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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease.
Several genetic abnormalities, including del (17p), del (11q) and TP53 gene mutations, are known to be poor prognostic indicators for CLL patients.
The BTK inhibitor ibrutinib can significantly improve the prognosis of CLL patients, and has been approved by the FDA for the treatment of newly treated, relapsed or refractory CLL.
At present, related studies have not yet determined whether the combination of ibrutinib and anti-CD20 monoclonal antibody can improve the prognosis of CLL patients.
Previous studies have shown that the combination of the first-generation anti-CD20 monoclonal antibody rituximab on the basis of the single-drug regimen of ibrutinib does not show an advantage in curative effect.
Compared with rituximab, a new generation of anti-CD20 monoclonal antibody, otuzumab can improve the treatment outcome of CLL patients.
At the same time, related studies have found that the combination of ibrutinib and otuzumab is superior to immunochemotherapy Efficacy, but there is no research to compare the efficacy of the combination regimen and the single-agent regimen of ibrutinib.
Ublituximab is a new glycosylated anti-CD20 monoclonal antibody.
A multicenter phase II study showed that the remission rate of Ublituximab combined with ibrutinib in the treatment of patients with relapsed and refractory CLL reached 88%, and the remission rate of patients with high-risk cytogenetic factors reached 95%.
On the basis of this study, the phase III GENUINE study compared the efficacy of Ublituximab combined with ibrutinib regimen and ibrutinib single-agent regimen in the treatment of CLL patients with high-risk cytogenetic factors, and judged the basis of iblituximab single-agent regimen Can Ublituximab improve the prognosis of these patients?
The main results of the research are summarized as follows for the reference of readers.
Research methods The study included patients with CLL who were ≥18 years of age and had received at least two cycles of standard treatment.
Patients included in the study need to have an ECOG score of 0-2, have high-risk cytogenetic factors (del (17p), del (11q) or TP53 gene mutation), have at least one measurable lymph node disease (the longest diameter> 2cm, the most Long vertical diameter> 1cm), normal organ function.
The study excluded the inapplicability of ibrutinib treatment, the need to receive moderate to high-intensity CYP3A inhibitor therapy, previous BTK inhibitor therapy, and anti-cancer therapy within 21 days before randomization (corticosteroids are allowed 7 days before the start of the study) Treatment), CLL patients who need to undergo transplantation within 3 months of the start of the study and have developed Richter transformation.
The study included patients who received ibrutinib (420mg/day) orally every day, and at the same time on the first day (≤150mg, lasting 4 hours), the second day (750mg, lasting 4 hours), and the first cycle of the first treatment cycle.
On 8 and 15 days (900 mg for 3 hours), the first day of cycles 2-6 (900 mg for 3 hours) received intravenous injection of Ublituximab (1 cycle for 28 days).
Patients received Ublituximab maintenance therapy (900 mg for 90 minutes) every 3 cycles after the 6th cycle of treatment until the disease progressed, intolerable toxicity, or the patient withdrew from the study.
In the study, patients need to receive antihistamines (such as diphenhydramine 50 mg) and corticosteroids (such as dexamethasone 10-20 mg) before receiving Ublituximab infusion.
If patients in the study have treatment-related serious adverse events (SAE), the relevant treatment drugs can be stopped for up to 4 weeks, but the dosage of Ublituximab cannot be reduced.
If there are ≥ grade 3 non-hematological events, ≥ grade 3 neutropenia events with infection or fever, and grade 4 hematological events, the dose of ibrutinib can be reduced.
If the patient has an infusion-related reaction, Ublituximab should be discontinued and the patient should be closely monitored and managed until the symptoms disappear.
Patients who withdrew from the study due to non-disease reasons were followed up every 3 months to pay attention to the progress of the disease.
The primary endpoint of the study was the overall response rate (ORR) assessed by the Independent Review Committee (IRC).
Patients in the study will be evaluated for efficacy after completing the second, fourth, and sixth cycles of treatment, and then every 3 treatment cycles (for patients who continue to receive treatment) or every 3 months (for patients who withdraw from treatment for follow-up) .
The secondary endpoints of the study include progression-free survival (PFS), MRD negative rate, complete remission (CR) rate, duration of remission, treatment onset time, and safety.
