Treatment Of Mantle Cell Lymphoma Research Articles

Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s lymphoma characterized by poor prognosis. The complexity of MCL pathogenesis arises from aberrant activities of diverse signaling pathways, including BTK, PI3K–AKT–mTOR and MYC-BRD4. Here, we report that MCL-related signaling pathways can be altered by a single small molecule inhibitor, SRX3305. Binding and kinase activities along with resonance changes in NMR experiments reveal that SRX3305 targets both bromodomains of BRD4 and is highly potent in inhibition of the PI3K isoforms α, γ and δ, as well as BTK and the drug-resistant BTK mutant. Preclinical investigations herein reveal that SRX3305 perturbs the cell cycle, promotes apoptosis in MCL cell lines and shows dose dependent anti-proliferative activity in both MCL and drug-resistant MCL cells. Our findings underscore the effectiveness of novel multi-action small molecule inhibitors for potential treatment of MCL.

Chimeric antigen receptor (CAR) T-cell treatment for mantle cell lymphoma (MCL).

Mantle cell lymphoma (MCL) is a rare B-cell malignancy that remains challenging to treat with high rates of relapse. Frontline strategies range from intensive chemotherapy followed by consolidation with autologous stem cell transplant (ASCT), to less-intensive therapies including combination regimens. The treatment landscape for relapsed patients includes Bruton tyrosine kinase (BTK) inhibitors among other targeted treatments. Novel agents such as the selective BCL2 inhibitor venetoclax showed high response rates when used as monotherapy for refractory relapsed MCL. The rituximab, bendamustine, and cytarabine (R-BAC) regimen, while response rates were high, were not durable. Chimeric antigen receptor (CAR) T-cell products targeting CD19 have been efficacious in relapsed and refractory MCL patients. Brexucabtagene autoleucel (brexu-cel, formerly KTE-X19) was approved by US Food and Drug Administration (FDA) in July, 2020, for treatment of refractory and relapsed MCL. This article provides an overview for the available management strategies for relapsed MCL and examines the role of CAR T-cell in the current and future treatment of MCL.

The Serum- and Glucocorticoid-Inducible Kinase 1 (SGK1) as a Novel Therapeutic Target in Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell-derived malignant disease. MCL is treated using general chemotherapy; however, disease progression and relapse are common; thus, the development of novel therapeutic targets for treatment of MCL is urgently required. Serum- and glucocorticoid-inducible kinase 1 (SGK1) is involved in various cellular activities, and its dysregulation contributes to the pathogenesis of multiple types of cancer. However, little is known regarding its functional roles and associated molecular mechanisms in MCL. SGK1 inhibition mediated by either shRNA or treatment with SGK1 inhibitor (GSK650394) was conducted in MCL cell lines. Western blotting analysis was performed to figure out the expression of related proteins. MCL-cell-derived xenograft models were constructed to evaluate the anti-tumor effects of SGK1 inhibition or/and Bruton's tyrosine kinase (BTK) inhibition in vivo. In this study, it was shown that inhibition of SGK1 significantly reduced cell proliferation, invasion and migration, increased apoptosis and blocked cell cycle progression in MCL cells. Furthermore, SGK1 inhibition significantly reduced the activation of ERK, AKT/mTOR, JAK2/STAT3 and the NF-κB signaling pathways. Using MCL-cell-derived xenograft mice models, SGK1 inhibition decreased tumor cell proliferation and tumor growth. Importantly, SGK1 overexpression significantly promoted xenograft tumor growth. Moreover, simultaneous inhibition of SGK1 and Bruton tyrosine kinase (BTK) resulted in synergistic anti-tumor effects on MCL both in vitro and in vivo. SGK1 may be a novel candidate therapeutic target and simultaneous inhibition of SGK1 and BTK may be a promising therapeutic strategy for MCL patients. Further pre-clinical and even clinical studies of SGK1 inhibitor or combination with BTK inhibitor are essential.

Zanubrutinib for the Treatment of B-cell Malignancies

Selective Bruton's tyrosine kinase (BTK) inhibition is an important therapeutic approach for B-cell malignancies. Ibrutinib, a first-in-class, oral, irreversible BTK inhibitor, has a toxicity profile attributed to off-target inhibition of kinases structurally related to BTK. A highly potent and selective next-generation BTK inhibitor, zanubrutinib, was designed to address intolerance and toxicity concerns associated with ibrutinib. Zanubrutinib provides complete and sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes, with reduced toxicity compared with ibrutinib. Zanubrutinib received accelerated approval in the USA for patients with previously treated mantle cell lymphoma (2019) and relapsed/refractory (R/R) marginal zone lymphoma (2021) and was approved for Waldenström's macroglobulinaemia (WM) in 2021. Key clinical trials evaluating the efficacy and safety of zanubrutinib include the ASPEN study in patients with WM (ClinicalTrials.gov identifier: NCT03053440), the ALPINE study in patients with R/R chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL; ClinicalTrials.gov identifier: NCT03734016) and the SEQUOIA study in treatment-naïve patients with CLL/SLL with and without del(17p) mutation (ClinicalTrials.gov identifier: NCT03336333). The more selective BTK binding profile, high potency, favourable pharmacokinetic and pharmacodynamic profile, and minimal cardiovascular toxicity of zanubrutinib compared with ibrutinib suggest that zanubrutinib may be an important treatment option when prescribed in accordance with guidelines.

