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Waldenström macroglobulinemia (Waldenström macroglobulinemia, WM) is an indolent non-Hodgkin lymphoma with a low clinical incidence.
According to the 2016 World Health Organization lymphoma classification, WM belongs to the subtype of lymphoplasmacytic lymphoma (LPL) among mature B-cell lymphomas, with lymphoplasmacytic cells infiltrating the bone marrow and accompanied by increased serum monoclonal immunoglobulin M (IgM) As a feature.
Idelalisib is an oral selective phosphatidylinositol-3-kinase delta (PI3K delta) inhibitor that has shown anti-tumor activity in previously treated patients with indolent non-Hodgkin's lymphoma.
Otuzumab is a type II humanized anti-CD20 monoclonal antibody made by glycosylation engineering.
Studies have shown that in patients with low-grade lymphoid malignancies (including newly treated, unfit chronic lymphocytic leukemia and follicular lymphatic leukemia) Tumor patients), otuzumab is more effective than rituximab.
The investigators conducted a single-arm, multi-center phase 2 study to evaluate the efficacy and safety of otuzumab + idelalisib in patients with relapsed/refractory (R/R) WM.
Research method research recruitment lasted from March 2017 to July 2018.
Patients who meet the diagnostic criteria and treatment criteria of the 2nd International Symposium on Waldenstrom's Macroglobulinemia meet the enrollment conditions, and all have relapsed after the previous 1-3 line treatment (the first-line or subsequent treatment progresses more than 6 months later) or Patients who are refractory (progressed after first-line or follow-up treatment ≤ 6 months).
The primary research endpoint is progression-free survival (PFS), and the secondary research endpoints include overall response rate (ORR), response rates at the 8th and 24th months (according to the standards of the 6th WM International Symposium), and overall survival Period (OS), time to minimal remission (MR), time to treatment failure (TTF), and time to start a new therapy.
The secondary goal is to evaluate safety and tolerability and the impact of MYD88 mutation and CXCR4 mutation on remission and progression-free survival (PFS).
Inclusion criteria: the patient’s disease is measurable (ie serum IgM ≥ 2 times the upper limit of normal [ULN]), and meets the following laboratory standards: platelet count ≥ 75×109/L, absolute neutrophil count ≥ 1.
5×109 /L (not caused by BM infiltration); creatinine clearance ≥40mL/min; total bilirubin ≤2 times ULN (unless it is clearly related to disease or idiopathic unconjugated hyperbilirubinemia); serum alanine Acid transaminase level ≤2.
5 times of ULN; Aspartate aminotransferase ≤2.
5 times of ULN; Eastern Cooperative Oncology Group (ECOG) performance status score is 0-2 points.
During induction therapy, intravenous otuzumab (100 mg on day 1 of the first cycle, 900 mg on day 2 and 1000 mg on days 8 and 15 of the first cycle; administration on day 1 of 2-6 cycles thereafter; 28 days as a cycle) combined with continuous administration of idelalisib (150 mg orally twice a day).
During maintenance treatment, idelalisib was given as a single agent for ≤ 2 years.
Results of the study 49 patients from 21 centers were included in the study, with a median age of 68.
5 years (range: 50-83 years).
Among the 49 enrolled patients, 1 died before any treatment (unknown cause), and 48 patients received combined induction therapy.
Induction therapy was discontinued in 14/28 patients (7 due to disease progression and 7 due to adverse events [AE]).
27 patients underwent maintenance treatment.
At the time of data analysis (May 20, 2020), 9 patients completed maintenance treatment and 18 patients stopped treatment (13 due to intolerance and 5 due to disease progression).
01 Remission: 43 patients underwent response assessment 8 months after induction, and 6 unassessed patients were considered treatment failure.
The best response achieved after a median of 6.
5 months (IQR: 3.
4-7.
1; range: 2.
6-22.
1 months), 5 patients achieved very good partial response (VGPR), and 27 patients achieved partial response (PR).
Three patients achieved MR.
The ORR and major response rate (MRR) were estimated to be 71.
4% (95% C: 56.
