Irreversible Bruton's Tyrosine Kinase Research Articles

Cost-Effectiveness of Zanubrutinib Versus Bendamustine and Rituximab in Patients With Untreated Chronic Lymphocytic Leukemia

Zanubrutinib, a potent and specific irreversible Bruton's tyrosine kinase inhibitor, has proven to be effective in untreated chronic lymphocytic leukemia (CLL), whether used alone or in combination with other therapies. Here, we compared the cost-effectiveness of zanubrutinib with bendamustine-rituximab (R-bendamustine) to determine its effectiveness as the first-line treatment for Chinese patients with untreated CLL. The evaluation utilized a partitioned survival model, constructed using TreeAge Pro 2011 software, incorporating data from SEQUOIA trial (NCT03336333). Transition probabilities were estimated from the reported survival probabilities in trials using parametric survival modeling. In this analysis, the quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and lifetime cost were calculated from the Chinese health care system perspective. Sensitivity analyses, including 1-way analysis and probabilistic sensitivity analysis, were carried out to explore the uncertainty of the modeling results. Additionally, several scenario analyses, including different zanubrutinib price calculation and 20-year time horizon, were evaluated. The findings revealed that zanubrutinib had an incremental cost-effectiveness ratio of $58,258.18 per additional QALYs gained compared with bendamustine-rituximab, with zanubrutinib being cost-effective only if its price was reduced by more than 30%. Research indicated that zanubrutinib achieved at least a 3.70% probability of cost-effectiveness at the threshold of $38,223.34/QALY. One-way sensitivity analysis revealed that the results were sensitive to the utility of progressed disease. The study highlighted the importance of considering the cost-effectiveness of zanubrutinib at its current price point for patients with untreated CLL in China, emphasizing the need for further assessment and potential pricing adjustments to enhance its economic viability in clinical practice.

Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Waldenström's Macroglobulinemia in a Single-Arm, Multicenter, Open-Label, Phase 2 Study: Long Term Follow-up Results

Background Orelabrutinib is a novel, small molecule, selective irreversible Bruton tyrosine kinase inhibitor, approved in China for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). The previous publication of this study reported that orelabrutinib is highly active in R/R Waldenström's macroglobulinemia (WM), with a well-tolerated safety profile (EClinicalMedicine. 2022;52:101682). We present here the long-term results of this study. Methods This is a prospective, multicenter study of orelabrutinib in patients with WM who had at least one prior line of treatment (ClinicalTrials NO. : NCT04440059). Orelabrutinib was administered orally at a daily dose of 150 mg until disease progression or unacceptable toxicity. Genotyping using MYD88 L265P and CRCR4 S338X mutation were performed with qPCR assay. The primary endpoint was major response rate (MRR) assessed by the Independent Review Committee (IRC) according to IWWM-6 (Br J Haematol. 2013; 160: 171-176). Results Between August 2019 and December 2020, 66 R/R WM patients were assessed for eligibility. Forty-seven eligible patients were evaluated for efficacy at a median follow-up of 31.9 months (interquartile range: 28.0，36.5). As assessed by IRC, the MRR was 80.9%, and the overall response rate was 91.5%. The PFS rates was estimated as 72.1% at 36 months and the median PFS has not been reached. There is no significant difference in PFS across various MYD88 L265P and CRCR4 S338X genotype (P=0.69; Figure 1). The 30-months PFS rate in MYD88 L265P/CXCR4 NEG, MYD88 L265P/CXCR4 S338X, and MYD88 NEG/CXCR4 NEG were 86.2%, 75% and 75%, respectively. Most adverse events were Grades 1 or 2 (63.8%). The common grade 3 or higher adverse events occurred were neutropenia (10.6%), thrombocytopenia (8.5%), and pneumonia (6.4%). Treatment related serious adverse events were reported in 8.5% patients. Adverse events leading to discontinuation occurred in 4 patients (8.5%). One treatment-related death was reported (hepatitis B reactivation). Conclusions Results with longer follow-up continue to show that orelabrutinib has high, deep and durable response in patients with R/R WM. Data support the safety of long-term orelabrutinib treatment in R/R WM, with no new safety signals identified.

NIR-Actuated Targeted Janus Nanomotors Remodel Immunosuppressive Tumor Microenvironment for Augmented Cancer Immunotherapy.

Tumor-associated macrophages (TAMs) always display immunosuppressive M2 phenotype in the tumor microenvironment to facilitate tumor growth, invasion, and metastasis. Ibrutinib (IBR), a novel irreversible Bruton's tyrosine kinase (BTK) inhibitor, has been employed to repolarize the BTK-overexpressed TAMs from M2 to M1 phenotype to remodel the immunosuppressive tumor microenvironment. However, the poor solubility of IBR extremely hinders its bioavailability, which results in low tumor accumulation and TAMs uptake in vivo. Herein, NIR laser-actuated Janus nanomotors are proposed for the effective and deep delivery of IBR to TAMs in solid tumor for targeted immunotherapy. Under NIR irradiation, the Janus nanomotors exhibit efficient photothermal conversion to produce powerful propulsion via self-thermophoresis with a speed of 12.15µm s-1 . Combined with the salic acid targeting and IBR loading, the nanomotors significantly boost their binding and uptake efficacy by M2-like macrophages during the active motion, which highly facilitate the reprogramming of M2 to M1 macrophages in vitro. Furtherly, the autonomous motion also validly improves in vivo accumulation and penetration depth in tumors to alter the M1/M2 polarization balance and activate T cells. Overall, the synthesized IC@MSA JNMs would provide a promising strategy for the efficient delivery of immunological agents toward targeted cancer immunotherapy.

Preliminary PET imaging of [11C]evobrutinib in mouse models of colorectal cancer, SARS-CoV-2, and lung damage: Radiosynthesis via base-aided palladium-NiXantphos-mediated 11C-carbonylation.

Evobrutinib is a second-generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and lipopolysaccharide (LPS)-induced lung damage. Herein, we report the automated radiosynthesis of [11C]evobrutinib using a base-aided palladium-NiXantphos-mediated 11C-carbonylation reaction. [11C]Evobrutinib was reliably formulated in radiochemical yields of 5.5 ± 1.5% and a molar activity of 34.5 ± 17.3 GBq/μmol (n =12) with 99% radiochemical purity. Ex vivo autoradiography studies showed high specific binding of [11C]evobrutinib in HT-29 colorectal cancer mouse xenograft tissues (51.1 ± 7.1%). However, in vivo PET/computed tomography (CT) imaging with [11C]evobrutinib showed minimal visualization of HT-29 colorectal cancer xenografts and only a slight increase in radioactivity accumulation in the associated time-activity curves. In preliminary PET/CT studies, [11C]evobrutinib failed to visualize either SARS-CoV-2 pseudovirus infection or LPS-induced injury in mouse models. In conclusion, [11C]evobrutinib was successfully synthesized by 11C-carbonylation and based on our preliminary studies does not appear to be a promising BTK-targeted PET radiotracer in the rodent disease models studied herein.

Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi-center, single-arm, open-label, phase 2 study.

Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single-arm, multi-center, open-label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression-free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80); complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3-month median follow-up, the median progression-free survival had not been achieved, while the 30-month progression-free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5-79.6) and 81.3% (95% CI, 70.8-88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy-chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

Efficacy and Safety of Zanubrutinib in Japanese Patients with Mature B-Cell Malignancies

Background/Introduction: Zanubrutinib is a potent, irreversible Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. Zanubrutinib is approved globally for the treatment of B-cell malignancies in adults. Here, we present the efficacy and safety of zanubrutinib assessed in patients with mature B-cell malignancies enrolled in the ongoing, multicenter, open-label phase 1/2 study in Japan (BGB-3111-111; NCT04172246). Methods: In part 1, safety and tolerability of zanubrutinib were evaluated in 6 enrolled patients with mature B-cell malignancies who received zanubrutinib 160 mg orally twice daily. In part 2, the safety and efficacy of zanubrutinib were evaluated in 47 enrolled patients with relapsed/refractory (RR) mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and Waldenström macroglobulinemia (WM). Responses were assessed by investigators based on the Lugano Classification for MCL and SLL, 2018 International Workshop on CLL (iwCLL) guidelines with modification for treatment-related lymphocytosis for CLL, and WM response criteria updated at the 6th International Workshop on WM. Results: As of May 10, 2022, 53 patients have been enrolled (12 RR MCL; 17 CLL/SLL; 21 WM; 2 follicular lymphoma; 1 marginal zone lymphoma). Fourteen (26.4%) patients discontinued treatment (9 progressive disease, 2 adverse event [AE], 2 investigator decision, 1 withdrawal by patient). The median age was 71 years (range, 37-84) and 67.9% were men. RR patients (49.1%) received a median of 2 lines of prior therapy (range, 1-8). The median follow-up time was 14.8 months (range, 1.4-27.3). Forty-eight (90.6%) patients experienced ≥1 treatment-emergent adverse event (TEAE). The most common any-grade AEs are summarized in Table 1. Twenty-two (41.5%) patients experienced grade ≥3 AEs; the most common grade ≥3 AEs were neutrophil count decreased (9.4%), platelet count decreased (9.4%), and neutropenia (5.7%). One patient with RR MCL experienced a fatal TEAE of septic shock. Thirty-five (66%) patients had ≥1 TEAE of special interest, including 21 (39.6%) patients with hemorrhage, 17 (32.1%) with infections, and 11 (20.8%) with thrombocytopenia. The most common grade ≥3 TEAEs of special interest were neutropenia (15.1%), infections (11.3%), hemorrhage (9.4%), and thrombocytopenia (9.4%). Investigator-assessed disease responses are reported from part 2. Among patients with MCL, the overall response rate (ORR) was 81.8%. Among patients with CLL/SLL, the ORR (partial response with lymphocytosis or better) was 92.9% in treatment-naïve (TN) patients and 100% in RR patients. The ORR among patients with WM was 92.3%, including 15.4% very good partial response (VGPR) in TN patients, and 100%, including 66.7% VGPR, in RR patients (Table 2). The median duration of overall response has not been reached for any disease cohort. Conclusion: Preliminary data from this phase 1/2 study demonstrate that zanubrutinib can be an efficacious and safe BTK inhibitor for Japanese patients with RR MCL, CLL/SLL, and WM. Safety and efficacy data are comparable with those observed in published data across ethnic groups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Type II Glycoengineered Humanized Anti-CD20 Monoclonal Antibody MIL62 Combined with Orelabrutinib in Chinese Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: Updated Results of a Multicenter, Phase I/IIa Trial

Background: A novel glycoengineered type II anti-CD20 antibody, MIL62 with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively. Orelabrutinib (ICP-022) is a novel and highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase (ITK) or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combined therapy with anti-CD20 antibodies. Methods: This was a phase I/IIa dose escalation and dose expansion study (NCT 04304040), which investigated MIL62 combination with orelabrutinib for the treatment of patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) with received at least one prior systemic regimen. The dose escalation was conducted with a standard 3+3 dose scheme in different dose combinations of MIL62 injection 800 mg or 1000 mg plus orelabrutinib 100 mg or 150 mg oral daily up to 120 weeks or until disease progression, or intolerable toxicity, respectively. The primary endpoint was objective response rate (ORR), defined as a complete response (CR) or partial response (PR) assessed by investigator per Lugano 2014 criteria. The secondary endpoints were duration of response, pharmacokinetics, and safety. Adverse events (AEs) were graded by CTCAE version 5.0. Results: From July 28th, 2020 to January 26th, 2022, 43 patients enrolled from 10 centers in China received at least one dose of either MIL62 or orelabrutinib. Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) accounted for 72.1% (31), 16.3% (7), 9.3% (4) and 2.3% (1), respectively. Median age was 66.0 (range: 31 to 77) years and 29 (67.5%) patients had ECOG PS score of 1-2. The median number of prior therapies was 2.0 (range: 1 to 7) and 22 (51.2%) patients were primary resistant to rituximab-containing regimens. The median treatment time of MIL62 and orelabrutinib was 4.7 (range: 0.2, 17.5) months and 3.9 (range: 0.2, 14.1) months, respectively. At the cut-off date (July 15th, 2022), the median OS follow-up time was 13.0 (95% confidence interval [95% CI]: 12.2, 15.0) months. Overall, 27 (64.3%) of 42 assessable patients had an objective response, including 13 (31%) with CR and 14 (33.3%) with PR. In addition, among 30 assessable patients with DLBCL, 17 (56.7%) patients had an objective response, including 7 (23.3%) with CR and 10 (33.3%) with PR. The median progression-free survival (PFS), 9-month remission rate and 12-month overall survival rate were 5.8 ([95%CI]: 3.9, Not reached) months, 71.4%, 73.0%, respectively. Especially, in 20 patients with resistance to rituximab, 10 (50%) patients had an objective response, and median PFS was 5.6 months (Table 1). Among 43 safety-evaluable patients, treatment emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) occurred in 39 (90.7%) patients, 38 (88.4%) patients respectively. Grade 3 or above TEAE were observed in 20 (46.5%) patients, among which TRAEs in 16 (37.2%) patients, with neutropenia (20.9%), thrombocytopenia (16.3%). Severe adverse events (SAEs) occurred in 14 (32.6%) patients, among which 11 (25.6%) were TRAEs. 4 (9.3%) patients were permanently stopped the study due to TEAEs. The incidence of MIL62 infusion-related reactions was 11.6%, all of which were grade 1-2. Conclusion: MIL62 combined with orelabrutinib showed promising efficacy in previously treated patients with r/r DLBCL, including those with resistance to rituximab, and has a manageable safety profile. Keywords: MIL62; type II anti-CD20 monoclonal antibody; r/r B-NHL; DLBCL; Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of orelabrutinib monotherapy in patients with relapsed or refractory Waldenström's macroglobulinemia in a single-arm, multicenter, open-label, phase 2 study.

