Therapy For Mantle Cell Lymphoma Research Articles

Resistance to PRMT5-targeted therapy in mantle cell lymphoma

AbstractMantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma, and patients who relapse on targeted therapies have poor prognosis. Protein arginine methyltransferase 5 (PRMT5), an enzyme essential for B-cell transformation, drives multiple oncogenic pathways and is overexpressed in MCL. Despite the antitumor activity of PRMT5 inhibition (PRT-382/PRT-808), drug resistance was observed in a patient-derived xenograft (PDX) MCL model. Decreased survival of mice engrafted with these PRMT5 inhibitor–resistant cells vs treatment-naive cells was observed (P = .005). MCL cell lines showed variable sensitivity to PRMT5 inhibition. Using PRT-382, cell lines were classified as sensitive (n = 4; 50% inhibitory concentration [IC50], 20-140 nM) or primary resistant (n = 4; 340-1650 nM). Prolonged culture of sensitive MCL lines with drug escalation produced PRMT5 inhibitor–resistant cell lines (n = 4; 200-500 nM). This resistant phenotype persisted after prolonged culture in the absence of drug and was observed with PRT-808. In the resistant PDX and cell line models, symmetric dimethylarginine reduction was achieved at the original PRMT5 inhibitor IC50, suggesting activation of alternative resistance pathways. Bulk RNA sequencing of resistant cell lines and PDX relative to sensitive or short-term–treated cells, respectively, highlighted shared upregulation of multiple pathways including mechanistic target of rapamycin kinase [mTOR] signaling (P < 10-5 and z score > 0.3 or < 0.3). Single-cell RNA sequencing analysis demonstrated a strong shift in global gene expression, with upregulation of mTOR signaling in resistant PDX MCL samples. Targeted blockade of mTORC1 with temsirolimus overcame the PRMT5 inhibitor–resistant phenotype, displayed therapeutic synergy in resistant MCL cell lines, and improved survival of a resistant PDX.

Chimeric antigen receptor T-cell therapy for mantle cell lymphoma with central nervous system involvement: Progress, but not perfect.

Chimeric antigen receptor T-cell therapy for mantle cell lymphoma with central nervous system involvement: Progress, but not perfect.

Clinical efficacy and safety of chimeric antigen receptor T-cell therapy for mantle cell lymphoma with secondary central nervous system involvement.

Data describing outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti-CD19 CAR T-cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1-year progression-free survival was 47%. Seven patients developed immune-effector-cell-associated-neurotoxicity-syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti-CD19 CAR T-cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted.

The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma-a pooled trials analysis.

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting.We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50-0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61-0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53-0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54-0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment.

Estimating the Associated Burden of Illness and Healthcare Utilization of Newly Diagnosed Patients Aged ≥65 with Mantle Cell Lymphoma (MCL) in Ontario, Canada.

With the emergence of therapies for mantle cell lymphoma (MCL), understanding the treatment patterns and burden of illness among older patients with MCL in Canada is essential to inform decision making. A retrospective study using administrative data matched individuals aged ≥65 who were newly diagnosed with MCL between 1 January 2013 and 31 December 2016 with general population controls. Cases were followed for up to 3 years in order to assess healthcare resource utilization (HCRU), healthcare costs, time to next treatment or death (TTNTD), and overall survival (OS); all were stratified according to first-line treatment. This study matched 159 MCL patients to 636 controls. Direct healthcare costs were highest among MCL patients in the first year following diagnosis (Y1: CAD 77,555 ± 40,789), decreased subsequently (Y2: CAD 40,093 ± 28,720; Y3: CAD 36,059 ± 36,303), and were consistently higher than the costs for controls. The 3-year OS after MCL diagnosis was 68.6%, with patients receiving bendamustine + rituximab (BR) experiencing a significantly higher OS compared to patients treated with other regimens (72.4% vs. 55.6%, p = 0.041). Approximately 40.9% of MCL patients initiated a second-line therapy or died within 3 years. Newly diagnosed MCL presents a substantial burden to the healthcare system, with almost half of all patients progressing to a second-line therapy or death within 3 years.

CO114 Real-World Experience Among Patients with Mantle Cell Lymphoma after Covalent Bruton Tyrosine Kinase Inhibitor Use in the United States: A Retrospective Electronic Health Record-Derived Study

This retrospective observational study was designed to evaluate the treatments and outcomes among patients after receiving covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy for mantle cell lymphoma (MCL).

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.

Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma.

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.

