Refractory Mantle Cell Lymphoma Research Articles

MO26-1 Efficacy and safety of zanubrutinib in patients with relapsed or refractory mantle cell lymphoma: a systematic review

MO26-1 Efficacy and safety of zanubrutinib in patients with relapsed or refractory mantle cell lymphoma: a systematic review

Pirtobrutinib: First Non-covalent Tyrosine Kinase Inhibitor for Treating Relapsed or Refractory Mantle Cell Lymphoma in Adults.

Mantle Cell Lymphoma (MCL) is an aggressive subtype of Non-hodgkin's Lymphoma (NHL). Bruton Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase, and is one of the therapeutic targets for B-cell-driven malignancies. Approved covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib are associated with treatment limitations due to off-target side effects and the development of C481 substitution resistance mutations. Pirtobrutinib was approved by the US FDA on January 27, 2023, for the treatment of relapsed or refractory mantle cell lymphoma, including the resistance to covalent BTK inhibitors. In this perspective, physicochemical properties, synthesis, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interactions, and treatment-emergent adverse events of pirtobrutinib are discussed.

An open label, single arm, multicenter phase II study of the efficacy and safety of LP-168 monotherapy for relapsed or refractory mantle cell lymphoma.

TPS7098 Background: Targeting Bruton’s tyrosine kinase (BTK) has demonstrated impressive efficacy in relapsed or refractory mantle cell lymphoma (R/R MCL). Covalent BTK inhibitors (cBTKi) have produced extended disease remission and durable responses in R/R MCL. However, patients with continuous cBTKi treatment tend to develop selection or outgrowth of resistant clones, which triggers disease relapse. Non-covalent binding BTKi has become a treatment option for patients who progressed on cBTKi. LP-168 is a highly selective next-generation inhibitor of BTK that can bind wild-type BTK covalently and C481-mutated BTK non-covalently (reversibly) Here, we propose to evaluate the safety and efficacy of LP-168 monotherapy in patients with R/R MCL. Methods: NCT05716087 is an open-label, multicenter, single-arm, phase II study to assess the efficacy, safety, tolerability, and pharmacokinetics of LP-168 in Chinese patients with R/R MCL who have failed prior cBTKi treatment. Responses were evaluated using Lugano 2014 criteria. Eligible patients with R/R MCL must show evidence of disease progression or intolerance to at least a prior cBTKi. Patients are also required to have adequate bone marrow, liver function, kidney function, and heart function, and an ECOG performance status of 0-2. Moreover, patients must have at least one measurable lesion. Key exclusion criteria include previous non-covalent BTKi or BTK proteolysis-targeting chimeras (PROTAC) treatment, uncontrolled systemic disease, active infection, central nervous system (CNS) involvement, prior history of other malignancies within two years, and current pregnancy or breastfeeding. Concomitant use of strong or moderate CYP3A4 inducers and inhibitors or OATP1B1/OATP1B3 sensitive substrates is prohibited. LP-168 is orally administered at 150mg once daily in 28-day/cycle until progressive disease (PD), unacceptable toxicity, withdrawal of consent, death, or other reasons for treatment discontinuation. In this study, the primary endpoint was ORR according to an independent review committee (IRC) assessment based on the best overall response (BOR) of PR or better per Lugano 2014 criteria. Secondary endpoints include safety evaluation, quality of life assessment, PK parameters, ORR by investigator’s assessment, and other efficacy parameters, such as complete response ratio (CRR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and time to response (TTR). First patient was enrolled on May 12, 2023. Currently 41 study sites across China are actively enrolling patients. ClinicalTrials.gov Identifier: NCT05716087. Clinical trial information: NCT05716087 .

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma—a randomized, open-label phase III trial of the European mantle cell lymphoma network

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47–1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29–0.79) and without previous ASCT (aHR 0.52, 0.28–0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344.

Ibrutinib (Imbruvica)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses ibrutinib (Imbruvica), 140 mg capsule, oral.
 Indication: For the treatment of adult patients with:
 
 Waldenström macroglobulinemia (WM) as a monotherapy or in combination with rituximab
 Previously untreated active chronic lymphocytic leukemia (CLL), including patients with 17p deletion
 CLL who received at least one prior therapy, in combination with bendamustine and rituximab
 Relapsed or refractory mantle cell lymphoma (MCL)
 marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy
 Steroid-dependent or refractory chronic graft vs. host disease (cGVHD)
 
 

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

Evaluation of second-generation Bruton's tyrosine kinase inhibitors for the treatment of mantle cell lymphoma.

Second-generation Bruton's tyrosine kinase (BTK) inhibitors, acalabrutinib and zanubrutinib, are preferred agents for the treatment of relapsed and/or refractory mantle cell lymphoma (MCL) over first-generation BTK inhibitor, ibrutinib. The comparative safety and efficacy of these two agents have not been studied. Currently, the decision between using one second-generation BTK inhibitor over the other is largely dependent on provider preference, cost, organ dysfunction, presence of drug-drug interactions, adherence considerations, and theorized differences in safety outcomes due to the lack of head-to-head trials in MCL. This retrospective, observational study seeks to provide real-world data on the safety and efficacy of second-generation BTK inhibitors in the setting of relapsed and/or refractory MCL. Thirty-eight patients treated with a second-generation BTK inhibitor were evaluated. Ten percent of patients experienced a select adverse drug event (ADE) in the acalabrutinib group that included hypertension and major hemorrhage with no patients experiencing a select ADE in the zanubrutinib group. Results support historical data that acalabrutinib and zanubrutinib have a more favorable safety profile compared to ibrutinib in MCL.