3200 – USING QUANTITATIVE PROTEOMICS TO IDENTIFY NEW THERAPEUTIC TARGETS IN MANTLE CELL LYMPHOMA

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma that affects 4-6% of the population. Despite the relatively low incidence of MCL compared to other lymphomas, MCL only has a 5-year survival rate of 50%, making it one of the most deadly. While 90% of patients exhibit the t(11;14) translocation resulting in overexpression of the cell cycle regulatory protein CyclinD1 (CCND1), this alone is not enough for disease initiation. Patients must also have secondary mutations for disease manifestation; however, the number and variety of these mutations differ between every patient. This genetic complexity lends to the difficulty in disease treatment, and there are no standard therapies currently available. Although some therapies have shown promise for treatment in the early stages of the disease, all cases eventually stop responding, resulting in relapse. As such, it is imperative that new therapies be identified to treat this deadly disease. To this end, our lab performed quantitative proteomics on B cells from five healthy donors and tumors from different lymphoma patients including sixteen MCL, seven follicular lymphoma, and seven chronic lymphocytic lymphoma in order to identify changes at the proteomic level that are specific to MCL. This analysis has identified eight proteins that are specifically upregulated in MCL but are unchanged transcriptionally and would have gone unidentified by typical patient screening methods. Dysregulation of one of these proteins, HMGB3, has been shown to lend drug resistance in ovarian cancer and poor prognosis in neuroblastoma; however, has never been associated with MCL. Knockdown of HMGB3 in MCL cell lines results in reduced proliferation, increased apoptosis, and alterations to cell cycle, indicating it may prove to be a potential therapeutic target for MCL treatment. Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma that affects 4-6% of the population. Despite the relatively low incidence of MCL compared to other lymphomas, MCL only has a 5-year survival rate of 50%, making it one of the most deadly. While 90% of patients exhibit the t(11;14) translocation resulting in overexpression of the cell cycle regulatory protein CyclinD1 (CCND1), this alone is not enough for disease initiation. Patients must also have secondary mutations for disease manifestation; however, the number and variety of these mutations differ between every patient. This genetic complexity lends to the difficulty in disease treatment, and there are no standard therapies currently available. Although some therapies have shown promise for treatment in the early stages of the disease, all cases eventually stop responding, resulting in relapse. As such, it is imperative that new therapies be identified to treat this deadly disease. To this end, our lab performed quantitative proteomics on B cells from five healthy donors and tumors from different lymphoma patients including sixteen MCL, seven follicular lymphoma, and seven chronic lymphocytic lymphoma in order to identify changes at the proteomic level that are specific to MCL. This analysis has identified eight proteins that are specifically upregulated in MCL but are unchanged transcriptionally and would have gone unidentified by typical patient screening methods. Dysregulation of one of these proteins, HMGB3, has been shown to lend drug resistance in ovarian cancer and poor prognosis in neuroblastoma; however, has never been associated with MCL. Knockdown of HMGB3 in MCL cell lines results in reduced proliferation, increased apoptosis, and alterations to cell cycle, indicating it may prove to be a potential therapeutic target for MCL treatment.

Sequential development of B-cell lymphoma of alternative lineage after treatment for mantle cell lymphoma in a dog

Sequential development of B-cell lymphoma of alternative lineage after treatment for mantle cell lymphoma in a dog

Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in recent years, different BTZ-based drug delivery systems have been evaluated. In this review, we firstly discussed the functions of proteasome inhibitors and their mechanisms of action. Secondly, the properties of BTZ, as well as recent advances in both clinical and preclinical research, were reviewed. Finally, progress in research regarding BTZ-based nanoformulations was summarized.

Forced Degradation Study of Zanubrutinib: An LC-PDA and LC-MS Approach.