SummaryBackgroundOrelabrutinib is a novel, small molecule, selective irreversible Bruton tyrosine kinase inhibitor. The purpose of this study was to evaluate the efficacy and safety of orelabrutinib in patients with relapsed or refractory Waldenström's macroglobulinemia (R/R WM).MethodsThis is a prospective, multicenter study of orelabrutinib in patients with WM who had at least one prior line of treatment. Orelabrutinib was administered orally at a daily dose of 150 mg until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR) assessed by the Independent Review Committee (IRC) according to IWWM-6. This study is registered with ClinicalTrials.gov, NCT04440059. This trial was also registered on Center for Drug Evaluation (www.chinadrugtrials.org.cn) in March 2019, with a number of CTR2019036.FindingsBetween August 2019 and December 2020, 66 R/R WM patients were assessed for eligibility. Forty-seven eligible patients were evaluated for efficacy at a median follow-up of 16.4 months (interquartile range: 12.5, 19.5). As assessed by IRC, the MRR was 80.9%, and the overall response rate was 89.4%. The median time to at least a minor response was 1.9 months. The PFS rates was 89.4% at 12 months. For patients with MYD88L265P/CXCR4NEG, MYD88L265P/CXCR4S338X, and MYD88NEG/CXCR4NEG mutations, the MRRs were 84.6%, 100%, and 25.0%. Most adverse events were Grades 1 or 2 (91.0%). The common grade 3 or higher adverse events occurring were neutropenia (10.6%), thrombocytopenia (6.4%), and pneumonia (4.3%). Serious adverse events (SAE) occurred in 10 patients (21.3%). One treatment-related death was reported (hepatitis B reactivation).InterpretationOrelabrutinib has shown good efficacy and manageable safety profiles in patients with R/R WM.FundingInnoCare Pharma.

Perioperative Bleeding Associated With Ibrutinib in Dermatologic Surgery: A Case-Control Study.

Ibrutinib, an irreversible Bruton tyrosine kinase inhibitor, has been associated with an increased risk of bleeding. There is a paucity of data on the risk of bleeding in patients on ibrutinib undergoing dermatologic surgery. To determine the frequency of bleeding complications associated with ibrutinib in patients undergoing dermatologic surgery. A retrospective, single-center, case-control study of patients on ibrutinib undergoing skin surgery between January 2013 and March 2020 compared with sex, disease, and age-matched control patients undergoing cutaneous surgeries. A total of 75 surgeries performed on 37 case patients and 116 surgeries performed on 64 control patients were included. Ibrutinib was associated with a statistically significant increased rate of bleeding events (6/75 [8%] vs 1/116 [0.8%], p -value = .02). Compared with ibrutinib patients who did not have a bleeding event, those on ibrutinib who suffered bleeding were all men, older (mean age 82.7 vs 73.0, p -value= .01), and had lower mean platelet counts (104.0 vs 150.5 K/μL, p -value = .03). Ibrutinib may be associated with increased risk of bleeding in patients with hematologic malignancies, particularly older men with lower platelet levels and on multiple anticoagulants. Transient discontinuation of ibrutinib should be considered for dermatologic surgeries.

Pyrazolo[3,4‐d]pyrimidine derivatives as irreversible Bruton's tyrosine kinase inhibitors

Abstract4,6‐Disubstituted pyrazolo[3,4‐d]pyrimidine derivatives were explored as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The structure–activity relationship was established with over 20 derivatives synthesized to determine initial hit compounds, based on activities against BTK enzyme and TMD8 cells. It turned out that introducing 1‐acrylamido‐4‐aminopiperdine (1b) at the C4 position of pyrazolopyrimidine as in 5e, and 3‐acrylamido‐aniline (1j) as 4‐position substituent, such as in 9d, 10d, and 10e, delivered potent in vitro enzyme activities as well as TMD8 cell‐based cytotoxicities. Considering kinase selectivity profiles, 5e was selected for in vivo efficacy studies with a murine xenograft model using TMD8 cells, where 5e exhibited moderate tumor growth inhibition activities. Further optimization of 5e and 9d may lead to clinically useful compounds to overcome B‐cell‐mediated hematologic cancers.

BTK-inhibitor drug covalent binding to lysine in human serum albumin using LC-MS/MS

Irreversible Bruton's tyrosine kinase (BTK) inhibitor drugs are designed to bind covalently to a free-thiol cysteine in the BTK protein active site. However, these reactive drugs bind to off-target proteins as well. In this study, seven BTK-inhibitor drugs containing acrylamide warheads were incubated with human serum albumin (HSA) and analyzed using an LC-MS/MS peptide mapping approach to determine the amino acid sites of drug covalent binding. Significant adduction at the free-thiol cysteine of HSA was only observed for two of the drugs. However, significant adduction was observed for at least four lysine residues. This is just a small percentage of the 59 total lysine residues in HSA. These four lysine residues are likely partially buried, accessible to the drugs, and exist at least partially in a neutral state. The levels of adduction observed in the in-vitro experimental conditions are only indicative of a relative propensity for adduction with the individual lysine residues of HSA, and are not in-vivo predictions. Widespread off-target lysine binding could impact clearance and bioavailability for irreversible inhibitor drugs. However, the extent of the impact on clearance may be limited in comparison to conjugation with glutathione.

Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Updated Long Term Results of Phase II Study

IntroductionOrelabrutinib is a novel and highly selective irreversible Bruton tyrosine kinase (BTK) inhibitor approved in China for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We previously reported that orelabrutinib had high bioavailability with ~100% BTK occupancy at 24 hours at 150 mg daily dosing regimen and had demonstrated excellent safety and efficacy profiles in a phase II trial of R/R CLL/SLL. Here we present the long-term result of this study.MethodsThis is an open-label, multicenter, phase II study to evaluate the safety and efficacy following 150 mg oral daily administration of orelabrutinib (NCT03493217). Responses were assessed per 2008 IWCLL criteria with modification for PR with lymphocytosis (PR-L) (Hallek 2008, Cheson 2012) or the Lugano Classification (Cheson 2014) for CLL and SLL, respectively.ResultsA total of 80 patients with R/R CLL/SLL were enrolled. All patients received ≥1 prior treatment with median age of 60.0 years. 70% of patients had Rai stage III-IV disease, 22.5% had del(17p) and/or TP53 mutation, 41.3% had unmutated immunoglobulin heavy chain variable region (IGHV) and 23.8% had del(11q). The median follow-up time was 31. 2 months, with 68.8% remaining on study treatment.The overall response rate (ORR) was 93.8 % (95% CI: 86.01 ~ 97.94%) with 23.8% complete response (CR), 2.5% incomplete marrow recovery (CRi), 56.3% partial response (PR) and 11.3% PR with lymphocytosis (PR-L) by investigators assessed. Median time for achieving first response was 1.84 months. The median duration of response (DOR) and progression-free survival (PFS) were not reached. The estimated 30-month DOR was 70.6%, 30-month PFS was 70.9 % by investigator assessed. The overall response rate was generally consistent across all subgroups analyzed, including those with unfavorable prognostic factors. Comparing to the previous CR/CRi rate of 8.8% reported at median follow up of 14.3 months, the updated CR/CRi rate had achieved 26.3%. Orelabrutinib showed a significant higher CR/CRi rate in R/R CLL/SLL in comparison with other BTK inhibitors at a similar median follow-up period.Extended follow-up demonstrates no emerging safety concerns. Similar to the previous reported safety results (Xu W 2020), most adverse events (AEs) were mild to moderate. The most frequent AEs (>30% of any grade) were neutropenia, thrombocytopenia, upper respiratory tract infection and urine red blood cells positive. No case of atrial fibrillation nor secondary malignancy was reported, no patient experienced ≥3 grade hypertension and only one patient had ≥3 grade diarrhea. Major hemorrhage was reported in 2 patients, one with intracranial hemorrhage (65-year old patient with >10 years hypertension) and the other with vitreous hemorrhage which was assessed as unlikely related to the treatment of orelabrutinib. There were 2 patients (2.5%) and 5 patients (6.3%) reported treatment related AEs leading to treatment discontinuation or dose reduction, respectively.ConclusionsThis updated study result further confirms that orelabrutinib is efficacious in treating R/R CLL patients with significant higher CR rate than other BTK inhibitors, durable response and improved safety profiles. Orelabrutinib provides a favorable therapeutic choice for patients with R/R CLL/SLL and has great potential to be the best candidate for the combination therapy. DisclosuresHu: Astellas Pharma, Inc.: Research Funding. Zhang: Innocare pharma: Current Employment. Zhao: Innocare pharma: Current Employment.

Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1–2 study

Patients with chronic lymphocytic leukaemia who progress to Richter transformation (diffuse large B-cell lymphoma morphology) have few therapeutic options. We analysed data from the Richter transformation cohort of a larger, ongoing, phase 1-2, single-arm study evaluating the safety and activity of the selective, irreversible Bruton's tyrosine kinase inhibitor acalabrutinib for the treatment of chronic lymphocytic leukaemia or small lymphocytic lymphoma. For this open-label, single-arm, phase 1-2 study, patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) were assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. Patients were enrolled across seven centres from four countries. Safety and pharmacokinetics were assessed as primary endpoints; secondary endpoints were overall response rate, duration of response, and progression-free survival. Safety was assessed in the all-treated population (patients who received ≥1 dose), and activity was assessed in the all-treated population (for progression-free survival) and efficacy-evaluable population (for response rate; patients in the all-treated population with ≥1 response assessment after the first dose). This trial is registered with ClinicalTrials.gov (NCT02029443). Between Sept 2, 2014, and April 25, 2016, 25 patients with Richter transformation were enrolled; 12 (48%) were male and 23 (92%) were White. As of data cutoff (March 1, 2021), two (8%) of 25 patients remained on acalabrutinib. The median time on study was 2·6 months (IQR 1·8-8·4). The most common adverse events (all grades) were diarrhoea (12 [48%] of 25 patients), headache (11 [44%]), and anaemia (eight [32%]). The most common grade 3-4 adverse events were neutropenia (seven [28%] of 25) and anaemia (five [20%]). The most common reason for treatment discontinuation was disease progression (17 [68%] of 25 patients). 11 (44%) deaths were reported within 30 days of the last acalabrutinib dose; none was considered treatment-related. Acalabrutinib was rapidly absorbed and eliminated, with similar day 1 and day 8 exposures. The overall response rate was 40·0% (95% CI 21·1-61·3), with two (8%) of 25 patients having a complete response and eight (32%) having a partial response; the median duration of response was 6·2 months (95% CI 0·3-14·8). Median progression-free survival in the overall cohort was 3·2 months (95% CI 1·8-4·0). Acalabrutinib appears to be generally well tolerated, although progression-free survival was relatively poor in this cohort of patients with Richter transformation. On the basis of these findings, the use of acalabrutinib monotherapy in this setting is limited; however, further assessment of acalabrutinib as part of combination-based regimens for patients with Richter transformation is warranted. Acerta Pharma, a member of the AstraZeneca Group.

Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function.

