P1103: OBINUTUZUMAB INDUCTION AND MAINTENANCE IN PATIENTS WITH RELAPSED/REFRACTORY WALDENSTROM MACROGLOBULINAEMIA
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ABSTRACT:
SUBMITTER: Wrobel T
PROVIDER: S-EPMC10430969 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:We present the results of a phase 2 study evaluating the combination of obinutuzumab + idelalisib in relapsed/refractory (R/R) Waldenström macroglobulinemia (WM). The goal was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received idelalisib + obinutuzumab for 6 cycles, followed by a maintenance phase with idelalisib alone for ≤2 years. Forty-eight patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (interquartile range, 3.4-7.1; range, 2.6-22.1 months), were very good partial response in 5 patients, partial response in 27 patients, and minor response in 3 patients, leading to overall response rate and major response rate estimates of 71.4% (95% confidence interval [CI], 56.7-83.4) and 65.3% (95% CI, 50.4-78.3), respectively. With a median follow-up of 25.9 months, median progression-free survival was 25.4 months (95% CI, 15.7-29.0). Univariate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade 5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4%), diarrhea (8.6%), and liver toxicity (9.3%). The combination of idelalisib + obinutuzumab is effective in R/R WM. Nonetheless, the apparent lack of impact of genotype on outcome could give new meaning to targeting of the phosphatidylinositol 3-kinase pathway in WM. This trial was registered at www.clinicaltrials.gov as #NCT02962401.
| S-EPMC8114554 | biostudies-literature
Project description:Zanubrutinib is a selective second-generation Bruton tyrosine kinase inhibitor approved in various B-cell malignancies globally. The phase 1/2 BGB-3111-111 study evaluated the efficacy and safety of zanubrutinib 160 mg twice daily orally in Japanese patients with treatment-naive or relapsed/refractory mature B-cell malignancies. Here, efficacy results from Part 2 in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 19) and Waldenström macroglobulinemia (WM; n = 19), and safety results from Parts 1 (N = 6) and 2 (N = 49) are presented, with the first dose between 30 January, 2020, and 31 October, 2022. As of 10 May, 2023, investigator-assessed overall response rates were 100% (19/19) and 94.7% (18/19) in CLL/SLL and WM, respectively, with median follow-up of 27.9 and 26.8 months; 24-month progression-free survival rates were 71.4% and 100% in treatment-naive and relapsed/refractory CLL/SLL and 83.9% and 100% in treatment-naive and relapsed/refractory WM, respectively. In patients with B-cell malignancies, any-grade treatment-emergent adverse events (TEAEs) occurred in 53 (96.4%) and serious TEAEs in 18 (32.7%). Common TEAEs were platelet count decreased (18.2%), pyrexia (18.2%), COVID-19 (14.5%), and neutrophil count decreased (12.7%). With median follow-up > 2 years, zanubrutinib demonstrated durable efficacy in Japanese patients with CLL/SLL or WM and a favorable safety profile consistent with global phase 3 studies.
| S-EPMC11922998 | biostudies-literature
Project description:BackgroundIxazomib-revlimid-dexamethason showed significant activity in relapsed/refractory multiple myeloma (RRMM). Here, we evaluate ixazomib in combination with thalidomide and dexamethasone for induction treatment followed by ixazomib maintenance therapy in RRMM patients.MethodsNinety patients have been included. Ixazomib-thalidomide-dexamethasone (4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly) was scheduled for eight cycles followed by maintenance with ixazomib for one year.ResultsThe overall response rate was 51.1%, 23.3% achieved CR or VGPR and 10% MR resulting in a clinical benefit rate of 61.1%. In patients completing ≥2 cycles, the rates were 60.5%, 27.6% and 68.4%, respectively. Median progression-free survival (PFS) was 8.5 months in all, and 9.4 months in those completing ≥2 cycles. Response rates, PFS and overall survival (OS) were similar in patients with and without t(4;14) and/or del(17p), but PFS and OS was significantly shorter in patients with gain of 1q21. Multivariate regression analysis revealed gain of 1q21 as the most important factor associated with OS. Ixazomib maintenance resulted in an upgrade in the depth of response in 12.4% of patients. Grade 3/4 toxicities were relatively rare.ConclusionsIxazomib-thalidomide-dexamethasone followed by ixazomib maintenance therapy is active and well tolerated in patients with RRMM.Trial registration numberNCT02410694.