Zanubrutinib is an unfamiliar second generation selective Brutson's Tyrosine Kinase inhibitor used to treat mantle cell lymphoma. In the present analysis, a new, stability indicating reverse-phase, high performance liquid chromatography method was developed and validated for the determination of Zanubrutinib succeeding degradation studies as pert the International Conference on Harmonization guidelines. The chromatographic separation of Zanubrutinib was achieved in a C18 column (250 × 4.6mm, 5-μm particle size) using a mobile phase of Acetonitrile: 0.1% Tri Ethyl Amine (65:35v/v) monitored at 219nm. The forced degradation studies were conducted by exposing the analyte to acidic, alkaline and neutral hydrolysis, oxidative, reductive, photolytic, and thermal stress conditions and the degradation behavior was studied. The analyte showed degradation under acidic, alkaline, oxidative and reductive stress conditions with additional peaks but, it was stable under neutral, photolytic and thermal stress conditions. The developed method was extended to triple quadruple mass spectrometry to characterize degradation products and to study the fragmentation pattern. Total four degradants were characterized including DP1 in acid &base hydrolysis, DP2 in oxidative and DP3, DP4 in reductive stress condition. As no substantial method was available for quantification of Zanubrutinib and to characterize zanubrutinib degradants, this method can be used for regular analysis in quality control labs.

Fever of unknown origin during treatment of mantle-cell lymphoma: is it relapsing disease?

Fever of unknown origin during treatment of mantle-cell lymphoma: is it relapsing disease?

Using the Iron Chelator Deferasirox to Overcome Drug Resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by the t(11,14) translocation, resulting in cyclin D1 (CD1) overexpression. In addition to CD1 overexpression, pathways such as the B-cell receptor, PI3K/AKT/ GSK3β, NFκB and Wnt have been reported to be deregulated in MCL. Despite advancements in MCL treatment, most patients still relapse. Although the introduction of ibrutinib to relapsed/refractory MCL significantly improved the outcome of MCL patients, ibrutinib resistance has become a clinical obstacle. MCL treatments are thus pursued by studying novel agents with a broad spectrum of targets or by rationally combining existing therapies aiming for synergistic antitumor activities. Deferasirox (DFX) is a clinically approved iron chelator with only few side effects. DFX has been reported to exert anti-tumoral and synergistic effects in several types of cancers by affecting a multitude of targets. We have previously shown that DFX exerts a vigorous anti-tumoral effect via growth inhibition and induction of apoptosis in MCL cells through ROS elevation, triggering of oxidative stress, induction of DNA damage, modulation of PI3K/AKT/GSK3β signaling and most importantly by elimination of CD1 expression. The capacity of DFX to affect a multitude of targets establishes a solid basis for a possible synergistic interaction with other drugs, such that may overcome drug resistance in MCL. In this study we focused on assessing the efficiency of DFX combined with the established therapeutic-agents etoposide, cytarabine and ibrutinib in MCL cell-lines. We found that DFX synergizes with etoposide, cytarabine and ibrutinib, prompting remarkable anti-tumoral effects in MCL cells with combination index (CI) values < 1. Interestingly, the DFX-drug combinations achieved synergism regardless of the innate sensitivity of the cell-lines to the treatment: ibrutinib-resistant cells restored their sensitivity to the drug when it was combined with DFX. In addition, we found that the sensitivity of MCL cells towards the drugs correlated with the drugs ability to induce CD1 degradation. In agreement, DFX co-treatment enhanced CD1 degradation, especially in resistant cells.We show here that DFX is a putative promising drug-sensitizing agent for the treatment of MCL. DFX-co-treatment not only enhances the efficacy of the tested drugs, but also restores the anti-proliferative activity of the drugs in resistant MCL cells. To the best of our knowledge, this study is the first to provide evidence on the potential of DFX to overcome drug resistance in MCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Influence of Treatment Facility Type and Annual Patient Volume on Overall Survival in Patients with Mantle Cell Lymphoma: A National Cancer Database Analysis

Influence of Treatment Facility Type and Annual Patient Volume on Overall Survival in Patients with Mantle Cell Lymphoma: A National Cancer Database Analysis

Improvement Diagnosis and Treatment of Mantle Cell Lymphoma in a Middle-Income Country: A Time-Dependent Analysis in Mexico

