse events in this trial, but 2 patients experienced grade 2 infusion reactions after the first MEDI-551 dose.
The team plans to conduct further studies to assess the long-term impact of MED-551 in MM patients and determine how the mAb might work in combination with other treatments, particularly transplant.
“In other studies at Johns Hopkins, we have found that antibody therapies can work much better after a bone marrow transplant, especially allogeneic transplants,” Dr Matsui said.
Funding and drugs for this study were provided by MedImmune Inc., the developers of MEDI-551. Drs Huff and Matsui served as a paid scientific advisory board member and a consultant to MedImmune Inc., respectively.
Antibody shows activity against ALL, CLL
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Model used to estimate CSCs in CML
Image from UC San Diego
Scientists say they have developed a model that can be used to calculate the proportion of cancer stem cells (CSCs) present over the course of treatment.
The model is designed to enable estimation of CSC fractions from longitudinal measurements of tumor burden.
The scientists tested the model in patients with chronic myeloid leukemia (CML) and found evidence to suggest the proportion of CSCs increases
substantially during extended treatment.
The team believes the model could eventually be used to help doctors predict tumor development and help them select suitable treatments for cancer patients.
“Cancer stem cells not only promote the growth of a tumor, they can also be resistant to radiotherapy and chemotherapy,” said Philipp Altrock, PhD, of the Dana Farber Cancer Institute in Boston, Massachusetts.
“If we can estimate the number of cancer stem cells at diagnosis and over the course of treatment, the treatment can be tailored accordingly.”
Dr Altrock and his colleagues discussed this possibility in Cancer Research.
The team first explained that their model incorporates tumor dynamics and tumor burden information. They said tumor expansion and regression curves can be leveraged to estimate the proportion of CSCs in individual patients at baseline and during therapy.
To test their model, the scientists used 2 independent cohorts of CML patients. The team evaluated the growth and decline of CML over the course of treatment with the tyrosine kinase inhibitor imatinib.
Based on the change of disease burden during treatment, the model calculated the proportion of CSCs.
Results suggested the proportion of CSCs in CML patients increases 100-fold after a year of treatment with imatinib. And that proportion continues to increase up to 1000-fold after 5 years of treatment.
The scientists noted that this model is parameter-free, so it can be applied to different types of cancer. However, they said further development is required before the model can be used in clinical practice.
Image from UC San Diego
Scientists say they have developed a model that can be used to calculate the proportion of cancer stem cells (CSCs) present over the course of treatment.
The model is designed to enable estimation of CSC fractions from longitudinal measurements of tumor burden.
The scientists tested the model in patients with chronic myeloid leukemia (CML) and found evidence to suggest the proportion of CSCs increases
substantially during extended treatment.
The team believes the model could eventually be used to help doctors predict tumor development and help them select suitable treatments for cancer patients.
“Cancer stem cells not only promote the growth of a tumor, they can also be resistant to radiotherapy and chemotherapy,” said Philipp Altrock, PhD, of the Dana Farber Cancer Institute in Boston, Massachusetts.
“If we can estimate the number of cancer stem cells at diagnosis and over the course of treatment, the treatment can be tailored accordingly.”
Dr Altrock and his colleagues discussed this possibility in Cancer Research.
The team first explained that their model incorporates tumor dynamics and tumor burden information. They said tumor expansion and regression curves can be leveraged to estimate the proportion of CSCs in individual patients at baseline and during therapy.
To test their model, the scientists used 2 independent cohorts of CML patients. The team evaluated the growth and decline of CML over the course of treatment with the tyrosine kinase inhibitor imatinib.
Based on the change of disease burden during treatment, the model calculated the proportion of CSCs.
Results suggested the proportion of CSCs in CML patients increases 100-fold after a year of treatment with imatinib. And that proportion continues to increase up to 1000-fold after 5 years of treatment.
The scientists noted that this model is parameter-free, so it can be applied to different types of cancer. However, they said further development is required before the model can be used in clinical practice.
Image from UC San Diego
Scientists say they have developed a model that can be used to calculate the proportion of cancer stem cells (CSCs) present over the course of treatment.