A306 A CASE OF SCLEROSING CHOLANGITIS AS A COMPLICATION OF CAR-T THERAPY

Abstract Background Chimeric antigen receptor T-cell (CAR-T) therapy is a novel immunotherapy for treating hematological malignancies. CAR-T therapy starts with the collection of T-cells from patients. Then, receptors on the T-cell membrane are re-engineered to become chimeric antigen receptors that specifically target antigens on the surface of malignant cells. These engineered cells are grown ex vivo and infused back into the patient, leading to a targeted immune response against cancer. While CAR-T therapy has shown promising results in treating malignancies refractory to conventional treatment, there have also been reports of complications from unwanted off-target effects with CAR-T therapy. Aims We report a case of sclerosing cholangitis secondary to CAR-T therapy for the treatment of mantle cell lymphoma. Methods Case report. Results A 67-year-old male with refractory stage IVB mantle cell lymphoma underwent CAR-T therapy. His lymphoma was first diagnosed in 2011 and previous treatment included R-CHOP followed by autologous stem cell transplant. He had disease progression despite rituximab maintenance therapy and was switched to ibrutinib therapy with good response until 2023. In 2023, he was noted to have progression of his lymphoma. He subsequently underwent CAR-T therapy. His treatment was complicated by grade 2 cytokine release syndrome requiring two doses of tocilizumab. Other complications included immune effector cell-associated neurotoxicity syndrome leading to status epilepticus. He was intubated and required monitoring in the ICU however he was not in shock, nor did he require vasopressors. Post-CAR-T therapy he developed an increase of his liver enzymes in a cholestatic pattern. Magnetic resonance cholangiopancreatography (MRCP) showed irregular biliary dilation with beading suggestive of sclerosing cholangiopathy. He subsequently underwent multiple endoscopic retrograde cholangiopancreatography (ERCP) with stent insertions but there were no improvements in his liver enzymes and jaundice. A liver biopsy was performed which showed large bile duct obstruction with extensive cholestasis and some evidence of non-caseating granulomatous inflammation. Given the timing of new sclerosing cholangiopathy post-CAR-T therapy along with multiple other complications related to CAR-T therapy, it was thought this patient developed sclerosing cholangitis secondary to CAR-T therapy. Due to worsening clinical status along with progression of mantle cell lymphoma, he was transitioned to comfort care. Conclusions CAR-T therapy is a novel immunotherapy for the treatment of refractory hematological malignancies. However, complications from the off-target effects of CAR-T therapy can occur. This case highlighted a rare side effect associated with CAR-T therapy. In the future, more research will be needed to further characterize the risks associated with CAR-T therapy. Cholangiogram showing no visible filling defects or obstructive lesion. Funding Agencies None

Pirtobrutinib in relapsed or refractory mantle cell lymphoma: a profile of its use

Pirtobrutinib in relapsed or refractory mantle cell lymphoma: a profile of its use

A retrospective analysis of ibrutinib outcomes in relapsed or refractory mantle cell lymphoma.

While treatment strategies for mantle cell lymphoma (MCL) have evolved, patients often experience disease progression and require additional treatment therapies. Ibrutinib presents a promising option for relapsed or refractory MCL (RR-MCL). This study investigated real-world treatment outcomes of ibrutinib in patients with RR-MCL. A single-center retrospective analysis investigated clinical characteristics and survival outcomes of patients with RR-MCL, treated with ibrutinib. Forty-two patients were included, with 16 received rituximab and bendamustine, and 26 receiving anthracycline-based regimens as front-line treatment. During a median follow-up of 46.0 months, the response rate to ibrutinib was 69%, with 12 CRs and 8 partial responses. Disease progression (54.8%) and adverse events (11.9%) were the primary reasons for discontinuation. Median progression-free survival (PFS) and overall survival (OS) were approximately 16.4 and 50.1 months, respectively. Patients older than 70 years (P=0.044 and P=0.006), those with splenomegaly (P=0.022 and P=0.006), and those with a high-risk simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) (P＜0.001 and P＜0.001) exhibited siginificantly inferior PFS and OS. Notably, patients with a high-risk sMIPI relapsed earlier. Post-ibrutinib treatment yilded an OS of 12.2 months, while clinical trial participants demonstrated superior survival compared to those receiving chemotherapy alone. This study underscores the importance of considering patient characteristics before administering ibrutinib as salvage therapy. Early relapse was associated with poor outcomes, highlighting the need for novel therapeutic strategies.