Study Results 01 Patient Characteristics The study included 126 patients from February 6, 2015 to December 19, 2016, who were randomly assigned to receive Ublituximab combined with Ibrutinib (n=64) or Ibrutinib as a single agent (n =62) Treatment (as shown below).
Nine patients received no treatment, and 117 patients received at least one treatment and received efficacy and safety evaluation (59 cases in the combined regimen group and 58 cases in the single-drug regimen group).
The median age of patients in the combined regimen group was 66 years (interquartile range [IQR]: 62-74 years), and the single-drug regimen group was 67 years old (IQR: 62-74 years).
Both groups of patients received a median of 1 line (range: 1-2 lines) treatment.
The baseline characteristics of the two groups of patients were basically similar, and the proportion of patients with huge tumors (≥5cm) in the combined regimen group was higher (48% vs 28%) (as shown in the figure below).
The median follow-up time of the patients in the study was 41.
6 months (range: 36.
7-47.
3 months).
In the combined regimen group, the median treatment duration of Ibrutinib was 31.
5 months (IQR: 12.
4-39.
5 months), and the median treatment duration of Ublituximab was 30.
3 months (IQR: 10.
3-38.
1 months); single The median treatment duration of Ibrutinib in the drug regimen group was 17.
0 months (IQR: 5.
2-35.
3 months). Patients in the combined regimen group received a median of 19 Ublituximab infusions (IQR: 11-21); 6 patients stopped Ublituximab, and this group of patients received a median of 15 Ublituximab infusions (IRQ: 11-19).
02 Remission The ORR of the combined regimen group evaluated by IRC was 83%, and the ORR of the single-drug regimen group was 65%.
After excluding 9 patients who did not receive treatment after random assignment, the ORR of the combined regimen group was 90%, and the ORR of the single-drug regimen group was 69% (P=0.
006).
The CR rate of the combined regimen group was 19%, and that of the single-drug regimen group was 5% (P=0.
016).
After excluding patients who did not receive treatment, the CR rate of the combined regimen group was 20%, and that of the single-drug regimen group was 5% (P=0.
024) (as shown in the figure below).
The median duration of remission in both groups was not reached.
The median first partial response (PR) time of the combined regimen group was 2.
0 months (IQR: 1.
9-3.
7 months), and the median time to first CR was 22.
1 months (IQR: 15.
5-28.
8 months); the single-drug regimen group The median time to first PR was 4.
4 months (IQR: 2.
0-9.
8 months), and the median time to first CR was 24.
8 months (IQR: 23.
6-31.
4 months).
At a median follow-up time of 41.
6 months, the PFS of the patients in the combined regimen group had not yet reached, and the PFS of the single-agent regimen group was 35.
9 months (range: 17.
0 months-NE) (HR: 0.
46; 95% CI: 0.
24-0.
87) ; P=0.
016) (as shown in the figure below).
The negative rates of peripheral blood and bone marrow MRD in the combined regimen group were higher than those in the single-agent regimen group (42% vs 6%; P<0.
0001).
Forty-five patients (76%) in the 03 safety combination regimen group and 48 patients (83%) in the single-drug regimen group had ≥3 grade adverse events (as shown in the figure below).
The incidence of atrial fibrillation and neutropenia in the combined regimen group was higher than that in the single-drug regimen group, and 1 patient in the combined regimen group had tumor lysis syndrome.
Although the incidence of neutropenia was higher in the combined regimen group, the number of patients hospitalized for neutropenia in the two groups was similar (3 cases vs.
1 case).
Nine patients (15%) in the combined regimen group and 5 patients (9%) in the single-drug regimen group received growth factor therapy.
The most common SAEs in the two groups were pneumonia, atrial fibrillation, sepsis, and neutropenic fever.
The most common SAEs that may be related to treatment are granulocytopenic fever, pneumonia, atrial fibrillation, dysphagia, sepsis, and pleural effusion.
There were 3 cases of bleeding events ≥ Grade 3 in the combined regimen group; 4 cases in the single-drug regimen group, and 1 patient died of intracranial hemorrhage.