Introduction: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma representing 4-9% of all lymphomas. The disease prognosis remains adverse. However, diagnosis and treatment of MCL have undergone a significant improvement in the last years.The World Bank considers Mexico as a Middle-Income Country (MIC). Therefore, MICs experience a delay in accomplishing diagnosis and prognosis strategies and low access to treatment innovation for hematologic malignancies. In Mexico, there is scarce information on the clinical features and treatment patterns of MCL over time. Mainly, the prognosis impact of these strategies is unknown.Methods: We retrospectively evaluated all consecutive patients with a pathological diagnosis of MCL in three referral centers for the uninsured population in Mexico from 2008 to 2020. We followed patients to June 2021 until lost follow-up or death. We made a Time-Dependent-Analysis (TDA) to evaluate the effect of the diagnosis and treatment improvements over time. We divided the population into two groups, from 2008 to 2014 (Group A) and from 2015 to 2020 (Group B). Hematopathologists reviewed all cases at their respective centers. We excluded patients that do not receive treatment and patients without pathological confirmation. Clinical, pathological, and treatment data were collected. Responses were assessed per the Lugano criteria. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method, differences between the groups were evaluated with a log-rank test. Multivariate analysis of factors associated with mortality was assessed with a Cox regression model with a Confidence Interval(CI) of 95%.Results: A total of 139 patients were included in the analysis; 67 patients from Group A; and 72 patients from Group B. The median age was 64 years, 42% were younger than 65 years, 76% were male, 22% had ECOG 2-4, 81% had extra nodal involvement, 28.1% had bulky disease, 94% had stage III/IV disease, 58% had bone marrow involvement, 40.7% had high risk simplified MIPI. Regarding diagnosis approaches between the two groups, only 23% in Group A had an immunohistochemical evaluation of Ki67 compared with an 84% of Group B (p<0.001). The rest of the differences between the groups are in Table 1.In terms of treatment, 84% received an anthracycline-based treatment, 3% bendamustine-based treatment, and 12% a low-intensity treatment, with no difference between the groups. In addition to base treatment, 30% received High-dose Cytarabine (HiDAC), been more frequent in Group B (p<0.001), 59% received rituximab during induction, 37% in Group A, and 80% in Group B, (p<0.001). The main reason to avoid the use of rituximab was the cost and only 20.3% used rituximab maintenance, being more frequent in Group B (p=0.018). The 13.7% received an autologous stem cell transplant, been more frequent in Group B (p= 0.002). Only two patients (1.4%) received treatment in a Clinical Trial setting. In terms of response, in Group A, 58% achieved Complete Response (CR) against 34% of Group B (p=0.006).Median OS on Group A was 38 months (95% CI 25.6 -50.3) against Not Reached in Group B (Log Rank p = 0.037). On the other hand, the median EFS on Group A was 17 months (95% CI 11.6-22.39) against 29 months (95% CI17.6-40.3) in Group B (Log Rank p = 0.005) Figure 2. A multivariate analysis of factors associated with higher mortality found a high-risk MIPI score with an HR of 2.54 (CI 95% 1.5-4.0, p <0.001). Factors associated with lower mortality were the addition of HiDAC in induction HR 0.39 (CI 95% 0.20- 0.75, p= 0.005) and rituximab maintenance HR 0.48 (CI 95% 0.24-0.94, p=0.035)Conclusion: This is the first real-world report of MCL in Mexico. Characteristics of the disease resemble the ones reported by other countries. Despite the limitations of a retrospective analysis, the TDA makes evident the prognosis improvement over time. With progress in EFS of 12 months and an OS impact. Even though the prognosis improvement, to the date, there is a 20% of patients with no rituximab access. Transplant access is low beside that 42% of patients were younger than 65 years, and Clinical Trial access is almost null. Novel therapies for MIC are under development with encouraging results in the first-line and relapsed/refractory setting. However, the high costs of these therapies will limit the access in MIC and would expand the gap of MCL prognosis if a health care strategy that allow access to them is not implemented. [Display omitted] DisclosuresRangel-Patiño: Abbvie: Speakers Bureau; Bristol: Consultancy. Agreda: Roche: Speakers Bureau; Astrofarma: Speakers Bureau; Janssen: Speakers Bureau. Gomez-Almaguer: Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Ramirez-Ibarguen: Takeda: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Astra Zeneca: Speakers Bureau; Abbvie: Speakers Bureau; MSD: Consultancy; Asofarma: Consultancy.

Preliminary Safety and Efficacy Data from Patients (Pts) with Relapsed/Refractory (R/R) B-Cell Malignancies Treated with the Novel B-Cell Lymphoma 2 (BCL2) Inhibitor BGB-11417 in Monotherapy or in Combination with Zanubrutinib

Preliminary Safety and Efficacy Data from Patients (Pts) with Relapsed/Refractory (R/R) B-Cell Malignancies Treated with the Novel B-Cell Lymphoma 2 (BCL2) Inhibitor BGB-11417 in Monotherapy or in Combination with Zanubrutinib

New Acalabrutinib Formulation Enables Co-Administration with Proton Pump Inhibitors and Dosing in Patients Unable to Swallow Capsules (ELEVATE-PLUS)

New Acalabrutinib Formulation Enables Co-Administration with Proton Pump Inhibitors and Dosing in Patients Unable to Swallow Capsules (ELEVATE-PLUS)