CAR T-cell therapy versus allogeneic HSCT for relapsed or refractory mantle cell lymphoma

CAR T-cell therapy versus allogeneic HSCT for relapsed or refractory mantle cell lymphoma

Patient-Reported Outcomes (PROs) Among Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Receiving Pirtobrutinib: Analysis from the BRUIN Phase 1/2 Study

Background PROs including health-related quality of life (HRQoL) and symptom burden can provide helpful information to support benefit-risk assessment of a new treatment. Pirtobrutinib, a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi), inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib recently received regulatory approval in the US for the treatment of patients with relapsed or refractory mantle cell lymphoma after two or more lines of systemic therapy, including a covalent BTKi (cBTKi). BRUIN (NCT03740529) is an ongoing, open-label, multi-center phase 1/2 study investigating the safety and efficacy of pirtobrutinib for the treatment of B-cell malignancies, including CLL/SLL. This current analysis reports PROs among patients enrolled in the BRUIN study with relapsed or refractory (R/R) CLL/SLL treated with prior cBTKi-containing regimens. Methods Pretreated patients with R/R CLL/SLL in the BRUIN study completed PRO assessments at each clinic visit. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) was used to measure physical function (PF) and HRQoL via PF and Global Health Status/QoL subscales. Patient-reported CLL/SLL symptoms and fatigue were assessed using 13 and 6 EORTC Item Library (IL) items, respectively. All subscales are scored 0-100. Higher scores represent better PF and HRQoL; and higher scores represent worse CLL/SLL symptoms and fatigue. Pre-specified clinically meaningful within patient change (MWPC) thresholds of at least 10-point changes in each PRO score were used to categorize patients based on their individual change from Cycle 1 Day 1 (i.e., baseline). Mean changes from baseline and proportions of patients with improved, stable, and worsened PROs from baseline were summarized by treatment cycle. PRO data were presented from Cycle 1 to 24 (a 28-day cycle) since the study median progression-free survival by investigator assessment was 19.6 months. The data cutoff date was 22 July 2022. Results There were 263 patients with CLL/SLL at the time of analysis; median (Quartile 1 and 3) age was 69 (62, 74) years and the majority were male (68%). All patients had received prior cBTKi; 21% received 2 or more prior cBTKi lines and 20% discontinued from their most recent cBTKi treatment due to toxicity. The mean overall completion rate of PRO instruments was 83% at baseline. 76% of all patients in the analysis completed at least one subsequent PRO assessment. Baseline mean (±SD [standard deviation]) score was 80.8 (±19.5) for PF, 61.6 (±23.2) for QoL, 24.8 (±18.4) for CLL/SLL symptoms, and 33.5 (±24.7) for fatigue. The majority of patients reported stable or clinically improved outcomes from baseline at each of the post-baseline visits (through Cycle 24) for PF (proportion of stable/improved ranged from 72.5% to 95.5%), QoL (range 80.4% to 95.0%), CLL/SLL symptoms (range 77.8% to 96.3%), and fatigue (range 77.3% to 89.9%). Conclusion Overall, consistent with the favorable safety profile of pirtobrutinib, HRQoL and symptoms were stable or improved for over 70% of patients with pretreated R/R CLL/SLL throughout the first 24 cycles of pirtobrutinib treatment. These PRO data should be interpreted with caution due to single arm trial design and small numbers of patients available for assessment in later cycles.

Indirect Comparison of Efficacy of Zanubrutinib Versus Orelabrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma (R/R MCL): An Updated Analysis with Long-Term Follow up

Introduction Zanubrutinib and orelabrutinib, both the next generation Bruton's tyrosine kinase inhibitors (BTKis), are used in China as treatment options for R/R MCL. A further evaluation to understand the differences between these two novel BTKis is helpful for future study. Our previously indirect comparison has suggested a favorable PFS trend in zanubrutinib over orelabrutinib in R/R MCL patients (Song Y, et al. Invest New Drugs 2023). Here, we conducted an updated analysis to indirectly compare the long-term efficacy between zanubrutinib (median follow up: 35.3 months) and orelabrutinib (median follow up: 23.8 months) in patients with R/R MCL. Methods Individual patient data from zanubrutinib study (BGB-3111-206, n=86; NCT03206970) were adjusted to match the patients population profile of the orelabrutinib study (ICP-CL-00102, n=106; NCT03494179). As both trials were single-arm and were not linked through a common control arm, an unanchored matching-adjusted indirect comparison (MAIC) was performed to adjust for effect modifiers and prognostic variables. The baseline characteristics included in population adjustment were identified from literature review and clinical experts' assessment, which were sex, bulky disease, bone marrow involvement, disease stage, simplified Mantle Cell Lymphoma International Prognostic Index, prior autologous stem cell transplantation, and the number of prior lines of treatment. The efficacy outcomes included investigator-assessed progression free survival (PFS), overall survival (OS), and overall response rate (ORR). After matching, a weighted Cox model or a weighted logistic model will be employed to analyze the PFS and OS through hazard ratio (HR) or to analyze the ORR through odds ratio (OR). Response evaluations were only CT-based assessment in orelabrutinib study, while PET- and CT-based assessment were both performed in zanubrutinib study. Thus, the PFS assessed by PET and CT of zanubrutinib study were used to compare with the PFS assessed by CT of orelabrutinib study, respectively. Results After matching, the baseline characteristics were balanced between zanubrutinib and orelabrutinib, with the (effective) sample size of 70 and 106 in zanubrutinib and orelabrutinib, respectively (Table). PFS assessed by CT was significantly longer in the zanubrutinib versus the orelabrutinib (median PFS: not estimable [NE] vs. 22.0 months; HR, 0.54 [95% CI: 0.34-0.86]; P = 0.009) (Figure). Additionally, PFS assessed by PET of zanubrutinib was also significantly longer than the PFS assessed by CT of orelabrutinib (median PFS: NE vs. 22.0 months; HR, 0.63 [95% CI: 0.40-0.99]; P = 0.044). There are clinically meaningful differences observed for both the PFS (assessed by CT or PET) of zanubrutinib versus the PFS assessed by CT of orelabrutinib and the 24-month PFS rate (assessed by CT or PET) in the zanubrutinib versus that assessed by CT in the orelabrutinib (67.3% vs. 46.5% and 62.2% vs. 46.5%, respectively). Due to very limited number of OS events, the analysis of OS was not powered enough to detect a statistical meaningful difference between two groups (median OS: NE vs. NE; HR, 0.68 [95% CI: 0.36-1.27]; P = 0.223). However, the 24-month OS rate was numerically higher in the zanubrutinib than the orelabrutinib (83.7% vs. 74.3%). ORR was comparable between zanubrutinib and orelabrutinib (85.5% vs. 82.1%; OR, 1.28 [95% CI: 0.56-2.94]; P = 0.556). Conclusions MAIC results demonstrated that zanubrutinib had significantly longer PFS compared with orelabrutinib in the treatment of R/R MCL patients.

