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The 63rd ASH Annual Conference in 2021 will be held both offline and online from December 11th to 14th, focusing on cutting-edge research on blood diseases and improving the level of disease diagnosis and treatment
.
A number of studies on the treatment of chronic lymphocytic leukemia (CLL) were announced in this ASH annual meeting.
There are two Umbralisib (a selective PI3Kδ and CK1ε inhibitor) and Ublituximab (a new type of anti-CD20 monoclonal antibody) (U2 ) The study of combination therapy was selected into the Oral and Poster sections respectively.
The editor summarizes its main contents as follows for the reference of readers
.
Abstract Number: 395 Title: Ublituximab and Umbralisib (U2) in combination with ibrutinib for the treatment of chronic lymphocytic leukemia (CLL) Phase 2 study: minimal residual disease (MRD)-driven time-limited method researchers explored in ibrutinib The safety and efficacy of U2 therapy in CLL patients whose MRD can be detected after the initial stage of Nimonotherapy
.
The goal of this strategy is to induce undetectable MRD (uMRD), minimize the risk of BTKi resistance mutations, stop all targeted CLL treatments, and achieve long-lasting treatment-free observations in CLL patients who benefit from combination therapy (TFO)
.
Research Method This is a phase II, multi-center, open-label clinical trial (NCT04016805)
.
The enrollment conditions are continuous treatment with ibrutinib for at least 6 months in any regimen, and residual CLL can be detected in the peripheral blood by MRD measurement (flow cytometry, uMRD cutoff value is 10-4)
.
Add Umbralisib (800mg/day) and Ublituximab (900mg intravenously) to the treatment of ibrutinib, on the 1/2 day of the first cycle [150/750mg respectively], 8, 15 days, and the first of cycles 2-6 Day, the first day of every 3 cycles after the 6th cycle), continuously monitor the patient’s MRD from the 1st day of the 3rd cycle
.
Once uMRD is achieved and confirmed after 4 weeks, the patient enters the TFO phase
.
Patients who have not obtained uMRD continue treatment for up to 24 cycles, and then enter the TFO phase
.
The main goal of this study is to achieve the uMRD ratio, with a pre-specified MRD conversion rate of 25%
.
Secondary endpoints include safety and durability of clinical benefit after discontinuation of the drug
.
Results of the study In this study, 26 patients were treated with U2 in Ibrutinib
.
The median age is 63 years (range: 48-81 years), and 77% are males
.
Disease characteristics: del(17p) accounted for 8%, del(11q) accounted for 12%, and unmutated IGHV accounted for 31%
.
Before joining U2, the median duration of ibrutinib treatment was 22 months (range: 7-66 months)
.
The figure below depicts the time of taking Ibrahimovic before participating in this study, the duration of triple therapy treatment, the realization of uMRD and TFO
.
Twenty-four patients underwent MRD assessment, and 71% (17/24) of patients achieved uMRD in at least one assessment
.
The median time to the first uMRD is 5 months (range: 2-12)
.
A total of 16 patients (67%) entered TFO; 15 patients were assessed as uMRD twice in a row, and 1 patient completed 24 cycles of treatment
.
As of the data cutoff, the median TFO was 242 days (range: 5-538 days), showing persistence
.
73% of patients were still uMRD at the last follow-up
.
According to the iwCLL criteria, no patients have progressed or required retreatment
.
U2 combined with ibrutinib is well tolerated
.
Grade 3/4 adverse events included: elevated ALT/AST (4%), diarrhea (4%), and hypertension (8%)
.
Two patients discontinued all treatments due to skin rashes, both were uMRD when the treatment was interrupted and continued to be uMRD
.
One patient died due to complications of COVID-19
.
Research conclusions This research is the first MRD-driven treatment that combines BTKi, PI3Ki and anti-CD20 monoclonal antibody
.
This new drug combination therapy is well tolerated and effective, with 71% of evaluable patients achieving uMRD
.
For patients who continue to take ibrutinib, this "add-on" therapy can achieve deep relief, allowing for individualized time-limited treatment and continuous treatment-free observation
.
Abstract Number: 1549 Title: Selective BTK inhibitor TG-1701 as a single agent and combined with Ublituximab and Umbralisib (U2) in the treatment of B-cell malignancies.