In the combined regimen group, 8 patients (14%) had postponed Ublituximab treatment, 6 patients (10%) withdrew from the study due to adverse events related to the combined regimen, and no patients discontinued the drug due to infusion reactions.
Nine patients (15%) in the combined regimen group and 8 patients (14%) in the single-drug regimen group reduced the dose of ibrutinib.
In the combined regimen group, 9 patients (15%) discontinued treatment due to adverse events (2 cases of atrial fibrillation, 2 cases of pneumonia, dysphagia, neutropenia, staphylococcal cellulitis, diarrhea, anemia, and pneumonia 1 each 7 cases (12%) in the single-drug regimen group discontinued treatment due to adverse events (2 cases of atrial fibrillation, 1 case each of diarrhea, pneumonia, cough, cardiac arrest, and retroperitoneal hemorrhage).
Ten patients (17%) in the combination regimen group died, and 16 patients (28%) in the single-agent regimen group died.
Most of the deaths (8 patients in the combination therapy group and 12 patients in the single-agent therapy group) were before the last treatment ≥30 days.
In the combined regimen group, 2 patients (3%) died of adverse events (1 case of cardiac arrest, 1 case of failure to survive), none of which was related to treatment.
In the single-drug regimen group, 5 patients (9%) died of adverse events (1 case of cardiac arrest, 1 case of cerebral infarction, 1 case of intracranial hemorrhage, 1 case of Pneumocystis pneumonia, 1 case of unknown cause), of which cardiac arrest Of deaths are related to treatment.
Research conclusions The combination of Ibrutinib single-drug regimen and Ublituximab has achieved a significantly higher overall remission rate in high-risk CLL patients with relapse and refractory, without affecting the safety of Ibrutinib single-agent therapy.
The results of this study support the use of Ublituximab combined with Ibrutinib in the treatment of high-risk patients with relapsed and refractory CLL.
References: Jeff P Sharman, Danielle M Brander, Anthony R Mato, Nilanjan Ghosh, et al.
Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open -label, randomised trial.
Lancet Haematol 2021.
Published Online.
February 22, 2021.
; https:// doi.
org/10.
1016/S2352-3026(20)30433-6 stamp "Read the original", we will make progress together
Several genetic abnormalities, including del (17p), del (11q) and TP53 gene mutations, are known to be poor prognostic indicators for CLL patients.
The BTK inhibitor ibrutinib can significantly improve the prognosis of CLL patients, and has been approved by the FDA for the treatment of newly treated, relapsed or refractory CLL.
At present, related studies have not yet determined whether the combination of ibrutinib and anti-CD20 monoclonal antibody can improve the prognosis of CLL patients.
Previous studies have shown that the combination of the first-generation anti-CD20 monoclonal antibody rituximab on the basis of the single-drug regimen of ibrutinib does not show an advantage in curative effect.
Compared with rituximab, a new generation of anti-CD20 monoclonal antibody, otuzumab can improve the treatment outcome of CLL patients.
At the same time, related studies have found that the combination of ibrutinib and otuzumab is superior to immunochemotherapy Efficacy, but there is no research to compare the efficacy of the combination regimen and the single-agent regimen of ibrutinib.
Ublituximab is a new glycosylated anti-CD20 monoclonal antibody.
A multicenter phase II study showed that the remission rate of Ublituximab combined with ibrutinib in the treatment of patients with relapsed and refractory CLL reached 88%, and the remission rate of patients with high-risk cytogenetic factors reached 95%.
On the basis of this study, the phase III GENUINE study compared the efficacy of Ublituximab combined with ibrutinib regimen and ibrutinib single-agent regimen in the treatment of CLL patients with high-risk cytogenetic factors, and judged the basis of iblituximab single-agent regimen Can Ublituximab improve the prognosis of these patients?
The main results of the research are summarized as follows for the reference of readers.
Research methods The study included patients with CLL who were ≥18 years of age and had received at least two cycles of standard treatment.
Patients included in the study need to have an ECOG score of 0-2, have high-risk cytogenetic factors (del (17p), del (11q) or TP53 gene mutation), have at least one measurable lymph node disease (the longest diameter> 2cm, the most Long vertical diameter> 1cm), normal organ function.