Late Effects after Treatment in Mantle Cell Lymphoma: No Difference By Intensity of First-Line Regimens with or without Autologous Stem Cell Transplantation

PurposeThe improved survival for mantle cell lymphoma (MCL) patients calls for updated knowledge about long-term adverse effects of treatment. We recently showed that younger MCL patients (≤65 years of age) selected for rituximab-cytarabine containing regimens and a consolidating high-dose chemotherapy with stem cell transplantation (HD-ASCT) had a 42% reduced all-cause mortality compared to patients selected for less intensive regimens with rituximab-bendamustine and/or rituximab-CHOP based treatment without HD-ASCT (non-HD-ASCT) (Blood Advances 2021, PMID: 3371034). The aim here was to describe long-term side-effects and outcome from these different treatment strategies.MethodsWe conducted a population-based cohort study including all Swedish MCL patients diagnosed between 2000 and 2014, and 1:10 matched comparators. First, transplantation-related mortality and acute side effects (within 60 days of HD-ASCT) were described. Next, for the analysis of late effects, we took a landmark approach with follow-up starting at 12 months after diagnosis (i.e., assuming treatment completion). Hazard ratios with 95% confidence intervals (CIs) of first hospital visit/admission/death due to a specific disease group (based on ICD chapters) were estimated using Cox regression models, comparing the rates among HD-ASCT and non-HD-ASCT patients to those among the comparators. Additionally, the 5-year cumulative incidence of death due to MCL, other malignancy, cardiovascular disease, or remaining causes was described for both patient treatment groups (HD-ASCT and non-HD-ASCT) and comparators.ResultsA total of 620 MCL patients were included with a median follow-up from diagnosis of 4.1 years (range: 0-15.7). In total, 280 (45%) received HD-ASCT (median age 58, range 32-69) and 340 (55%) R-CHOP/R-Bendamustin and non-HD-ASCT (median age 65, range 22-69). Four out of 280 (1.5%) HD-ASCT treated patients died within 60 days of their transplantation. Acute side effects of transplantation were mainly infections and diseases of the circulatory or digestive systems.In relation to the 6,200 matched comparators (median age 63, range 22-70) the rate of hospital visits/admissions/death after 12 months was significantly higher among MCL patients (irrespective of treatment intensity) for neoplasms (excluding MCL), other blood disorders, infections, respiratory, genitourinary, digestive, and skin disorders (Figure 1A). Patients treated with HD-ASCT did not experience a higher rate of late effects than those treated without HD-ASCT, for any of the disease groups (Figure 1A).The 5-year cumulative incidence of MCL-specific death in HD-ASCT treated patients was 0.23 (95% CI: 0.18-0.30) and 0.32 (95% CI: 0.26-0.38) in non-HD-ASCT treated patients (Figure 1B). Fatal long-term (≥12 months) side effects were rare in HD-ASCT treated patients, and the absolute majority of MCL patients died from their lymphoma and not from a complication.ConclusionsMCL patients have a higher risk of long-term complications than comparators particularly in the disease groups respiratory disorder, blood disorders (other than MCL) and infections. Intensive first-line treatment including HD-ASCT was however associated with a similar rate of long-term side-effects in all disease groups as among patients selected for less intensive treatments and non-HD-ASCT. Hence, given the previously shown favourable long-term survival associated with HD-ASCT, it appears that this treatment should not be avoided based on fear of neither fatal acute side effects nor more long-term side effects. Instead symptomatic lymphoma disease and death from the lymphoma seem to drive the majority of long-term health problems in MCL patients regardless of treatment intensity.Figure 1. A) Hazard ratios for hospital visits/admissions/deaths due to specific disease groups (based on ICD chapters) among MCL patients and comparators, stratified by treatment with consolidative autologous stem cell transplant (ASCT) or (non-ASCT). All models were adjusted for age at diagnosis, sex, calendar year of diagnosis, and Charlson comorbidity index. Grey dots; comparators, blue dots MCL patients (non-ASCT-treated) and red dots MCL patients (ASCT treated) B) Cumulative incidence of death due to MCL, other malignancies, cardiovascular disease (CVD), and other causes among MCL patients without (upper panel) and with (lower panel) ASCT. [Display omitted] DisclosuresEkberg: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Smedby: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Albertsson-Lindblad: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Jerkeman: Jansen-Cilag, AbbVie, Gilead, Celgene: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support, Research Funding. Weibull: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Glimelius: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support.