TG-1701 is an irreversible and selective new BTK inhibitor, administered daily Once (QD)
.
The combination of BTKi and U2 is very effective in the treatment of CLL.
The researchers imagine that the combination of U2 and TG-1701 double-blocking the B cell receptor (BCR) pathway can bring greater benefits to patients
.
Research methods This phase I trial mainly included patients with CLL and non-Hodgkin's lymphoma (NHL)
.
After confirming the safety of TG-1701 monotherapy, a parallel dose trial of TG-1701 combined with U2 was carried out
.
The study of TG-1701 monotherapy and different doses of TG-1701 combined with U2 was also expanded
.
All patients received treatment until the disease progressed, intolerable toxicity appeared, or treatment was withdrawn
.
The safety assessment was conducted on all patients receiving treatment, and the efficacy assessment was conducted on all patients who underwent at least one post-baseline assessment after receiving treatment
.
Here, the investigator reported data on the TG-1701+U2 dose escalation and TG-1701 monotherapy CLL expansion cohort
.
The results of the study as of July 2021, 142 patients received TG-1701 treatment, of which 36 patients were included in the TG-1701+U2 group
.
The median of previous treatments for all patients receiving treatment was 1 (range: 0-10), and none of the patients had received BTKi treatment
.
Among the 36 patients who received U2+TG-1701 treatment, 19 patients could be evaluated for efficacy and safety (the other 17 patients were evaluated too early)
.
The median age is 69 years (47-81 years), and 56% are men
.
TG-1701+U2 is well tolerated at 4 different dose levels and has no dose-limiting toxicity
.
The most common (>30%) "treatment period" adverse events (TEAE) of TG-1701+U2 of any grade were diarrhea (53%), ecchymosis (42%), nausea (37%), hypertension, ALT/ Increased AST and fatigue (32% each)
.
Grade 3/4 AEs with an incidence of >15% are limited to elevated ALT/AST (21%)
.
One patient had a dose reduction due to an AE, and 4 patients stopped using at least one drug due to an AE.
Two patients stopped using Umbralisib, one patient stopped Umbralisib and TG-1701, and one patient stopped all 3 drugs
.
At the time of the data cutoff, the overall response rate (ORR) of 19 evaluable patients was 84% (4 CR and 12 PR), and the remaining patients were waiting for evaluation after baseline
.
In the monotherapy CLL specific cohort (200mgQD, n=20; 300mgQD, n=20), 40 patients can be evaluated for safety and 39 patients can be evaluated for effectiveness (1 patient was affected by COVID before the first response evaluation) Exit)
.
The median age was 71 years (range: 49-86), and 43% were men
.
The most common TEAEs were elevated ALT/AST (all grades: 18%; ≥3 grade: 3%), followed by diarrhea (all grades: 15%; ≥3: none) and neutropenia (all grades) ：13%; ≥3 grade: 13%)
.
At a median follow-up of 12.
8 months (range: 2.
5-20.
8), there were no cases of atrial fibrillation, hemorrhage, or ventricular tachyarrhythmia in the CLL cohort
.
One (3%) patient had a TEAE that resulted in a dose reduction of TG-1701
.
No patients in the 200mg or 300mg CLL cohort discontinued due to AE
.
In patients with anemia and thrombocytopenia at baseline, continuous improvement in hematological indicators can be observed
.
The ORR of 39 patients was 97% (all PR/PR-L)
.
69% (24 out of 35 patients with lymphocytosis) had lymphocytosis to return to normal or <50% of baseline
.
A consistent response rate was observed in all subgroups, including the following high-risk genomic characteristics: del(17p)/TP53 mutation, IGHV unmutated, and complex karyotype (defined as cytogenetic abnormality ≥ 3)
.
The median duration of remission in either cohort was not reached
.
The best change in tumor burden of CLL patients from baseline is shown in the figure below
.
Research conclusions TG-1701 monotherapy showed certain safety and effectiveness in CLL patients.
In addition, combined therapy with U2 also showed higher activity and controllable tolerability
.
Reference source: 1.
LindseyE.
Roeker, et al.
2021ASH.
Abstract#395.
2.
ChanYoonCheah, et al.