All irreversible Bruton tyrosine kinase (Btk) inhibitors including ibrutinib and acalabrutinib induce platelet dysfunction and increased bleeding risk. New reversible Btk inhibitors were developed, like MK‐1026. The mechanism underlying increased bleeding tendency with Btk inhibitors remains unclear. We investigated the effects of ibrutinib, acalabrutinib and MK‐1026 on platelet function in healthy volunteers, patients and Btk‐deficient mice, together with off‐target effects on tyrosine kinase phosphorylation. All inhibitors suppressed GPVI‐ and CLEC‐2‐mediated platelet aggregation, activation and secretion in a dose‐dependent manner. Only ibrutinib inhibited thrombus formation on vWF‐co‐coated surfaces, while on collagen this was not affected. In blood from Btk‐deficient mice, collagen‐induced thrombus formation under flow was reduced, but preincubation with either inhibitor was without additional effects. MK‐1026 showed less off‐target effects upon GPVI‐induced TK phosphorylation as compared to ibrutinib and acalabrutinib. In ibrutinib‐treated patients, GPVI‐stimulated platelet activation, and adhesion on vWF‐co‐coated surfaces were inhibited, while CLEC‐2 stimulation induced variable responses. The dual inhibition of GPVI and CLEC‐2 signalling by Btk inhibitors might account for the increased bleeding tendency, with ibrutinib causing more high‐grade bleedings due to additional inhibition of platelet‐vWF interaction. As MK‐1026 showed less off‐target effects and only affected activation of isolated platelets, it might be promising for future treatment.

Abstract 1267: Combination therapy of JNJ-67856633, a novel, first-in-class MALT1 protease inhibitor, and JNJ-64264681, a novel BTK inhibitor, for the treatment of B-cell lymphomas

Abstract Background: Constitutive activation of the classical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway is a clear driver of B-cell non-Hodgkin lymphomas (NHL). Bruton's Tyrosine Kinase (BTK) and Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which lies downstream of BTK, are key mediators of the classical NF-κB signaling pathway activated by BCR and TCR receptors. JNJ-67856633 is a first-in-class MALT1 protease inhibitor. JNJ-64264681 is a BTK inhibitor with improved selectivity against BTK. Blocking the BCR pathway at multiple points using these two orally bioavailable compounds could enhance clinical activity in B-cell lymphoma patients. Methods: JNJ-67856633 and JNJ-64264681 are currently being evaluated in phase 1 clinical trials designed to establish safety, PK, PD and the Recommended Phase 2 Dose (RP2D) of each agent. Results: JNJ-67856633 is a potent, selective, orally bioavailable, allosteric inhibitor of MALT1 protease activity. The compound inhibits proliferation of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines bearing CD79b or CARD11 mutations as well as models mimicking resistance to covalent BTK inhibitors. JNJ-67856633 exhibits potent tumor growth inhibition in two human DLBCL xenograft models, OCI-Ly3 and OCI-Ly10, and mutation selected patient derived DLBCL xenografts. Furthermore, treatment with JNJ-67856633 leads to dose dependent inhibition of the generation of Tregs (CD4+CD25+FoxP3+) following CD3/28 stimulation in vitro, suggesting a potential immune modulatory role of MALT1 inhibition. JNJ-64264681 is an orally active small molecule that is a potent, selective, and irreversible covalent BTK inhibitor. JNJ-64264681 inhibits the growth of CD79b-mutant DLBCL cell lines in vitro and potently inhibits tumor growth in xenograft- or patient-derived DLBCL models in vivo. Treatment with JNJ-64264681 and JNJ-67856633 administered together demonstrated statistically significant tumor growth inhibition compared with vehicle control in two CD79b mutant mouse lymphoma models, one based on a DLBCL cell line (OCI-Ly10) and one based on a patient-derived DLBCL model (LY2298). In both models, the combination showed increased growth inhibition compared with single agents and tumor regression in the combination arm. Synergistic anti-proliferative activity was observed in three DLBCL cell lines carrying CD79b mutations and one MCL cell line. Conclusions: Taken together, the in vitro and in vivo data for JNJ-67856633 and JNJ-64264681 suggest that combination therapy can increase the anti-tumor effect of the monotherapies and provide a more sustained response, offering strong support for clinical investigation of the combination of these two novel agents. A phase 1b combination study is scheduled to initiate. Citation Format: Ulrike Philippar, Lorena Fontan, Ivo Cornelissen, Haopeng Rui, Sriram Balasubramanian, Marcello Gaudiano, Mariette Bekkers, Luc Van Nuffel, Tianbao Lu, Tianbao Lu, John Wiener, Mark Tichenor, Tony Greway, Kathryn Packman, Bie Verbist, Yusri Elsayed, Ricardo Attar, Jacqueline Bussolari, John Gerecitano. Combination therapy of JNJ-67856633, a novel, first-in-class MALT1 protease inhibitor, and JNJ-64264681, a novel BTK inhibitor, for the treatment of B-cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1267.

Dissection of Clonal Evolution By Temporal Mutation Profiling in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib

Introduction: The irreversible Bruton tyrosine kinase (BTK) inhibitor ibrutinib is changing the paradigm of the treatment of chronic lymphocytic leukemia (CLL) with remarkable outcomes in first line as well as in relapsed CLL, including high risk patients with TP53 aberration. While the majority of patients demonstrate durable responses, with a median follow up of 3 years, approximately 18% of them develop resistance and relapse. Mutations in the BTK and PLCG2 genes emerged as predominant mechanisms conferring secondary ibrutinib resistance with BTK and/or PLCG2 mutations detected in the majority of resistant patients, often even 10 months before the clinical relapse. Given the very poor outcome of patients discontinuing ibrutinib, comprehensive understanding of the mechanisms of ibrutinib resistance and changes in the clonal architecture induced by the selective pressure of the drug are of major clinical importance. To dissect the clonal evolution in the context of all relevant mutation targets in CLL, we performed a temporal mutation profiling of 31 genes in paired pre- and post-treatment samples of patients receiving ibrutinib therapy.Methods: Sequential samples from 18 patients treated with single-agent ibrutinib were included in this study. Pre-treatment peripheral blood samples were available in all patients, with post-treatment samples at 18 months for 6 patients, at 12 months for 7 patients, at 8 months for 3 patients and at 3 months for 2 patients, with a median follow up of 12 months. Targeted deep NGS analysis of 31 recurrently mutated target genes, including ATM, BCOR, BIRC3, BRAF, BTK, CHD2, DDX3X, EGR2, EIF2A, EP300, FBXW7, HIST1H1E, IGLL5, KLHL6, KMT2D, LRP1B, MAPK1, MED12, MGA, MYD88, NFKBIE, NOTCH1, PLCG2, POT1, RIPK1, RPS15, SAMHD1, SF3B1, TP53, XPO1 and ZMYM3 was performed using the TruSeq Custom Amplicon approach (Illumina) on genomic DNA specimens extracted from peripheral blood mononuclear cells. Variant calling was performed using the VariantStudio3.0 application (Illumina) and only variants supported with more than 100 mutant reads were considered. Our cohort represented a heavily pretreated patient group with a median of 2.5 (range: 1-5) lines of prior therapies.Results: The ultra-deep NGS analysis revealed a total of 473 somatic mutations in the 18 paired samples with a median allelic depth of 25.550x across the 31 genes analyzed. The post-treatment samples carried a considerably higher number of mutations compared to the pre-treatment samples (114 vs 359 mutations) with more than half of the variants representing subclonal alterations with variant allele frequencies (VAF) of <10%. The most frequently mutated genes at baseline included TP53 (50%) , NOTCH1 (50%) and POT1 (28%) with similarly high mutation frequencies in the post-treatment samples. MYD88, BIRC3 and SF3B1 mutations were enriched in the post-ibrutinib samples with mutation frequencies of 11% vs 33%, 11% vs 39% and 11% vs 50%, respectively. Interestingly, XPO1 mutations emerged only in the post-treatment samples of five (28%) patients. As for the BTK and PLCG2 mutations, none of the pre-treatment samples carried a mutation in either of these genes, however, we detected emerging subclonal BTK and PLCG2 mutations (with VAFs between 1.5% and 11%) in 28% (5/18) and 33% (6/18) of the post-treatment samples, respectively. A subset of cases harbored multiple mutations in both genes with some of these representing novel BTK and PLCG2 mutations affecting previously unreported amino acid residues. Scrutiny of the clonal evolution revealed that all individual cases were characterized by almost unique combinations of mutations as well as patterns of emerging and disappearing mutant subclones upon the selective pressure of ibrutinib.Conclusions: The ultra-deep NGS analysis performed on paired samples of CLL patients treated with ibrutinib provided a significant insight into the mutational repertoire as well as subclonal dynamics of the leukemic compartment. Furthermore, it has revealed a profound subclonal heterogeneity that seems to be further enhanced by ibrutinib therapy, as demonstrated by a higher frequency of subclonal variants in the post-treatment samples. The clinical significance and the potential role of the novel BTK and PLCG2 variants identified in our study will require a longer follow up time, as currently all patients harboring these subclonal variants are still on ibrutinib therapy. DisclosuresNo relevant conflicts of interest to declare.

Disease Progression on Ibrutinib Therapy Is Associated with a Poor Clinical Outcome in Chronic Lymphocytic Leukemia (CLL) Patients Managed in Standard Clinical Practice

Introduction: Ibrutinib is an irreversible Bruton Tyrosine Kinase (BTK) inhibitor that has shown efficacy in the treatment of CLL as a front-line therapy or in patients with relapse/refractory (RR) disease. Anecdotally, accelerated disease progression and refractoriness to subsequent therapies in CLL or other B-cell malignancies patients treated with ibrutinib has been observed. In our present contribution, we studied in a real-world patient population the clinical outcome of CLL patients treated with ibrutinib who discontinued therapy. Methods: We conducted a comprehensive retrospective analysis on CLL patients receiving ibrutinib at our Institute. Demographic characteristics, response to subsequent therapies, and results of FISH analysis were obtained. Correlation between clinical outcomes and status on ibrutinib therapy (responding, progressing, or discontinuing due to toxicity) was performed. Statistical analysis was carried out in SPSS v20. Chi Square, Fisher's exact test were used to compare categorical data, Kaplan Meier and Log rank tests for time to event analysis and Cox regression for univariate analysis. Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 19.4 mo [ range 0.3 - 41.3]. Sixty-three patients had RR CLL and 7 received ibrutinib as frontline therapy. Our patients had a median age of 67.9 years (46 - 92), a majority had advanced stage disease (Rai stage 3 - 31.4%, Rai stage 4 - 41.4%). Median number of prior treatments was 2 (range 0-7). Overall response rate (ORR) to ibrutinib was 52.8% (complete response [CR] - 11.4%, partial response [PR] - 41.4%]. Additionally, stable disease [SD] was present in 25.7% leading to a Clinical Benefit Rate (CBR) of 78.5%. A total of 25 (38%) patients discontinued therapy. Reasons for discontinuation included progressive disease (PD) in 13 (52%) (5 with Richter's transformation [RT]), drug toxicity (DT) in 7 (28%), and other reasons in 5 (20%) patients. DTs included atrial fibrillation (n=2), sepsis (n=2), pneumonia (n=1), congestive heart failure (n=1) and fatigue (n=1). Other reasons for discontinuation were other terminal cancer (n=2), patient preference, alcoholism and insurance issues. Univariate analysis showed an increased risk of discontinuation associated with del(13q) (HR 1.56, 95%CI 0.7-3.7, p=0 .32), ATM deletion (HR 1.32, 95%CI 0.5-3.4, p=0 .57), Unmutated IgH (HR 3.5, 0.5-27.3, p=0 .23) though none reached statistical significance. We did not observe an increased risk of discontinuation in patients with del(17p) (HR 0.80, 95%CI 0.3-2.7, p=0 .72). Cytogenetic data after ibrutinib discontinuation was available in 12 patients and showed new onset del(13q) (n= 3), del(17p) (n= 4) and ATM deletion (n= 1) including 1 patient who had complex cytogenetics (≥3 cytogenetic abnormalities). In patients who discontinued therapy, we observed a mortality rate of 72% (18/25) with a median overall survival (OS) of 17.8 mo (95% CI, 7.4-28.2); in comparison, median OS was not reached in patients who remained on therapy (p <0.05). A lower median OS was observed in patients who discontinued due to DT (5.9 mo, 95% CI, 3.9-8), compared to those with RT (11.5 mo, 95% CI 3.1-20), PD (18.2 mo, 95%CI 3.8-32.6) though this was not statistically significant (p= 0.117). Despite trends towards lower median OS in patients who discontinue ibrutinib, univariate analysis did not show a statistically significant association with del(13q) (HR 1.8, 95%CI 0.7-5, p=0 .248), ATM deletion (HR 1.32, 95%CI 0.5-3.9, p=0 .61), Unmutated IGH (HR 1.08, 95%CI 0.13-9, p=0 .94), and ZAP70+ (HR 1.15, 95%CI 0.36-3.64, p=0 .81). Two patients had complex cytogenetics with a median OS of 1.5 mo (HR 4.5, 95%CI 0 .9-22.4, p <0.05). Thirteen patients received subsequent therapy after ibrutinib discontinuation with idelalisib (n=3), lenalidomide (n=3), rituximab with bendamustine (n=2), R-CHOP (n=2), or other treatments (n=3). ORR to post ibrutinib therapy was 23.1% with CR in 3/13 patients (reason for discontinuation- RT - 1, other reasons- 2). Two patients had SD (both discontinued Ibrutinib for PD) leading to a CBR of 38.5%. Eight of 13 patients had PD and died during follow up period. Conclusion: Ibrutinib has good efficacy in the treatment of CLL as front-line therapy and in relapse refractory disease in a real-world setting. However, patients who discontinue therapy have poor survival outcomes and poor response to salvage therapy. DisclosuresNo relevant conflicts of interest to declare.