Novel Mechanisms of Acalabrutinib Resistance in Patients with Chronic Lymphocytic Leukemia By Whole Genome Methylome Sequencing

Novel Mechanisms of Acalabrutinib Resistance in Patients with Chronic Lymphocytic Leukemia By Whole Genome Methylome Sequencing

A Phase 1 Study of the Combination of Acalabrutinib and AZD9150 in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

A Phase 1 Study of the Combination of Acalabrutinib and AZD9150 in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Real-World Bruton Tyrosine Kinase Inhibitor Treatment Patterns, Compliance, Costs, and Hospitalizations in Patients with Mantle Cell Lymphoma in the United States

Introduction: Mantle cell lymphoma (MCL) is a rare, aggressive, and incurable B-cell malignancy. MCL patients may initially respond well to frontline treatments; however, most will relapse or become refractory (r/r) to treatment. While there are real-world data available on the use of ibrutinib, the first Bruton tyrosine kinase inhibitor (BTKi) approved in 2013 for the treatment of r/r MCL, there is limited data on the more recently approved BTKis, acalabrutinib (approved in 2017) and zanubrutinib (approved in late 2019), primarily due to disease rarity and time lag of claims dataset. This study aimed to examine (1) clinical and sociodemographic characteristics of patients receiving BTKi, (2) treatment patterns and compliance by each BTKi, and (3) costs and hospitalizations associated with each BTKi use in the real-world setting in the United States.Methods: A retrospective observational study was conducted using the patient longitudinal data between July 2017 and May 2021 from the Symphony Health's IDV® (Integrated Dataverse), a de-identified, open-source claims database. IDV captures and aggregates data from different data vendors and assigns a unique patient identifier to each claim through a proprietary patient matching process. Patients were considered to be active in the open-source database and eligible for the study if they have ≥ 1 MCL diagnosis and ≥ 1 BTKi prescription claim for two consecutive semesters (1 semester = 6 months) pre- and post- index date. The index date was defined as the use of one of the BTKis of interest: ibrutinib, acalabrutinib, or zanubrutinib. The BTKi groups were not mutually exclusive to capture the potential switching between groups. Descriptive analysis was conducted to examine patient sociodemographic characteristics, comorbidities, concomitant medications, treatment patterns, costs, and hospitalizations in overall BTKi users, and by each BTKi. Treatment patterns were evaluated by frequency and duration of each BTKi use. Days of supplies and medication possession ratio were used to calculate persistency and compliance rates.Results: Among 30,199 patients with MCL identified from the database, 3,821 MCL patients were on BTKi therapy, and the final study population consisted of 1,653 active patients with MCL and BTKi treatment. Patients in the zanubrutinib group were older (n=67, median age=78, 67.2% male) than those in either the acalabrutinib group (n=485, median age=74, 74.9% male) and ibrutinib group (n=1,242, median age=70, 73.8% male). Among zanubrutinib users, 22% were switched from ibrutinib and 7% switched from acalabrutinib, while 21% of acalabrutinib users were switched from ibrutinib. Over half of the ibrutinib use was in the frontline setting (68.4%) while the use of acalabrutinib and zanubrutinib was more in the r/r setting (68.9% and 80.6%, respectively). The most common comorbidities at BTKi treatment initiation were hypertension (41.1%), followed by dyslipidemia (28.6%), diabetes (17.5%), cardiac arrhythmia (15.6%), and gastroesophageal reflux disease (14.5%). However, 28.5% of acalabrutinib users were concurrently on proton pump inhibitors even though such concomitant use should be avoided. The compliance rate was higher in zanubrutinib group (65%) than acalabrutinib (62%) and ibrutinib (59%) groups. Overall, the average length of stay (LOS) is 5.9 days among MCL patients who used BTKi and had at least 1 hospitalization. Patients in the zanubrutinib group had a shorter LOS (4.0 days) than those in the ibrutinib (5.9 days) and acalabrutinib (5.8 days) groups (Figure 1A). On average, the total submitted inpatient charge per stay is lower for patients in the zanubrutinib group ($51,051) than patients in the ibrutinib ($79,482) and acalabrutinib ($74,546) groups (Figure 1B).Conclusions: This study provides the first real-world evidence on patients with MCL treated with all currently available BTKis, zanubrutinib, ibrutinib and acalabrutinib. BTKis are largely being used in second-line plus settings. Future studies are needed to understand the long-term outcomes of BTKi treatment as data matures. [Display omitted] DisclosuresShah: Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; BeiGene: Consultancy, Honoraria; Acrotech/Spectrum: Honoraria; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Sivanantham: PRA Symphony Health Solutions: Consultancy; BeiGene, Ltd.: Consultancy. Ali: BeiGene, Ltd.: Current Employment. Casten: PRA Symphony Health Solutions: Consultancy; BeiGene, Ltd.: Consultancy. Satya: PRA Symphony Health Solutions: Consultancy; BeiGene, Ltd.: Consultancy. Tang: BeiGene, Ltd.: Current Employment.