The study excluded the inapplicability of ibrutinib treatment, the need to receive moderate to high-intensity CYP3A inhibitor therapy, previous BTK inhibitor therapy, and anti-cancer therapy within 21 days before randomization (corticosteroids are allowed 7 days before the start of the study) Treatment), CLL patients who need to undergo transplantation within 3 months of the start of the study and have developed Richter transformation.
The study included patients who received ibrutinib (420mg/day) orally every day, and at the same time on the first day (≤150mg, lasting 4 hours), the second day (750mg, lasting 4 hours), and the first cycle of the first treatment cycle.
On 8 and 15 days (900 mg for 3 hours), the first day of cycles 2-6 (900 mg for 3 hours) received intravenous injection of Ublituximab (1 cycle for 28 days).
Patients received Ublituximab maintenance therapy (900 mg for 90 minutes) every 3 cycles after the 6th cycle of treatment until the disease progressed, intolerable toxicity, or the patient withdrew from the study.
In the study, patients need to receive antihistamines (such as diphenhydramine 50 mg) and corticosteroids (such as dexamethasone 10-20 mg) before receiving Ublituximab infusion.
If patients in the study have treatment-related serious adverse events (SAE), the relevant treatment drugs can be stopped for up to 4 weeks, but the dosage of Ublituximab cannot be reduced.
If there are ≥ grade 3 non-hematological events, ≥ grade 3 neutropenia events with infection or fever, and grade 4 hematological events, the dose of ibrutinib can be reduced.
If the patient has an infusion-related reaction, Ublituximab should be discontinued and the patient should be closely monitored and managed until the symptoms disappear.
Patients who withdrew from the study due to non-disease reasons were followed up every 3 months to pay attention to the progress of the disease.
The primary endpoint of the study was the overall response rate (ORR) assessed by the Independent Review Committee (IRC).
Patients in the study will be evaluated for efficacy after completing the second, fourth, and sixth cycles of treatment, and then every 3 treatment cycles (for patients who continue to receive treatment) or every 3 months (for patients who withdraw from treatment for follow-up) .
The secondary endpoints of the study include progression-free survival (PFS), MRD negative rate, complete remission (CR) rate, duration of remission, treatment onset time, and safety.
Study Results 01 Patient Characteristics The study included 126 patients from February 6, 2015 to December 19, 2016, who were randomly assigned to receive Ublituximab combined with Ibrutinib (n=64) or Ibrutinib as a single agent (n =62) Treatment (as shown below).
Nine patients received no treatment, and 117 patients received at least one treatment and received efficacy and safety evaluation (59 cases in the combined regimen group and 58 cases in the single-drug regimen group).
The median age of patients in the combined regimen group was 66 years (interquartile range [IQR]: 62-74 years), and the single-drug regimen group was 67 years old (IQR: 62-74 years).
Both groups of patients received a median of 1 line (range: 1-2 lines) treatment.
The baseline characteristics of the two groups of patients were basically similar, and the proportion of patients with huge tumors (≥5cm) in the combined regimen group was higher (48% vs 28%) (as shown in the figure below).
The median follow-up time of the patients in the study was 41.
6 months (range: 36.
7-47.
3 months).
In the combined regimen group, the median treatment duration of Ibrutinib was 31.
5 months (IQR: 12.
4-39.
5 months), and the median treatment duration of Ublituximab was 30.
3 months (IQR: 10.
3-38.
1 months); single The median treatment duration of Ibrutinib in the drug regimen group was 17.
0 months (IQR: 5.
2-35.
3 months). Patients in the combined regimen group received a median of 19 Ublituximab infusions (IQR: 11-21); 6 patients stopped Ublituximab, and this group of patients received a median of 15 Ublituximab infusions (IRQ: 11-19).
02 Remission The ORR of the combined regimen group evaluated by IRC was 83%, and the ORR of the single-drug regimen group was 65%.
After excluding 9 patients who did not receive treatment after random assignment, the ORR of the combined regimen group was 90%, and the ORR of the single-drug regimen group was 69% (P=0.
006).
The CR rate of the combined regimen group was 19%, and that of the single-drug regimen group was 5% (P=0.
016).
After excluding patients who did not receive treatment, the CR rate of the combined regimen group was 20%, and that of the single-drug regimen group was 5% (P=0.