Phase I Study of a CD19-Directed CAR-T Cell Therapy for Relapsed/Refractory Mantle Cell Lymphomas(MCL)

Background: IM19 is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product, which is manufactured in China using a commercial process. We aimed to evaluate the efficacy and safety of IM19 in patients with relapsed or refractory mantle cell lymphomas in a Phase I clinical study. Methods: A phase 1 clinical trial has been launched to evaluate the safety and efficacy of IM19 for the treatment of relapsed/refractory MCL. We enrolled adult patients (aged ≥18 years) with relapsed or refractory MCL who had received at least 2 prior treatment regimens(including BTK inhibitor). Patients were assigned to one of two target dose levels of IM19 as they were sequentially tested in the trial (100×10⁶ CAR+ T cells [one or two doses], 200×10⁶ CAR+ T cells [one or two doses]). Leukapheresed patients could receive bridging chemotherapy based on investigator assessment of disease burden and tumor progression risk. Lymphodepleting (LD) chemotherapy was administered over 3 days, including fludarabine (30 mg/m2 i.v. daily) and cyclophosphamide (300 mg/m 2 i.v. daily), followed 2 days later by intravenous infusion of IM19 at the assigned dose. The first three subjects in each dose group will receive the second LD chemotherapy and infusion of IM19 CAR-T cells for consolidation treatment (with the same dosage as the first treatment) if the efficacy evaluation after the first infusion shows no progression and no DLT occurs. The investigators can determine the start time of consolidation treatment based on the patient's tolerance, but no later than 60 days after the first infusion. Efficacy was assessed at 1, 3, 9, 12, 18, and 24 months post first infusion. Safety events were monitored from beginning of LD through 2 years follow-up. The primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate. Results: Between Mar 3, 2022, and May 5, 2023, Five patients underwent leukapheresis for manufacture of CAR+ T cells (IM19) and all received bridging chemotherapy during the production of IM19. ALL 5 patients received LD and first infusion of IM19 at a dose of 100*10^6 CAR+ cells and no DLTs were observed. CRS was reported only in 1 patient(grade 1) and no patients developed ICANS. ALL 5 patients achieved CR on 28 days after first infusion. The median maximum CAR-T cells expansion (Cmax) was 156×10⁶ CAR+ cells/L, and median area under the curve from 0-28 days post-first infusion (AUC0-28d) was 860 day×CAR+ cells/L. 2 patients received the second LD chemotherapy and infusion of IM19 CAR-T cells for consolidation treatment (with the same dosage as the first treatment) at 44th days post first infusion. No DLTs，CRS or ICANS were observed after second infusion. Meanwhile, CAR-T cells can not be detected at 1, 4, 7, 10, 14, 21 and 28 days post second infusion by Flow cytometry in 2 patients. One patient maintained complete remission after 9 months of follow-up and another patient experience PD at 7th month after first infusion. For three patients who received single infusion of IM19, one maintained complete remission after 6 months of follow-up，one progressed at 3th month after infusion and one are still waiting for second efficacy evaluation. Conclusions: Initial data from this Phase I study demonstrate that use of IM19 resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory MCL. We observed that CAR-T cells cannot expand in vivo after secondary infusion. Therefore, secondary infusion may not be necessary.

The Efficacy of Obinutuzumab Combined with Pomalidomide and Covalent Btki for the Treatment of TP53 Mutated Mantle Cell Lymphoma (MCL): A Prospective, Open-Label, Single-Arm Study