| S-EPMC6889132 | biostudies-literature
Project description:Ibrutinib is highly active in Waldenström macroglobulinaemia (WM) patients, but disease progression can occur due to acquired mutations in BTK, the target of ibrutinib, or PLCG2, the protein downstream of BTK. However, not all resistant patients harbour these alterations. We have performed a whole-exome sequencing study to identify alternative molecular mechanisms that can drive ibrutinib resistance. Our findings include deletions on chromosomes 6q, including homozygous deletions, and 8p, which encompass key regulators of BTK, MYD88/NF-κB, and apoptotic signalling. Moreover, we have identified recurring mutations in ubiquitin ligases, innate immune signalling, and TLR/MYD88 pathway regulators in ibrutinib-resistant WM patients.
| S-EPMC7299825 | biostudies-literature
Project description:Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2-6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL. SIGNIFICANCE: Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity-enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.This article is highlighted in the In This Issue feature, p. 327.
| S-EPMC8176161 | biostudies-literature
Project description:CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti-CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib-resistant lines) elicited antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI-WM1-xenografted mice. CD38 is reported to augment B-cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib-resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single-agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti-WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co-targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.
| S-EPMC7294509 | biostudies-literature
Project description:CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.
| S-EPMC5409813 | biostudies-literature
Project description:PurposeThis study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM).Patients and methodsPatients who had at least one previous therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response.ResultsThirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached.ConclusionThe combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.
| S-EPMC2834499 | biostudies-literature
Project description:Data on cause-specific mortality after lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinaemia (WM) are lacking. We identified causes of death amongst 7289 adults diagnosed with incident first primary LPL (n = 3108) or WM (n = 4181) during 2000-2016 in 17 USA population-based cancer registries. Based on 3132 deaths, 16-year cumulative mortality was 23·2% for lymphomas, 8·4% for non-lymphoma cancers and 14·7% for non-cancer causes for patients aged <65 years at diagnosis of LPL/WM, versus 33·4%, 11·2% and 48·7%, respectively, for those aged ≥75 years. Compared with the general population, patients with LPL/WM had a 20% higher risk of death due to non-cancer causes (n = 1341 deaths, standardised mortality ratio [SMR] 1·2, 95% confidence interval [CI] 1·1-1·2), most commonly from infectious (n = 188; SMR 1·8, 95% CI 1·6-2·1), respiratory (n = 143; SMR 1·2, 95% CI 1·0-1·4), and digestive (n = 80; SMR 1·8, 95% CI 1·4-2·2) diseases, but no excess mortality from cardiovascular diseases (n = 477, SMR 1·1, 95% CI 1·0-1·1). Risks were highest for non-cancer causes within 1 year of diagnosis (n = 239; SMR<1year 1·3, 95% CI 1·2-1·5), declining thereafter (n = 522; SMR≥5years 1·1, 95% CI 1·1-1·2). Myelodysplastic syndrome/acute myeloid leukaemia deaths were notably increased (n = 46; SMR 4·4, 95% CI 3·2-5·9), whereas solid neoplasm deaths were only elevated among ≥5-year survivors (n = 145; SMR≥5years 1·3, 95% CI 1·1-1·5). This work identifies new areas for optimising care and reducing mortality for patients with LPL/WM.
| S-EPMC7299735 | biostudies-literature
Project description:This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.
| S-EPMC6706803 | biostudies-literature