Safety and Activity of the Highly Specific BTK Inhibitor BGB-3111 in Combination with the PD-1 Inhibitor BGB-A317 in Patients with B-Cell Lymphoid Malignancies

IntroductionBGB-3111 is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity for BTK vs other TEC- and EGFR-family kinases, and demonstrates favorable pharmacokinetic and pharmacodynamics properties (Tam et al. ASH 2016). BGB-A317, a humanized IgG4 variant monoclonal antibody with no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor and is being developed for the treatment of solid and hematologic malignancies (Friedlander, ASCO, 2017). The combination of PD-1/PD-L1 inhibitors with B-cell receptor pathway inhibitors is being evaluated in different B-cell malignancies with the expectation of greater benefit for patients. Here, we present early safety data from a Phase 1b trial exploring the combination of BGB-3111 and BGB-A317.MethodsThis is an open-label, multicenter, phase 1b study to evaluate safety, tolerability, and preliminary efficacy of BGB-3111 in combination with BGB-A317 in subjects with B-cell malignancies, including Waldenström's macroglobulinemia (WM), aggressive and indolent non-Hodgkin's lymphoma, and transformed chronic lymphocytic leukemia/follicular lymphoma (FL) amongst other B-cell malignancies. The study includes a standard 3+3 dose escalation phase followed by dose expansion. The dose levels are: Cohort 1, BGB-3111 320 mg once a day (QD) combined with BGB-A317 2.0 mg/kg every 3 weeks (Q3W); Cohort 2, BGB-3111 320 mg QD combined with BGB-A317 5.0 mg/kg Q3W; and Cohort 3, BGB-3111 160 mg BID combined with BGB-A317 200 mg (flat dose) Q3W.ResultsAs of 01 June 2017, 25 pts were enrolled in the dose escalation portion of the trial: 15 pts in Cohort 1 and 10 pts in Cohort 2. Key patient characteristics, safety, and efficacy are shown in the Table.Safety: Median follow - up was 2.8 (range, 0.4-10.7) months. There were no dose-limiting toxicities (DLTs) in Cohort 1. Cohort 2 saw hemolysis in 2 pts, both with WM; one qualified as a DLT. These events were not associated with a positive direct antiglobulin test and resolved with immunosuppressive therapy, but resulted in the decision to exclude further enrollment of WM pts in the trial. No further DLTs were observed after exclusion of WM pts.The most frequent adverse events (AEs) of any cause in Cohort 1 were diarrhea (n=4, 26.7%), fatigue (n=4, 26.7%), and pyrexia (n=3, 20%) and in Cohort 2 were contusion (n=3, 30%), anemia, hemolysis, headache, peripheral edema, thrombocytopenia, and upper respiratory tract infection (n=2, 20% each). Frequent AEs ≥ Grade 3 from both Cohorts included anemia (n=32, 12%), and thrombocytopenia and hemolytic transfusion reaction (n=2, 8% each).Serious AEs related to study treatment were seen in 8 patients: hemolysis (n=2), pneumonitis, infusion-related reaction, abscess limb, pneumonia, anemia, ulcerative keratitis, catheter site hemorrhage, autoimmune encephalitis, dyspnea, and eczema (n=1 each). The encephalitis could not be attributed to other causes and resolved with immunosuppressive therapy. No serious hemorrhages or atrial fibrillation have been reported to date.Discontinuation due to AEs occurred in six patients for the following AEs: hemolysis (n=2), nausea, lymph gland infection, ALT increased and GGT increased (same patient), auto-immune encephalitis, and progression-related complications (n=1 each).Efficacy: Efficacy data is very early with limited follow-up and most pts treated at the lowest dose. So far, 30% of pts have responded, including responses in both WM pts as well as complete responses seen in FL and non-GCB DLBCL pts.ConclusionsThe combination of BGB-3111 and BGB-A317 has a manageable toxicity profile in a wide variety of B-cell malignancies. Autoimmune adverse events, consistent with anti-PD-1 therapy, were observed and managed with supportive care. Notably, hemolysis in 2 WM patients suggestlimitations of this combination in indolent lymphoid diseases such as WM, especially given the risk/ benefit profile of single-agent BGB-3111 in indolent settings .Enrollment is now open for Cohort 3, which will be followed by expansion cohorts to further characterize safety and efficacy of the combination. [Display omitted] DisclosuresCull:Amgen Australia: Other: travel expenses Lugano lymphoma conference 2017; Takeda Australia: Other: travel expenses Highlights of ASH march 2017, Brisbane. Opat:Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Beigene: Research Funding; Mundipharma: Consultancy; Amgen: Research Funding. Trotman:Janssen Cilag: Other: Funding facilitating research paid to third party (BioGrid Australia), Research Funding. Hilger:BeiGene: Employment. Zhang:BeiGene: Employment. Feng:BeiGene: Employment. Ro:BeiGene: Employment. Huang:BeiGene: Employment. Tam:Abbvie: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

Phase II/1b Trial of Ibrutinib Plus Prednisone and Rituximab Induction Followed By Venetoclax Plus Ibrutinib Maintenance in Newly Diagnosed High-Risk Chronic Lymphocytic Leukemia