Clinical Characteristics, Treatment and Outcome of Patients with Mantle Cell Lymphoma: A Large, Multicenter Retrospective Analysis in China

Background Mantle cell lymphoma (MCL) is an uncommon heterogeneous subtype of B cell non-Hodgkin lymphoma, most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome. Clinical features in mantle cell lymphoma appeared regional characteristics and the epidemiology of MCL in Asia is not accurate documented. MCL treatment opinions are not uniform between country/region within Asia and China. At present, the large-scale Asian patient-specific data for the treatment of MCL are lacking.Aims To obtain ‘real world’ clinical characteristics,treatment patterns and prognosis factors of MCL patients in China and to address the knowledge gap in Chinese MCL patients.Methods Patients diagnosed with MCL between April 1999 and December 2019 at 19 comprehensive hospitals in China were included in this retrospective analysis. The median follow-up times was 36.0 months. The data of total 805 patients with mantle cell lymphoma were collected, 112 patients with incomplete clinical data, no chemotherapy and missing follow-up data were excluded. Finally, 693 patients with complete clinical data, treatment information and survival follow-up data were included in this study.Fully detailed information of patients, disease characteristics, treatments and outcomes were collected. Fisher's exact test or Pearson's Chi-squared test were used to compare categorical variables.Survival analysis was performed by Kaplan-Meier.Results The median age of the cohort was 60.0 years with a male-to-female ratio of 3.36:1. 477 patients (68.8%) were younger than 65 years at diagnosis.Advanced stage of diseases were 90.0%. Extranodal organ involvement was 83.4% and the most frequently involved extranodal organs were bone marrow(46.2%), spleen(36.1%), gastrointestinal tract(24.8) and oropharynx(17.7%). Blastic/pleomorphic mantle cell lymphoma accounted for 12.8%, and non-nodular mantle cell lymphoma accounted for 3.3%. Ki-67 more than 30% was 57.7% and Ki-67 ≥ 50% was 26.1%. The intermediate /high risk group was 49.8% according to MIPI score. The first-line therapeutic schedule is not completely unified, the most frequently regimen was CHOP/CHOP-like±R (n=312,45.0%) ,then high-dose cytarabine (n=222,32.0%), VR-CAP(n=44,6.3%), BR(n=30,4.3%), R-EPOCH (n = 17, 2.5%), FC / FCM±R regimen (n = 13,1.9%),and 55 patients(7.9%) uesd chemo-free regimen including IR / R2 / IR2 .Only 80 patients (11.5%) received autologous hematopoietic stem cell transplantation as consolidation therapy after chemotherapy remission. The ORR rate was 85.0%with 46.6% CR and 38.4% PR in the initial treatment.During the follow-up to June 2021(2-204months), 222 patients(32.0%) had died. The 5-year PFS and OS was 30.9% and 65.0%respectively.In the multivariate Cox regression model, ki67 ≥ 50% (HR 1.27, 95%CI 1.01-1.60, p = 0.038) ,stageⅢ/Ⅳ (HR1.56, 95%CI 1.05-2.33, p = 0.029),high- intermediate/high risk group accouding to MIPI-c (HR1.56, 95%CI 1.05-2.33, p = 0.008),spleen involvment (HR1.35, 95%CI 1.08-1.69, p = 0.009),without maintenance treatment (HR0.71, 95%CI 0.56-0.88, p = 0.003) ,SD/PD in inital treatment (HR6.20, 95%CI4.71-8.14, p < 0.001) were independently associated with poorer PFS while ki67 ≥50% (HR 1.74, 95%CI 1.31-2.31, p< 0.001),B symtom (HR 1.52, 95%CI 1.15-2.00, p = 0.003), high-intermediate/high risk group accouding to MIPI-c (HR1.43, 95%CI 1.24-1.64, p < 0.001),without high-dose cytarabine (HR0.47, 95%CI 0.31-0.70 ,p < 0.001) ,without maintenance treatment (HR0.40, 95%CI 0.28-0.58,p < 0.001)and relapse/refractory state (HR 4.04, 95%CI 2.21-7.39, p < 0.001) were independently associated with poorer OS.Conclusions This study describes the characteristics of mantle cell lymphoma in Chinese population with younger onset age and a higher tumor proliferation index. High dose cytarabine treatment and maintenance treatment have shown survival benefits in real-world.Recurrence and refractory is an important factor affecting survival,the strategy of combining molecular biological characteristics with novel strategies may improve outcome in these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Novel Multitarget Small-Molecule Inhibitor SRX3177 Overcomes Ibrutinib Resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive, rare, and difficult to treat subtype of non-Hodgkin's Lymphoma (NHL) that accounts for about 6% of all cases. Although there is no defined standard of care for MCL treatment, some