The model is designed to enable estimation of CSC fractions from longitudinal measurements of tumor burden.
The scientists tested the model in patients with chronic myeloid leukemia (CML) and found evidence to suggest the proportion of CSCs increases
substantially during extended treatment.
The team believes the model could eventually be used to help doctors predict tumor development and help them select suitable treatments for cancer patients.
“Cancer stem cells not only promote the growth of a tumor, they can also be resistant to radiotherapy and chemotherapy,” said Philipp Altrock, PhD, of the Dana Farber Cancer Institute in Boston, Massachusetts.
“If we can estimate the number of cancer stem cells at diagnosis and over the course of treatment, the treatment can be tailored accordingly.”
Dr Altrock and his colleagues discussed this possibility in Cancer Research.
The team first explained that their model incorporates tumor dynamics and tumor burden information. They said tumor expansion and regression curves can be leveraged to estimate the proportion of CSCs in individual patients at baseline and during therapy.
To test their model, the scientists used 2 independent cohorts of CML patients. The team evaluated the growth and decline of CML over the course of treatment with the tyrosine kinase inhibitor imatinib.
Based on the change of disease burden during treatment, the model calculated the proportion of CSCs.
Results suggested the proportion of CSCs in CML patients increases 100-fold after a year of treatment with imatinib. And that proportion continues to increase up to 1000-fold after 5 years of treatment.
The scientists noted that this model is parameter-free, so it can be applied to different types of cancer. However, they said further development is required before the model can be used in clinical practice.
Drug granted breakthrough designation for cHL
Photo courtesy of Merck
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for pembrolizumab (Keytruda) to treat patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The breakthrough designation for pembrolizumab in cHL is based on data from the phase 1b KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.
Findings from the KEYNOTE-013 study were presented at ASH 2014 (in patients with cHL) and ASH 2015 (in primary mediastinal large B-cell lymphoma).
Data from KEYNOTE-087 will be presented at an upcoming medical meeting, according to Merck, the company developing pembrolizumab.
Pembrolizumab also has breakthrough designation from the FDA as a treatment for advanced melanoma, advanced non-small cell lung cancer, and advanced colorectal cancer.
The drug is already FDA-approved to treat melanoma and non-small cell lung cancer. Pembrolizumab is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks for the approved indications.
Photo courtesy of Merck
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for pembrolizumab (Keytruda) to treat patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The breakthrough designation for pembrolizumab in cHL is based on data from the phase 1b KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.
Findings from the KEYNOTE-013 study were presented at ASH 2014 (in patients with cHL) and ASH 2015 (in primary mediastinal large B-cell lymphoma).
Data from KEYNOTE-087 will be presented at an upcoming medical meeting, according to Merck, the company developing pembrolizumab.
Pembrolizumab also has breakthrough designation from the FDA as a treatment for advanced melanoma, advanced non-small cell lung cancer, and advanced colorectal cancer.
The drug is already FDA-approved to treat melanoma and non-small cell lung cancer. Pembrolizumab is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks for the approved indications.
Photo courtesy of Merck
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for pembrolizumab (Keytruda) to treat patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.
The FDA’s breakthrough therapy designation is intended to expedite the development and review of new therapies for serious or life threatening conditions, which have shown encouraging early clinical results demonstrating substantial improvement on a clinically significant endpoint over available therapies.
The breakthrough designation for pembrolizumab in cHL is based on data from the phase 1b KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.
Findings from the KEYNOTE-013 study were presented at ASH 2014 (in patients with cHL) and ASH 2015 (in primary mediastinal large B-cell lymphoma).
Data from KEYNOTE-087 will be presented at an upcoming medical meeting, according to Merck, the company developing pembrolizumab.
Pembrolizumab also has breakthrough designation from the FDA as a treatment for advanced melanoma, advanced non-small cell lung cancer, and advanced colorectal cancer.
The drug is already FDA-approved to treat melanoma and non-small cell lung cancer. Pembrolizumab is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks for the approved indications.