7-83.
4) and 65.
3% (95% CI: 50.
4-78.
3), respectively.
5 patients had stable disease and 3 patients had disease progression.
02 After a median follow-up of 25.
9 months (IQR: 22.
3-30.
5), the median PFS was 25.
4 months (95% CI: 15.
7-29.
0), and the PFS rates at 12 and 24 months were 75.
5% ( 95% CI: 64.
4-88.
6) and 55% (95% CI: 42.
7-70.
9).
The median TTF was 25.
6 months (95% CI: 19.
9-30.
4), and the cumulative incidence of new therapies starting at 12 and 24 months was 22.
5% (95% CI: 11.
9-35.
0) and 36.
8% (95%).
CI: 23.
4-50.
2).
The 12-month and 24-month OS rates were 97.
8% (95% CI: 94.
1-100) and 89.
8% (95% CI: 81.
7-98.
7), respectively.
A total of 28 patients had disease progression.
Of the 24 patients who received the new therapy, 14 received no chemotherapy (Ibrutinib [n=10], and 9 patients still had remission; bortezomib + dexamethasone + rituximab [n=1]; rituximab[n=1]; idelalisib[n=1]; bispecific antibody[n=1]), 10 of which received combined immunochemotherapy treatment.
03 Effect of molecular profile on remission and survival CXCR4 genotype has no significant effect on remission and survival rate, but TP53 mutation has a deleterious effect on survival rate.
04 Safety Although there was no grade 5 toxicity, 26 patients were excluded from the study due to side effects.
The most common are neutropenia (9.
4%), diarrhea (8.
6%) and liver toxicity (9.
3%).
Study conclusions The study results show that the combination of otuzumab + idelalisib has considerable efficacy in the treatment of symptomatic R/R WM patients, but toxicity is still a major limitation.
The combination therapy of otuzumab + idelalisib still needs to be studied in further clinical trials.
Reference source: Cécile Tomowiak, Stéphanie Poulain, Charles Herbaux, et al.
Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia.
Blood Adv (2021) 5 (9): 2438-2446.
Stamp "read the original text", let's work together progress
According to the 2016 World Health Organization lymphoma classification, WM belongs to the subtype of lymphoplasmacytic lymphoma (LPL) among mature B-cell lymphomas, with lymphoplasmacytic cells infiltrating the bone marrow and accompanied by increased serum monoclonal immunoglobulin M (IgM) As a feature.
Idelalisib is an oral selective phosphatidylinositol-3-kinase delta (PI3K delta) inhibitor that has shown anti-tumor activity in previously treated patients with indolent non-Hodgkin's lymphoma.
Otuzumab is a type II humanized anti-CD20 monoclonal antibody made by glycosylation engineering.
Studies have shown that in patients with low-grade lymphoid malignancies (including newly treated, unfit chronic lymphocytic leukemia and follicular lymphatic leukemia) Tumor patients), otuzumab is more effective than rituximab.
The investigators conducted a single-arm, multi-center phase 2 study to evaluate the efficacy and safety of otuzumab + idelalisib in patients with relapsed/refractory (R/R) WM.
Research method research recruitment lasted from March 2017 to July 2018.
Patients who meet the diagnostic criteria and treatment criteria of the 2nd International Symposium on Waldenstrom's Macroglobulinemia meet the enrollment conditions, and all have relapsed after the previous 1-3 line treatment (the first-line or subsequent treatment progresses more than 6 months later) or Patients who are refractory (progressed after first-line or follow-up treatment ≤ 6 months).
The primary research endpoint is progression-free survival (PFS), and the secondary research endpoints include overall response rate (ORR), response rates at the 8th and 24th months (according to the standards of the 6th WM International Symposium), and overall survival Period (OS), time to minimal remission (MR), time to treatment failure (TTF), and time to start a new therapy.
The secondary goal is to evaluate safety and tolerability and the impact of MYD88 mutation and CXCR4 mutation on remission and progression-free survival (PFS).