Background TP53 mutated MCL lacks effective treatment options and has a poor prognosis, posing challenges in management. The guidelines recommend clinical trials as the first choice, pomalidomide as a new generation of immunomodulators (IMiDs), which have immunomodulatory effects and modulates the tumor microenvironment. Individual cases have been reported about pomalidomide be used for relapsed and refractory MCL. In this study, we investigated the application of Pomalidomide combined with Obinutuzumab and covalent BTKi (Ibrutinib and Zanubrutinib) for the treatment of TP53 mutated MCL to provide a new treatment evidence for clinical practice. Methods This was a prospective, single-center, clinical study. The key inclusion criteria include: confirmed diagnosis of MCL, age≥18 years, appropriate organ function, etc, both previously untreated and relapsed patients are eligible for inclusion. All patients receive Obinutuzumab (1000 mg d1) combined with Pomalidomide (4 mg d1-21) and covalent BTKi (Ibrutinib 560mg qd or Zanubrutinib 160mg bid)for 4 cycles, every 28 days as a cycle; If the treatment is effective, patients receive Obinutuzumab (1000 mg d1, every 3 months/time) combined with Pomalidomide (4 mg d1-14/28 days) and covalent BTKi triplet combination maintenance therapy until disease progression. The primary endpoint was overall response (Lugano 2004 criteria). Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. Minimal residual disease was assessed by NGS in peripheral blood. Results The study included 14 patients with relapsed or refractory mantle-cell lymphoma (12 patients) or previously untreated mantle-cell lymphoma (2 patient). Patients median age 59(44 to 74) with a male-to-female ratio of 6:1, and the lines of previous treatments ranged from none to three. 85.7%（12/14）of patients had mutation of TP53, 28.6%(4/14) had mutation of CCND1, 21.4%(3/14)had mutation of SMARCA4/SAMHD1. 64.3% had a higher Ki-67≥30% and 50% had a high-risk prognostic score of MIPI-c. The complete response rate at 4 course was 64.3% and the overall response rate was 85.7%. 9 patients underwent MRD testing after 4 cycles of treatment, and MRD negative was confirmed in 100% of the patients by NGS. The most common grade 3-4 adverse events were neutropenia (in 5 [35.7%] of 14 patients), thrombocytopenia (in 3 [21.4%] of 14 patients), infections (in 2[14.3%] patients), severe Covid-19 infection was in 2[14.3%] patients. Conclusions Our results provide preliminary evidence that the triplet combination of Obinutuzumab, pomalidomide, and covalent BTKi is an active regimen in MCL patients with the mutation of TP53, and should be evaluated in a prospective randomized controlled trial.

A Propensity Score-Matched Analysis on the Outcomes of Brexucabtagene Autoleucel from Zuma-2 Study and Allogeneic Stem Cell Transplantation from the EBMT Database in Relapsed and Refractory Post-Btki Mantle Cell Lymphoma

Introduction Brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 CAR T-cell therapy, is approved in the US for the treatment of relapsed/refractory (r/r) mantle cell lymphoma (MCL) and in Europe for r/r MCL after ≥2 prior lines of therapies, including Bruton's tyrosine kinase inhibitor (BTKi). The pivotal ZUMA-2 trial demonstrated very good efficacy of brexu-cel in r/r MCL and tolerable safety including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (Wang et al. J Clin Oncol. 2022). Allogeneic stem cell transplantation (alloSCT) is potentially curative but is associated with high treatment related mortality (TRM) and clinically significant graft-versus-host disease (GvHD). The optimal choice of treatment between brexu-cel and alloHCTs is unclear. We conducted a propensity score matched (PSM) analysis of brexu-cel and alloSCT in patients (pts) with r/r MCL. Methods Pts from ZUMA-2 were matched with alloSCT pts from the EBMT database. Selection criteria to identify pts in the EBMT registry were: r/r MCL diagnosis and receipt of alloSCT from 2010 to 2020, age ≥18 years, prior treatment with anti-CD20, prior anthracycline- or bendamustine containing regimens, and prior BTKi. We performed a 1:1 nearest neighbor matching without replacement, balanced for 5 baseline parameters: age, sex, number of prior treatment lines, time from diagnosis to cellular immunotherapy, and prior autologous stem cell transplantation (autoSCT). The primary endpoint was overall survival (OS) from cellular immunotherapy. The following secondary endpoints were analyzed: progression-free survival (PFS), TRM, defined as incidence of deaths which are related to the treatment and occurred in absence of disease progression, and rate of GvHD. Competing risks were defined as relapse, progression or treatment-unrelated death for TRM, and death for GvHD. The EBMT registry includes pts who actually underwent alloSCT. To characterize the dropout rate prior to cellular therapy, we conducted a multicenter intent-to-treat (ITT) analysis and identified 77 pts with r/r MCL for whom an unrelated donor search was initiated and an alloSCT was intended. Results Sixty-four of 68 pts from the ZUMA-2 cohort were included in the study; 4 pts were excluded because of inability to anonymize. A total of 270 pts who had undergone alloSCT and met eligibility criteria were identified in the EBMT registry. Patient characteristics between the brexu-cel and the alloSCT cohorts were imbalanced. Brexu-cel pts were older (p<0.001), had more prior lines of treatment (median 3 vs 2, p<0.001), had less prior autoSCT (41% vs 71%, p<0.001), and had longer time between diagnosis and treatment (53 vs 40 months, p=0.01). After 1:1 PSM matching, criteria were well balanced between cohorts. Median follow-up time was 36.5 and 46.4 months for the brexu-cel and the matched alloSCT cohort, respectively. PFS and long-term OS were similar between both cohorts (Fig. 1A). However, the risk of death within the first 12 months was significantly lower in the brexu-cel cohort vs the alloSCT cohort (logistic regression with inverse probability of censoring weighting, risk ratio=0.5, 95% confidence interval [CI] 0.3-0.9, p=0.02). This was mainly attributable to the significantly higher TRM rate in the alloSCT cohort (alloSCT vs brexu-cel: cause specific hazard ratio=7.7, 95% CI 1.9-31.6, p=0.005, Fig. 1B). The cumulative incidence of acute GvHD grade ≥3 at 3 months and chronic GvHD at 24 months was 17.9% (95% CI 9.1-29.0%) and 44.3% (95% CI 30.6-57.2%), respectively. In our ITT analysis, the dropout rate was significantly higher in the cohort intended to receive alloHCT (23%, [18/77]) vs the cohort intended to receive brexu-cel (8% [6/74]; Fisher test, p=0.01). For alloSCT, failure to proceed to cellular therapy was related to progression in 13%, change of patient's preference in 5% and ineligibility in 4%; in the brexu-cel cohort this was due to manufacturing failures in 4% and progression in 3%. Conclusion Brexu-cel is an effective treatment in pts with r/r MCL post-BTKi with a superior safety profile compared with alloSCT, as indicated by lower 12-month mortality, lower TRM, and absence of chronic GVHD-related morbidity. Despite efforts to match pts between the cohorts, the inherent limitations of this study, such as incongruent data sources and case selection bias, have to be considered. Additional analyses will be presented.