2021ASH.
Abstract#1549.
Stamp "read the original text" and we will make progress together
.
A number of studies on the treatment of chronic lymphocytic leukemia (CLL) were announced in this ASH annual meeting.
There are two Umbralisib (a selective PI3Kδ and CK1ε inhibitor) and Ublituximab (a new type of anti-CD20 monoclonal antibody) (U2 ) The study of combination therapy was selected into the Oral and Poster sections respectively.
The editor summarizes its main contents as follows for the reference of readers
.
Abstract Number: 395 Title: Ublituximab and Umbralisib (U2) in combination with ibrutinib for the treatment of chronic lymphocytic leukemia (CLL) Phase 2 study: minimal residual disease (MRD)-driven time-limited method researchers explored in ibrutinib The safety and efficacy of U2 therapy in CLL patients whose MRD can be detected after the initial stage of Nimonotherapy
.
The goal of this strategy is to induce undetectable MRD (uMRD), minimize the risk of BTKi resistance mutations, stop all targeted CLL treatments, and achieve long-lasting treatment-free observations in CLL patients who benefit from combination therapy (TFO)
.
Research Method This is a phase II, multi-center, open-label clinical trial (NCT04016805)
.
The enrollment conditions are continuous treatment with ibrutinib for at least 6 months in any regimen, and residual CLL can be detected in the peripheral blood by MRD measurement (flow cytometry, uMRD cutoff value is 10-4)
.
Add Umbralisib (800mg/day) and Ublituximab (900mg intravenously) to the treatment of ibrutinib, on the 1/2 day of the first cycle [150/750mg respectively], 8, 15 days, and the first of cycles 2-6 Day, the first day of every 3 cycles after the 6th cycle), continuously monitor the patient’s MRD from the 1st day of the 3rd cycle
.
Once uMRD is achieved and confirmed after 4 weeks, the patient enters the TFO phase
.
Patients who have not obtained uMRD continue treatment for up to 24 cycles, and then enter the TFO phase
.
The main goal of this study is to achieve the uMRD ratio, with a pre-specified MRD conversion rate of 25%
.
Secondary endpoints include safety and durability of clinical benefit after discontinuation of the drug
.
Results of the study In this study, 26 patients were treated with U2 in Ibrutinib
.
The median age is 63 years (range: 48-81 years), and 77% are males
.
Disease characteristics: del(17p) accounted for 8%, del(11q) accounted for 12%, and unmutated IGHV accounted for 31%
.
Before joining U2, the median duration of ibrutinib treatment was 22 months (range: 7-66 months)
.
The figure below depicts the time of taking Ibrahimovic before participating in this study, the duration of triple therapy treatment, the realization of uMRD and TFO
.
Twenty-four patients underwent MRD assessment, and 71% (17/24) of patients achieved uMRD in at least one assessment
.
The median time to the first uMRD is 5 months (range: 2-12)
.
A total of 16 patients (67%) entered TFO; 15 patients were assessed as uMRD twice in a row, and 1 patient completed 24 cycles of treatment
.
As of the data cutoff, the median TFO was 242 days (range: 5-538 days), showing persistence
.
73% of patients were still uMRD at the last follow-up
.
According to the iwCLL criteria, no patients have progressed or required retreatment
.
U2 combined with ibrutinib is well tolerated
.
Grade 3/4 adverse events included: elevated ALT/AST (4%), diarrhea (4%), and hypertension (8%)
.
Two patients discontinued all treatments due to skin rashes, both were uMRD when the treatment was interrupted and continued to be uMRD
.
One patient died due to complications of COVID-19
.
Research conclusions This research is the first MRD-driven treatment that combines BTKi, PI3Ki and anti-CD20 monoclonal antibody
.
This new drug combination therapy is well tolerated and effective, with 71% of evaluable patients achieving uMRD
.
For patients who continue to take ibrutinib, this "add-on" therapy can achieve deep relief, allowing for individualized time-limited treatment and continuous treatment-free observation
.
Abstract Number: 1549 Title: Selective BTK inhibitor TG-1701 as a single agent and combined with Ublituximab and Umbralisib (U2) in the treatment of B-cell malignancies.