024) (as shown in the figure below).
The median duration of remission in both groups was not reached.
The median first partial response (PR) time of the combined regimen group was 2.
0 months (IQR: 1.
9-3.
7 months), and the median time to first CR was 22.
1 months (IQR: 15.
5-28.
8 months); the single-drug regimen group The median time to first PR was 4.
4 months (IQR: 2.
0-9.
8 months), and the median time to first CR was 24.
8 months (IQR: 23.
6-31.
4 months).
At a median follow-up time of 41.
6 months, the PFS of the patients in the combined regimen group had not yet reached, and the PFS of the single-agent regimen group was 35.
9 months (range: 17.
0 months-NE) (HR: 0.
46; 95% CI: 0.
24-0.
87) ; P=0.
016) (as shown in the figure below).
The negative rates of peripheral blood and bone marrow MRD in the combined regimen group were higher than those in the single-agent regimen group (42% vs 6%; P<0.
0001).
Forty-five patients (76%) in the 03 safety combination regimen group and 48 patients (83%) in the single-drug regimen group had ≥3 grade adverse events (as shown in the figure below).
The incidence of atrial fibrillation and neutropenia in the combined regimen group was higher than that in the single-drug regimen group, and 1 patient in the combined regimen group had tumor lysis syndrome.
Although the incidence of neutropenia was higher in the combined regimen group, the number of patients hospitalized for neutropenia in the two groups was similar (3 cases vs.
1 case).
Nine patients (15%) in the combined regimen group and 5 patients (9%) in the single-drug regimen group received growth factor therapy.
The most common SAEs in the two groups were pneumonia, atrial fibrillation, sepsis, and neutropenic fever.
The most common SAEs that may be related to treatment are granulocytopenic fever, pneumonia, atrial fibrillation, dysphagia, sepsis, and pleural effusion.
There were 3 cases of bleeding events ≥ Grade 3 in the combined regimen group; 4 cases in the single-drug regimen group, and 1 patient died of intracranial hemorrhage.
In the combined regimen group, 8 patients (14%) had postponed Ublituximab treatment, 6 patients (10%) withdrew from the study due to adverse events related to the combined regimen, and no patients discontinued the drug due to infusion reactions.
Nine patients (15%) in the combined regimen group and 8 patients (14%) in the single-drug regimen group reduced the dose of ibrutinib.
In the combined regimen group, 9 patients (15%) discontinued treatment due to adverse events (2 cases of atrial fibrillation, 2 cases of pneumonia, dysphagia, neutropenia, staphylococcal cellulitis, diarrhea, anemia, and pneumonia 1 each 7 cases (12%) in the single-drug regimen group discontinued treatment due to adverse events (2 cases of atrial fibrillation, 1 case each of diarrhea, pneumonia, cough, cardiac arrest, and retroperitoneal hemorrhage).
Ten patients (17%) in the combination regimen group died, and 16 patients (28%) in the single-agent regimen group died.
Most of the deaths (8 patients in the combination therapy group and 12 patients in the single-agent therapy group) were before the last treatment ≥30 days.
In the combined regimen group, 2 patients (3%) died of adverse events (1 case of cardiac arrest, 1 case of failure to survive), none of which was related to treatment.
In the single-drug regimen group, 5 patients (9%) died of adverse events (1 case of cardiac arrest, 1 case of cerebral infarction, 1 case of intracranial hemorrhage, 1 case of Pneumocystis pneumonia, 1 case of unknown cause), of which cardiac arrest Of deaths are related to treatment.
Research conclusions The combination of Ibrutinib single-drug regimen and Ublituximab has achieved a significantly higher overall remission rate in high-risk CLL patients with relapse and refractory, without affecting the safety of Ibrutinib single-agent therapy.
The results of this study support the use of Ublituximab combined with Ibrutinib in the treatment of high-risk patients with relapsed and refractory CLL.
References: Jeff P Sharman, Danielle M Brander, Anthony R Mato, Nilanjan Ghosh, et al.
Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open -label, randomised trial.
Lancet Haematol 2021.
Published Online.
February 22, 2021.
; https:// doi.
org/10.
1016/S2352-3026(20)30433-6 stamp "Read the original", we will make progress together