CD19-Directed CAR T-Cells (CD19-CAR) Combined with Acalabrutinib Achieves Durable Remissions in Patients with Relapsed or Refractory (r/r) Mantle Cell Lymphoma (MCL)

Background: MCL is an aggressive non-Hodgkin lymphoma (NHL) subtype which remains incurable despite improvements in progression free survival with consolidative autologous transplant and the introduction of novel targeted therapies [Dreyling et al. Blood 2012]. CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CD19-CAR) has shown durable disease control in r/r MCL, but current standard of care products are limited by high rates of grade 3+ immune-related toxicities [Wang et al. NEJM 2020]. We hypothesized that combining a naïve/stem-memory (T N/SCM) phenotype-enriched CD19-CAR T-cell product with the selective BTK inhibitor (BTKi) acalabrutinib would attenuate the rates of severe toxicities, improve durable remission rates, and obviate the need for indefinite use of acalabrutinib in r/r MCL. Methods: We conducted a phase 1 single center, prospective clinical trial (NCT04484012) evaluating a single infusion of T N/SCM-enriched CD19.28.z.EGFRt-CAR at a target dose of either 2x10 8 (DL1) or 5x10 8 (DL2) CAR+ cells (≤20% lower dose allowed) in combination with ongoing acalabrutinib 100 mg twice daily for patients with r/r MCL after at least 1 prior line of therapy. Patients were required to undergo at least 3 months but less than 7 months of treatment with a BTKi prior to enrollment without evidence of progression and with measurable disease per Lugano criteria. All patients were switched to acalabrutinib for protocol therapy prior to lymphodepletion, and planned to continue until day 180 post CD19-CAR infusion at which time all therapy would be discontinued. We report outcomes from the dose finding portion of the study. Descriptive statistics were utilized for baseline characteristics and survival analyses were calculated utilizing the Kaplan-Meier method. Investigator-assessed response rates were based on Lugano criteria. Minimal residual disease (MRD) status was determined using either multiparameter flow cytometry (FCM) or next-generation sequencing (NGS). Results: To date, 8 patients enrolled and have received CD19-CAR (n=4 at DL1; n=4 at DL2). Manufacturing was successful in 100% of patients. Median time from leukapheresis to product infusion was 53 days (range, 41-114). Treated patients were 75% male; with a median age of 63 years (range, 38-70); and median number of prior therapies of 2 (range, 2-3). All patients had bone marrow involvement, and had high risk features including progression of disease within 24 months (n=6), relapse after autologous HCT (n=2), TP53 mutations (n=6), Ki-67 ≥30% (n=4), and/or complex karyotype (n=1). Prior to enrollment, all patients had received BTKi (n=8 acalabrutinib) for a median of 6.1 months (range, 4.5-7.3). No BTK and PLC-γ mutations were detected in patients with available samples. The combination of acalabrutinib and CD19-CAR was well tolerated; 5 patients (63%; n=1 grade 2; n=4 grade 1) had cytokine release syndrome (CRS), with no severe cases. No patients (0%) had immune effector cell associated neurotoxicity syndrome (ICANS) [Figure 1A]. No patient required corticosteroids for toxicity management, and only 2 patients (n=2/5, 40%) required tocilizumab for CRS. There were no serious adverse events (SAEs), and no treatment discontinuations due to AEs observed. The best ORR was 88% [n=6 CR (75%); n=1 PR (13%)], with median time to best response of 28 days. In those 6 patients who achieved CR, 2 patients were FCM-MRD negative (<10 -4) and 2 were NGS-MRD negative (<10 -6) (n=4/6, 67%) [Figure 1B]. After a median follow-up of 18.5 months (range, 8.3-28.9), 5 of 6 patients remain in CR, while1 patient who achieved an initial CR relapsed at 9.2 months. At 1-year post-infusion, the cumulative incidence of relapse and NRM were 30% (95% CI, 3%-67%) and 0%, respectively. The 1-year PFS and OS were 70% (95% CI: 22%-92%) and 100%, respectively. Conclusion: The combination of CD19-CAR with acalabrutinib was well tolerated and effective, yielding an ORR 88% and MRD- rate 50% in a cohort of patients with high-risk MCL. Notably, CRS events were manageable and low grade, and no ICANS was observed. Enrollment is ongoing in the expansion cohort (DL2), and additional clinical and correlative analyses will be presented at the meeting.

Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies

Background: Small molecule GSK3B inhibitors were developed for solid tumors and neurological conditions, including Alzheimer's and Parkinson disease. Five GSK3B inhibitors achieved favorable safety and PK/PD profiles in a total of 22 Phase 1 and 2 clinical trials but no clinical response for any of these indications. GSK3B is the kinase that phosphorylates β-catenin to initiate its degradation, hence GSK3B small molecule inhibition results in rapid nuclear accumulation of β-catenin protein. Significance: Activating mutations in the Wnt/β-catenin pathway are common oncogenic drivers throughout all main types of cancer (n=64,812) but not found in B- and T-lymphoid malignancies (n=2,137). Studying tissue microarrays by β-catenin immunohistochemistry, lung, colon, breast, and melanoma specimen (n=57) showed consistently high levels of nuclear β-catenin, whereas B- and T-cell lymphomas (n=84) lacked β-catenin signal. Despite comparable mRNA levels, proteomic analyses revealed 60-400-fold lower β-catenin levels in lymphoid compared to epithelial tumors (n=1,389) suggesting that lymphoid malignancies rely on powerful mechanisms for β-catenin degradation, e.g. by GSK3B. Results: To study the effects of β-catenin activation in human cells, we induced expression of stabilized form of β-catenin in 18 lymphoid (B- and T-ALL, MCL, DLBCL, PTCL) and four myeloid leukemia cell lines. In B- and T-lymphoid cells, β-catenin accumulation compromised clonal fitness, colony formation and induced cell death, but increased competitive fitness and colony formation in myeloid leukemia cells. CEBPα-mediated reprogramming of B-ALL cells into a myeloid phenotype reversed the deleterious effects highlighting that effects of β-catenin-accumulation strictly depend on lymphoid lineage-identity. RNA-seq studies upon inducible activation of β-catenin in lymphoid cells, revealed transcriptional repression of Myc and Myc target genes as principal gene expression change. Unlike activating β-catenin:TCF7 complexes in epithelial cells, our global interactome studies in B- and T-ALL and lymphoma cells identified repressive β-catenin complexes with lymphoid-specific Ikaros zinc finger (IKZF1/2/3) proteins and several components of the NuRD complex including Mta1/2, Gatad2a/b, Chd4, HDAC1/2. Interactome and ChIP-seq analyses revealed that β-catenin together with lymphoid-specific Ikaros factors recruited repressive NuRD complex members to deacetylate H3K27 and repress MYC superenhancer (SE) regions. Genetic deletion of both IKZF1 and IKZF3 or HDRT-based mutation of Ikaros binding motifs within the Myc-SE enabled resistance to β-catenin accumulation. To leverage this previously unrecognized vulnerability of lymphoid malignancies, we examined five clinically approved GSK3B small molecule inhibitors that achieved favorable safety profiles at micromolar plasma concentrations in clinical trials for neurological disorders and solid tumors. Strikingly, LY2090314 and CHIR99021 were effective at low nanomolar concentrations in B- and T-cell malignancies that expressed lymphoid Ikaros factors. At IC50 concentrations of <5 nM, GSK3B-inhibitors induced massive accumulation of β-catenin, repression of MYC and acute cell death. In B-ALL cells with IKZF1-deletion, expression of the remaining IKZF3 factor was sufficient to retain full sensitivity to GSK3B-inhibition. Deletion of β-catenin, however, abolished the effects of GSK3B inhibitors and relieved suppression of MYC, demonstrating accumulation of β-catenin represents as central mechanism of action. Preclinical in vivo treatment experiments of refractory B-ALL and mantle cell lymphoma PDX validated small molecule GSK3B-inhibition as strategy to overcome conventional mechanisms of drug-resistance. Conclusions: B- and T-lymphoid malignancies not only lacked expression of β-catenin but critically depend on GSK3B for effective β-catenin degradation. Our interactome studies in lymphoid tumors revealed that β-catenin formed repressive complexes with lymphoid-specific Ikaros and NuRD complex factors. Strikingly, GSK3B small molecule inhibitors engage this new pathway at low nanomolar concentrations and demonstrated favorable safety profiles in Phase 1 and Phase 2 trials. Safety and efficacy of GSK3B-inhibitors opens up an immediate path for repurposing these agents towards refractory B-cell malignancies.

Inhibition of Lysine Acetyltransferases p300/CBP Overcomes BTK Inhibitor Resistance in Mantle Cell Lymphoma Cells