Introduction: Therapy options for chronic lymphocytic leukemia (CLL) are rapidly changing with the approval of ibrutinib, an irreversible Bruton's tyrosine kinase inhibitor, and venetoclax, a Bcl2 inhibitor. In the RESONATE studies, ibrutinib showed significant improvements in overall response rates (ORR), progression-free-survival (PFS), and overall survival (OS). Nonetheless, complete response (CR) rates were only about 4%.During the first few weeks of treatment, ibrutinib will mobilize CLL cells from tissue sites into peripheral blood. Rituximab, a chimeric monoclonal CD20 antibody, when used with ibrutinib, has shown to immediately clear CLL from the blood with durable responses but with CR's of only 8%.Venetoclax is approved for relapsed or refractory CLL with 17p deletion. In a phase 2 study, at a median follow-up of 12.1 months, the ORR was ~79%, but with only 16% CR's. Amongst the 45 patients of whom minimal residual disease (MRD) was assessed, 24 were negative for MRD.In vitro studies have shown that nurse-like cells (NLCs) will protect CLL cells against spontaneous apoptosis by producing chemokines and interleukins such as SDF1, suggestive of a mechanism of ibrutinib resistance. SDF1 was shown to bind to its receptor CXCR4 located on CLL cells and activate a signal transduction pathway that would reduce spontaneous apoptosis. Dexamethasone was found to decrease NLC viability. This suggests that a combined therapy of ibrutinib plus steroids along with rituximab and venetoclax may be necessary to achieve deeper CR's in high-risk CLL.In addition, CLL with overexpression of exosome miR-155 is associated with a poor response to chemoimmunotherapy. In prior preclinical studies, exosome miR-150 and miR-155 have been shown to increase with BCR activation via α-IgM stimulation. We hope that via next generation microRNA sequencing from our patients' CLL plasma cells we will observe a decrease in the levels of exosome miR-150 and miR-155 in response to inhibition of BCR-pathway by ibrutinib as seen in preclinical studies.Methods: Patients with newly diagnosed high-risk CLL per FISH studies will be enrolled. Ibrutinib will be administered orally 420 mg daily, rituximab will be dosed at 375 mg/m2 intravenously on days 1, 8, 15, 22 of cycle 1 and on day 1 for cycle 2-6. Prednisone will be administered as 10 mg one week on, one week off per cycle. Each cycle will last 28 days. After 6 cycles, if patients have MRD, venetoclax will be added in on a weekly schedule with weekly ramp up from 20mg to 50mg, 100mg, and 200mg for a total duration of 6 months plus ibrutinib at 420mg as maintenance until disease progression or drug intolerance. There is the option to reintroduce venetoclax, prednisone, or rituximab if patients progress during maintenance.Results: The primary objectives of this study are to evaluate safety and MRD negative CR rates based on IWG-CLL criteria. For the evaluation of safety, the proportions of the 29 subjects with any adverse events, each specific adverse event, and study-related adverse events will be reported along with the 95% confidence intervals. The proportion of the 29 subjects who demonstrate a MRD negative CR will be reported along with the 95% confidence interval. A sample size of 29 will produce a two-sided 95% confidence interval with a width≤ 0.380.In addition, Kaplan-Meier method will be performed to evaluate time to first MRD negativity (TTMN), time to first relapse (TTFR), PFS and OS, respectively. Based on the Kaplan-Meier curve, the median time to TTMN, TTFR, PFS and OS, respectively, will be reported along with the 95% confidence interval if it exists. Correlation coefficients will be derived to describe the relationship between continuous endpoints and Kendall's tau will be derived to describe the relationship between categorical endpoints.There is no planned interim analysis for the CR rate. However, at any time point if an excessive number of adverse events are observed, the study will be terminated.Conclusion: In this Phase IB/II clinical trial, we seek to observe prolonged response rates of ibrutinib via inhibiting NLC's by adding prednisone. Also, we anticipate that rituximab will further amplify the CR's. For maintenance therapy, we hope that by combining venetoclax with ibrutinib in high-risk CLL patients who were unable to achieve negative MRD's, we will be able to induce deeper remissions. [Display omitted] DisclosuresPersky:Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.

ESCALADE: A phase 3 study of acalabrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for patients ≤65y with untreated non-germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).

TPS7572 Background: R-CHOP remains the standard of care for DLBCL. Although most patients (pts) can be cured, 35–40% will experience relapsed/refractory disease, leading to poor outcomes in the majority of pts. Covalent irreversible Bruton tyrosine kinase inhibitors (BTKi) have shown higher responses in pts with non-GCB DLBCL than with GCB DLBCL. In untreated non-GCB DLBCL pts, the phase 3 PHOENIX study (Younes et al. J Clin Oncol. 2019;37:1285-95) showed that addition of the BTKi ibrutinib to R-CHOP (R-CHOP-I) did not improve outcomes in the intent-to-treat population. However, pts age &lt; 60y treated with R-CHOP-I had significantly improved progression-free survival (PFS) and overall survival (OS) compared with those receiving R-CHOP alone. Acalabrutinib (A) is a second-generation BTKi with enhanced kinase selectivity and potential for better efficacy and tolerability than first-generation BTKis. There is a strong rationale for combining A with R-CHOP in pts with untreated DLBCL, and safety of A + R-CHOP has been shown in a phase 1b/2 study (Davies et al. ASH 2020). The aim of this study is to determine if the addition of A to R-CHOP leads to improved PFS in pts age ≤65y with untreated non-GCB DLBCL. Methods: ESCALADE (ACE-LY-312; NCT04529772) is a phase 3, randomized, global, double-blind study of A vs placebo in combination with R-CHOP for treatment of newly diagnosed non-GCB DLBCL. The study is recruiting adults ≥18y and ≤65y with previously untreated DLBCL stage II–IV disease with a Revised International Prognostic Index (R-IPI) score of 2–5. Prior to randomization, all pts will receive an initial R-CHOP cycle (cycle 1) as standard-of-care treatment to prevent delays in therapy initiation. Based on central Gene Expression Profile (GEP) testing performed after enrollment, pts with non-GCB DLBCL (activated B-cell like or unclassified) will be randomized into 2 arms to receive A 100 mg twice daily plus R-CHOP or placebo plus R-CHOP from cycle 2 to cycle 6 followed by 2 additional cycles of rituximab + A or placebo (cycles 7 and 8). All pts will receive primary prophylaxis with granulocyte colony-stimulating factors accompanying all R-CHOP cycles. The study aims to randomize 600 pts (̃300 per arm). The primary objective is to evaluate whether the addition of A to R-CHOP will prolong PFS. Secondary endpoints include event-free survival, complete response rate, OS, pharmacokinetics, and safety. Key exclusion criteria are central nervous system involvement, primary mediastinal lymphoma, high-grade B-cell lymphoma, diagnosis or treatment of malignancy other than DLBCL, and history of indolent lymphoma. Approximately 250 sites globally will enroll pts. Enrollment began in Q3 of 2020. Clinical trial information: NCT04529772.