Inclusion criteria: the patient’s disease is measurable (ie serum IgM ≥ 2 times the upper limit of normal [ULN]), and meets the following laboratory standards: platelet count ≥ 75×109/L, absolute neutrophil count ≥ 1.
5×109 /L (not caused by BM infiltration); creatinine clearance ≥40mL/min; total bilirubin ≤2 times ULN (unless it is clearly related to disease or idiopathic unconjugated hyperbilirubinemia); serum alanine Acid transaminase level ≤2.
5 times of ULN; Aspartate aminotransferase ≤2.
5 times of ULN; Eastern Cooperative Oncology Group (ECOG) performance status score is 0-2 points.
During induction therapy, intravenous otuzumab (100 mg on day 1 of the first cycle, 900 mg on day 2 and 1000 mg on days 8 and 15 of the first cycle; administration on day 1 of 2-6 cycles thereafter; 28 days as a cycle) combined with continuous administration of idelalisib (150 mg orally twice a day).
During maintenance treatment, idelalisib was given as a single agent for ≤ 2 years.
Results of the study 49 patients from 21 centers were included in the study, with a median age of 68.
5 years (range: 50-83 years).
Among the 49 enrolled patients, 1 died before any treatment (unknown cause), and 48 patients received combined induction therapy.
Induction therapy was discontinued in 14/28 patients (7 due to disease progression and 7 due to adverse events [AE]).
27 patients underwent maintenance treatment.
At the time of data analysis (May 20, 2020), 9 patients completed maintenance treatment and 18 patients stopped treatment (13 due to intolerance and 5 due to disease progression).
01 Remission: 43 patients underwent response assessment 8 months after induction, and 6 unassessed patients were considered treatment failure.
The best response achieved after a median of 6.
5 months (IQR: 3.
4-7.
1; range: 2.
6-22.
1 months), 5 patients achieved very good partial response (VGPR), and 27 patients achieved partial response (PR).
Three patients achieved MR.
The ORR and major response rate (MRR) were estimated to be 71.
4% (95% C: 56.
7-83.
4) and 65.
3% (95% CI: 50.
4-78.
3), respectively.
5 patients had stable disease and 3 patients had disease progression.
02 After a median follow-up of 25.
9 months (IQR: 22.
3-30.
5), the median PFS was 25.
4 months (95% CI: 15.
7-29.
0), and the PFS rates at 12 and 24 months were 75.
5% ( 95% CI: 64.
4-88.
6) and 55% (95% CI: 42.
7-70.
9).
The median TTF was 25.
6 months (95% CI: 19.
9-30.
4), and the cumulative incidence of new therapies starting at 12 and 24 months was 22.
5% (95% CI: 11.
9-35.
0) and 36.
8% (95%).
CI: 23.
4-50.
2).
The 12-month and 24-month OS rates were 97.
8% (95% CI: 94.
1-100) and 89.
8% (95% CI: 81.
7-98.
7), respectively.
A total of 28 patients had disease progression.
Of the 24 patients who received the new therapy, 14 received no chemotherapy (Ibrutinib [n=10], and 9 patients still had remission; bortezomib + dexamethasone + rituximab [n=1]; rituximab[n=1]; idelalisib[n=1]; bispecific antibody[n=1]), 10 of which received combined immunochemotherapy treatment.
03 Effect of molecular profile on remission and survival CXCR4 genotype has no significant effect on remission and survival rate, but TP53 mutation has a deleterious effect on survival rate.
04 Safety Although there was no grade 5 toxicity, 26 patients were excluded from the study due to side effects.
The most common are neutropenia (9.
4%), diarrhea (8.
6%) and liver toxicity (9.
3%).
Study conclusions The study results show that the combination of otuzumab + idelalisib has considerable efficacy in the treatment of symptomatic R/R WM patients, but toxicity is still a major limitation.
The combination therapy of otuzumab + idelalisib still needs to be studied in further clinical trials.
Reference source: Cécile Tomowiak, Stéphanie Poulain, Charles Herbaux, et al.
Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia.
Blood Adv (2021) 5 (9): 2438-2446.
Stamp "read the original text", let's work together progress