Background: Although Bruton's Tyrosine Kinase inhibitors (BTKis) are effective against relapsed refractory mantle cell lymphoma (MCL), the limited duration of therapeutic response and the emergence of resistance remain clinical issues. We conducted a CRISPR/Cas9 screen to identify the genes responsible for BTKi sensitivity and resistance. Materials and Methods: To identify the genes responsible for BTKi resistance, we used a CRISPR library (Kosuke Yusa, V3), targeting 18,740 human genes. We compared three BTKis, ibrutinib, acalabrutinib and tirabrutinib, using DMSO as a control. We transduced Granta519, an ibrutinib-resistant MCL cell line expressing Cas9 with the CRISPR library lentiviruses. Next, we counted sgRNA copy numbers using next generation sequencing after a two-week drug treatment. We identified 76 genes that sensitized cells to the BTKis upon knockout. After excluding common essential genes based on the Cancer Dependency Map portal (depmap.org/portal/), we ranked these genes according to the extent to which the combination of their knockout and BTKis inhibited cell proliferation. Results: Lysine acetyltransferases (KATs), p300 and CBP were ranked first and ninth, respectively. Knockout of p300 or CBP alone moderately decreased cell numbers, where as their combination with BTKi treatment significantly decreased cell numbers. To further validate this synergistic effect, we performed an MTS assay in combination with p300/CBP inhibitors (C-646 and A-485) and ibrutinib in MCL cell lines (Granta519 and Mino). The p300/CBP inhibitor increased ibrutinib sensitivity, leading to a up to four-fold greater suppression of cell viability. This effect was even greater than that of existing drugs, including venetoclax (a BCL-2 inhibitor), and idelalisib (a PI3K inhibitor), which are thought to have synergistic effects. The synergistic effect of a p300/CBP inhibitor and ibrutinib was also observed in long-term cultures for up to two weeks in both ibrutinib-resistant and ibrutinib-sensitive MCL cell lines. Furthermore, combination treatment resulted in an enhancement of G0/G1 cell cycle arrest and an increase in apoptotic cells in the MCL cell lines. To elucidate the mechanism underlying this synergistic effect, we measured the expression of IκBα mRNA as an indicator of NFκB activity by real-time PCR. In Granta519, ibrutinib alone caused an initial decrease in IκBα mRNA expression followed by a rebound increase. However, the addition of A-485 decreased the rebound and suppressed IκBα mRNA expression. These results indicate that ibrutinib and A-485 cooperatively suppress NFκB activity. The combination of ibrutinib and A-485 synergistically suppressed phosphorylation of PLCγ2 and of AKT as confirmed by Western blotting. This suggests that downstream PLCγ2 and AKT activation might be involved in ibrutinib resistance. Lentiviral overexpression of p300 in Granta519 cells enhanced phosphorylation of AKT. On the other hand, ibrutinib suppressed the expression of p300, and conversely, p300/CBP inhibitors suppressed the expression of BTK. These data suggest that the expression of p300 and BTK are dependent on each other. We hypothesize that direct or indirect interactions may occur through phosphorylation by BTK and acetylation by p300. Conclusion: Our CRISPR screen identified lysine acetyltransferases p300/CBP as BTK inhibitor resistance genes in human MCL cells. The combination of a p300/CBP inhibitor and a BTK inhibitor synergistically suppresses both BTK and AKT, leading to NFκB suppression. Taken together, we first identified that the combination of p300/CBP inhibition and BTK inhibition could be a promising strategy for treating patients with MCL.

Optical Genome Mapping Provides New Molecular Insights in High-Risk Mantle Cell Lymphoma: A Lysa Study

Introduction Around 5-10% of mantle cell lymphoma (MCL) patients are primary refractory to chemotherapy. They have an extremely dismal prognosis, as do responsive patients that relapsed within 12 months. Despite better understanding of risk factors and evolving classifications, these scores do not predict all high-risk patients and were not designed to guide treatment strategy in newly diagnosed MCL. Optical genome mapping (OGM) is a cutting-edge technology developed for genome-wide detection of structural variants (SVs) including balanced and unbalanced translocations, inversions, insertions, deletions, duplications as well as copy number variations (CNVs). Methods High-risk (HR) patients included in the prospective phase III LyMa trial (NCI NCT00921414; Le Gouill et al. NEJM 2017), were identified as patients experiencing early progression of disease (i.e. within 1 year after randomization). We performed OGM in the HR cohort using available frozen tumoral tissue. Low-risk patients (LR) were used as a control. The data were analyzed with the Bionano Solve software. Results Among 299 MCL patients included in the LyMa trial, 31 high-risk MCL patients were identified (10.4%). OGM was performed in 15 patients: 8 HR and 7 LR. OGM successfully detected the t(11;14) in all patients. We detected a median of 38 SVs (range, 16-129) and 12 CNVs (range, 1-119) per case, higher in HR patients than in LR patients (median 51 vs. 32, p=0.07 for SVs; and 14 vs. 5, p=0.11 for CNVs). Chromothripsis and chromoplexia occurred in both cohorts, but breakage-fusion-bridge (BFB) cycles was only observed in 2 HR MCL. HR MCL were characterized by frequent loss of 17p/ TP53 (63% vs. 0%, p=0.03), and rare deletions of 11q22-q23/ ATM (13% vs. 57%, p=0.12). Three HR patients had no TP53 deletions, two of whom presented a gain of BCL2. Gain of UBR5, that influence transcription and posttranscription processes, was found in 3/8 HR patients compared to 1/8 LR patients. MTAP deletion that has been recently described as biomarkers predicting refractory MCL was found in 5/8 HR MCL and is associated with CDKN2A/2B deletions, compared to 0/8 LR. MTAP deletion was associated with TP53 deletions in two HR MCL, that is supposed to confer resistance to PRMT5 targeted therapy (Sloan SL et al. Blood 2023). Deletion of the chromatin modifier MEF2B occurred in 3/8 HR MCL and 1/8 LR MCL. Two patients had deletion of SMARCA4 at diagnosis, that confers resistance to the BCL-2 inhibitor venetoclax (Agarwal et al. Nature Med 2018). Mutations in the NF-κB alternative pathway, responsible for resistance to ibrutinib, are found in both LR and HR patients. Conclusion In this small cohort of MCL patients included in a trial, complex structural alterations were identified by OGM at the time of diagnosis. OGM is a very promising technology that demonstrated its potential in the cytogenetic prognostic staging of MCL.