combination of chemo-immunotherapy and rituximab maintenance with or without autologous stem cell transplantation is generally employed depending on the age and fitness of the patient. Despite recent development of novel therapeutics, there is inevitable disease relapse with progressively declining efficacy and increasing frequency of resistance with single agent targeted therapy. Here, we describe the novel multitarget inhibitor SRX3177 which simultaneously hits three oncogenic targets: phosphatidylinositol-3 kinase (PI3K), cyclin-dependent kinases 4 and 6 (CDK4/6), and the epigenetic reader protein BRD4. This in silico designed, thieno-pyranone (TP) scaffold-based small molecule inhibitor orthogonally disrupt three targets within the cancer cell with one agent.Targeting the cell cycle with small molecule inhibitors represents a reasonable attempt to treat MCL, as cell cycle-associated genes like ATM, TP53, CDKN2A, CCND1 and CDK4/6 are most frequently mutated in patients. Palbociclib is a well-known single agent CDK4/6 inhibitor that has been employed in both solid and hematological malignancies. Due to its cytostatic nature, treatment with single agent palbociclib often results in the emergence of treatment-resistant clones. Therefore, a combination strategy would theoretically be more effective and can overcome the development of resistance. Moreover, prolonged G1 arrest by CDK4/6 inhibition sensitizes lymphoma cells to PI3K inhibition, suggesting a synthetic lethality relationship between these two agents. Inhibiting the chromatin reader protein BRD4 causes downregulation of target genes c-MYC and BCL2, further increasing cytotoxic capabilities. Hence, we developed SRX3177 as a potent CDK4/6/PI3K/BRD4 triple inhibitor to synergistically inhibit cell cycle progression and induce cancer cell apoptosis.SRX3177 is an ATP competitive CDK4/6 inhibitor (IC 50: CDK4 = 2.54 nM, CDK6 = 3.26 nM), PI3K inhibitor (IC 50: PI3Kα = 79.3 nM, PI3Kδ = 83.4 nM), and BRD4 inhibitor (IC 50: BD1 = 32.9 nM, BD2 = 88.8 nM). We have tested the efficacy of SRX3177 against a panel of MCL cell lines and report that SRX3177 induces a strong antiproliferative activity with maximal IC 50 0f 340 nM in JeKo-1, 29 nM in Mino cells, and 630 nM for Rec-1 cells while IC 50 values for cell lines Granta and JVM-2 were 1.3 µM and 1.5 µM, respectively. Further, we show that SRX3177 is more potent to tumor cells than the individual PI3K (BKM120), BTK (Ibrutinib), BRD4 (JQ1), and CDK4/6 (palbociclib) inhibitors, and dual PI3K/BRD4 inhibitor SF2523 (backbone for SRX3177) in JeKo-1 cells. Next, we examine the cytotoxic effect of SRX3177 in ibrutinib/palbociclib resistant primary MCL cells. Our results show that SRX3177 triggers cytotoxic response at 500 nM and 1000 nM as compared to the lack of cytotoxicity of combination Ibrutinib and palbociclib at 150 nM and 1000 nM (Fig 1). SRX3177 induces a strong apoptotic response and cell cycle arrest in JeKo-1 and Mino cells at 24hrs. Annexin V/7AAD apoptosis staining confirmed the induction of PCD by SRX3177with increase in c-PARP. Western blot analysis shows SRX3177 treatment blocks both PI3K/AKT signaling and Rb phosphorylation. Moreover, analysis by chromatin immunoprecipitation revealed that SRX3177 effectively blocked BRD4 binding to both the promoter and enhancer of c-MYC (p≤0.01 and p≤0.001) and BCL2 (p≤0.05). SRX3177 also suppresses the c-MYC and BCL2 transcriptional program in both a time- and dose-dependent manner. Our findings also demonstrate a SRX3177-dependent reduction in c-MYC half-life via induction of proteasomal-mediated degradation. This degradation is associated with decreased phosphorylation of c-MYC at Ser62 and increased phosphorylation of c-MYC at Thr58 - indicative of differential regulation of c-MYC stability. Finally, we show that SRX3177 overcomes chronic ibrutinib resistance in Jeko-1 cells with a maximal IC 50 of 150 nM as compared to 64 µM with ibrutinib. Hence, the triple inhibitor SRX3177 has superior potency to ibrutinib in MCL cell lines and succeeds in overcoming ibrutinib-resistance at nanomolar doses. Taken together, our data supports the development of SRX3177 as a novel therapeutic agent for treatment of MCL. [Display omitted] DisclosuresMartin: ADCT: Consultancy. Park: Takeda: Research Funding; G1 Therapeutics: Consultancy; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Morphosys: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Durden: SignalRx Pharmaceuticals: Current holder of individual stocks in a privately-held company.