TG-1701 is an irreversible and selective new BTK inhibitor, administered daily Once (QD)
.
The combination of BTKi and U2 is very effective in the treatment of CLL.
The researchers imagine that the combination of U2 and TG-1701 double-blocking the B cell receptor (BCR) pathway can bring greater benefits to patients
.
Research methods This phase I trial mainly included patients with CLL and non-Hodgkin's lymphoma (NHL)
.
After confirming the safety of TG-1701 monotherapy, a parallel dose trial of TG-1701 combined with U2 was carried out
.
The study of TG-1701 monotherapy and different doses of TG-1701 combined with U2 was also expanded
.
All patients received treatment until the disease progressed, intolerable toxicity appeared, or treatment was withdrawn
.
The safety assessment was conducted on all patients receiving treatment, and the efficacy assessment was conducted on all patients who underwent at least one post-baseline assessment after receiving treatment
.
Here, the investigator reported data on the TG-1701+U2 dose escalation and TG-1701 monotherapy CLL expansion cohort
.
The results of the study as of July 2021, 142 patients received TG-1701 treatment, of which 36 patients were included in the TG-1701+U2 group
.
The median of previous treatments for all patients receiving treatment was 1 (range: 0-10), and none of the patients had received BTKi treatment
.
Among the 36 patients who received U2+TG-1701 treatment, 19 patients could be evaluated for efficacy and safety (the other 17 patients were evaluated too early)
.
The median age is 69 years (47-81 years), and 56% are men
.
TG-1701+U2 is well tolerated at 4 different dose levels and has no dose-limiting toxicity
.
The most common (>30%) "treatment period" adverse events (TEAE) of TG-1701+U2 of any grade were diarrhea (53%), ecchymosis (42%), nausea (37%), hypertension, ALT/ Increased AST and fatigue (32% each)
.
Grade 3/4 AEs with an incidence of >15% are limited to elevated ALT/AST (21%)
.
One patient had a dose reduction due to an AE, and 4 patients stopped using at least one drug due to an AE.
Two patients stopped using Umbralisib, one patient stopped Umbralisib and TG-1701, and one patient stopped all 3 drugs
.
At the time of the data cutoff, the overall response rate (ORR) of 19 evaluable patients was 84% (4 CR and 12 PR), and the remaining patients were waiting for evaluation after baseline
.
In the monotherapy CLL specific cohort (200mgQD, n=20; 300mgQD, n=20), 40 patients can be evaluated for safety and 39 patients can be evaluated for effectiveness (1 patient was affected by COVID before the first response evaluation) Exit)
.
The median age was 71 years (range: 49-86), and 43% were men
.
The most common TEAEs were elevated ALT/AST (all grades: 18%; ≥3 grade: 3%), followed by diarrhea (all grades: 15%; ≥3: none) and neutropenia (all grades) ：13%; ≥3 grade: 13%)
.
At a median follow-up of 12.
8 months (range: 2.
5-20.
8), there were no cases of atrial fibrillation, hemorrhage, or ventricular tachyarrhythmia in the CLL cohort
.
One (3%) patient had a TEAE that resulted in a dose reduction of TG-1701
.
No patients in the 200mg or 300mg CLL cohort discontinued due to AE
.
In patients with anemia and thrombocytopenia at baseline, continuous improvement in hematological indicators can be observed
.
The ORR of 39 patients was 97% (all PR/PR-L)
.
69% (24 out of 35 patients with lymphocytosis) had lymphocytosis to return to normal or <50% of baseline
.
A consistent response rate was observed in all subgroups, including the following high-risk genomic characteristics: del(17p)/TP53 mutation, IGHV unmutated, and complex karyotype (defined as cytogenetic abnormality ≥ 3)
.
The median duration of remission in either cohort was not reached
.
The best change in tumor burden of CLL patients from baseline is shown in the figure below
.
Research conclusions TG-1701 monotherapy showed certain safety and effectiveness in CLL patients.
In addition, combined therapy with U2 also showed higher activity and controllable tolerability
.
Reference source: 1.
LindseyE.
Roeker, et al.
2021ASH.
Abstract#395.
2.
ChanYoonCheah, et al.
2021ASH.
Abstract#1549.
Stamp "read the original text" and we will make progress together