Combined Inhibition of CDK2 and BCL2 Overrides Resistance to Targeting BTK and CDK4/6 in Mantle Cell Lymphoma Therapy

Mantle cell lymphoma (MCL) remains incurable due to the development of drug resistance, despite the plethora of therapies available. Each successive treatment failure is associated with a more rapidly proliferating disease and fewer treatment options. Understanding the drug-resistance mechanism and developing effective, well-tolerated, new therapies for MCL are urgently needed. Unrestrained proliferation of MCL cells is mainly driven by aberrant cyclin D1 expression and dysregulated CDK4 activity that promotes cell cycle progression from G1 to S. In our phase 1 clinical trial inhibiting CDK4/6 with palbociclib and BTK with ibrutinib (PALIBR) in recurrent MCL, the complete response rate (CR) was 42% compared to 21% in response to ibrutinib alone, despite a comparable 67% overall response rate. Moreover, 5 patients remain on therapy (2 CR and 3 PR) for ~ 8 years, suggesting that CDK4/6 inhibition deepens and prolongs the clinical response to BTK inhibition in MCL. However, resistance emerges in some patients. To elucidate the underpinnings, we undertook integrative longitudinal genomic analysis of sequential tissue and blood specimens (n=53) of 27 MCL patients before, during therapy and on progression, and 4 treatment-naïve MCL patients and 4 normal subjects as controls. Whole exome and whole transcriptome sequencing of freshly isolated MCL cells and B cells revealed that resistance to PALIBR is rooted in homozygous deletion of RB1 (direct target of CDK4/6) or compound copy number variation (cCNV) - concurrent hemizygous loss of RB1 and CDKN2A (p16, CDK4/6 inhibitor) and gain of CDK4. In other resistant patients, the RB protein is silenced by translational termination mutation. Single-cell RNA-sequencing (scRNA-seq, 210,000 cells) of corresponding PBMCs using a unique in-house MCL RNA reference library reveals that MCL cells comprise 4 transcriptomically distinct clusters. Cluster 1 (C1) is similar to quiescent normal B cells; C2 resembles hyper-activated B cells enriched for signatures of BCR and cytokine signaling; C3 represents non-proliferating, long-lived MCL cells; and C4 is highly proliferative, expanding with disease progression. RNA velocity analysis further uncovered that C2 fuels the transition to C4 with disease progression, whereas C3 is a terminal node (Fig 1). In C2 and C3 MCL cells, CDK2 is highly elevated, indicating evasion of CDK4/6 inhibition, and PIK3IP1 (negative PI3K regulator) is silenced, suggesting that compensatory PI3K activation in BTKi resistance (Chiron et al, Cancer Discovery 2014) is secondary to loss of cell cycle control. BCL2 is markedly elevated in C2, greater in C3 MCL cells along with increases in anti-apoptotic BCL2L1(BCL-XL) and BCL-2A1 and decreases in pro-apoptotic PMAIP1 (NOXA) expression. This suggests combined CDK2 and BCL2 inhibition as a rational approach to override CDK4/6i and BTKi resistance. Indeed, combined inhibition of CDK2 with PF-07104091 and BCL2 with venetoclax (PF-VEN) cooperatively impaired growth and killed ibrutinib-resistant MAVER-1 cells, more effectively in the isogenic derivative MAVER-1R cells which we generated to recapitulate cCNV in PALIBR resistance - depletion of RB protein through translational termination mutation (W99, AAF 75%) in RB1, loss of CDKN2A and gain of CDK4. Mechanistically, MAVER-1R cells are accelerated in G1 to S progression, based on elevation of CDK2 and TK1 expression and cell cycle profiling. They are intrinsically apoptotic and vulnerable to BCL2 inhibition due to a marked reduction in cells expressing anti-apoptotic BCL2L1 and IRF4, and universal expression of pro-apoptotic PMAIP1 (NOXA). Importantly, combined CDK2 and BCL2 inhibition synergistically kills MCL cells of a patient resistant to PALIBR ex vivo. In summary, by longitudinal genomic analysis, we have provided the first evidence that 1) resistance to CDK4/6i and BTKi stems from MCL intrinsic cCNV; 2) MCL cells comprise 4 major transcriptomically distinct clusters; cluster 2 expressing copious CDK2 and BCL2 is pivotal in fueling proliferation of MCL cells in resistance; 3) cluster 3 cells also accumulate with resistance due to longevity; 4) combined inhibition of CDK2 and BCL2 overrides resistance to CDK4i and BTKi, in MCL cell lines and primary MCL cells from PALIBR resistant patient. Combined inhibition of CDK2 and BCL2, therefore, represents a mechanism-based strategy to overcome CDK4/6i and BTKi resistance in MCL therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Patterns and Outcomes in Relapsed/Refractory Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is an uncommon B-cell lymphoma with heterogeneous clinical presentations and treatment response. Over the last two decades, the frontline therapy for MCL has evolved and we previously characterized this shift and the associated improvement in survival outcomes (Castellino, Blood Advances 2022). The evolved landscape of frontline therapy, as well as the emergence of new agents, may have impacted second-line (2L) treatment choice, response and survival. In this study we investigated the treatment patterns and survival outcomes for patients with R/R MCL treated with 2L therapy. Methods: Consecutive patients with newly diagnosed MCL from September 2002 through June 2015 were offered enrollment in the Mayo Clinic/University of Iowa Molecular Epidemiology Resource (MER). All participants were prospectively followed for disease relapse/progression, subsequent treatments, and death. Patients who initiated 2L therapy for R/R MCL through 2021 were included in this analysis. Clinical characteristics, 1L, and 2L therapies were abstracted from MER and medical records. Treatment outcomes were calculated from the start of 2L therapy. Event-free survival (EFS) was defined as time from 2L initiation to progression, retreatment, or death due to any cause. Overall survival (OS) was defined as the time from 2L initiation to death due to any cause. A spline plot was generated to visualize the hazard ratio (HR) for EFS and OS over time from the initiation of 2L treatment. Three eras were defined based on the timing of 2L treatment: 2003-2009 (Era 1), 2010-2014 (Era 2), and 2015-2021 (Era 3). Eras were chosen to align with approval of novel therapies. Results: Among a total of 343 MCL patients, with a median follow up of 7.6 years, 59 died without progression and 194 relapsed. Of those, 177 received 2L therapy and had complete treatment information available (N=58 in Era 1, N=71 in Era 2, N=48 in Era 3). At the time of 2L therapy, 127 (72%) patients had an age >60 years, 143 (81%) were male, 139 (79%) had stage III/IV disease, and simplified MIPI was low in 37 (34%), intermediate in 42 (39%), and high in 30 patients (28%; simplified MIPI missing in 68 patients). No statistical differences in age, sex, stage, or simplified MIPI were found among different eras. The patterns of 2L treatment by era, and previous 1L treatment, are shown in Figure 1. There were substantial heterogeneities in both 2L and 1L treatments across all eras. Notable changes in 2L treatment patterns were observed among different eras, likely related to drug availability and 1L treatment choices. Few to no patients received a Bruton's tyrosine kinase (BTK) inhibitor in 2L in Era 1 (N=0) and Era 2 (N=4; 6%), largely due to lack of availability, in contrast to Era 3 (N=21; 44%). The use of bendamustine-rituximab (BR) in 2L was minimal in Era 1 (N=2; 3%) and less in Era 3 (N=8; 17%) compared to Era 2 (N=26; 37%). High dose cytarabine use in 2L was higher in Era 1 (N=4; 7%) and Era 2 (N=4; 6%) compared to Era 3 (N=0). The percentage of patients who received autologous or allogeneic stem cell transplant appeared similar: Era 1 (N=5; 9%), Era 2 (N=10; 14%), and Era 3 (N=6; 13%). The median follow-up from 2L therapy in Eras 1-3 was 13.3, 8.7, and 4.2 years, respectively. The overall response rate to 2L therapy was 57%, 79% and 83%, respectively (complete response rate 30%, 52% and 51%, respectively). The estimated 2-year EFS rate was 21% (95% CI: 13-34) in Era 1, 39% (95% CI: 29-52) in Era 2, and 58% (95% CI: 44-75) in Era 3. The estimated 5-year OS rate was 31% (95% CI: 21-46) in Era 1, 38% (95% CI: 28-52) in Era 2, and 69% (95% CI: 56-86) in Era 3. The spline plot depicts a trend in decreased hazard in EFS and OS over time (Figure 2). For example, compared to 2L start in April 2012 (median 2L start date, reference point), 2L start in January 2008 and January 2017 had a HR for EFS of 1.6 and 0.8 respectively, and a HR for OS of 1.4 and 0.4, respectively. Conclusion: 2L therapy for MCL evolved with time and was likely affected by 1L treatment choice as well as the availability of treatment options at the time of need. The changes in 2L treatment correlated with improved EFS and OS, suggesting that treatment advances were associated with improved outcomes in patients with R/R MCL. Larger real-world studies are needed to further understand treatment patterns, changes with time, and the association with outcomes in R/R MCL, including 2L and subsequent lines of therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Randomized Phase 2 Trial of First-Line Bendamustine-Rituximab (BR)-Based Induction Followed By Rituximab (R) ± Lenalidomide (L) Consolidation for Mantle Cell Lymphoma ECOG-ACRIN E1411

Introduction: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. Bendamustine-rituximab (BR) is commonly used. Rituximab consolidation is often added post-BR but lacks randomized supporting data. Bortezomib (V) and lenalidomide (L) have activity against MCL. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to BR (BVR vs BR) induction and/or by addition of lenalidomide (L) (15 mg/d days 1-21/28) to rituximab (LR vs R) consolidation. Prior report (ASCO 2021) indicated no significant benefit of addition of V to BR. Here we report efficacy and toxicity of LR vs R consolidation. Methods: E1411 randomized 373 patients into induction (step 1) between 2012-16, stratified by MIPI (low v intermediate v high) and age (<60 v ≥60). Randomization was to 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR, or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease (PD) during induction proceeded to consolidation (step 2) R vs LR. For the endpoint of PFS from start of consolidation, patients were stratified by induction strategy (BR vs BVR) for the pooled analysis of LR vs R. For step 2, 290 eligible treated consolidation patients were required to provide 89.4% statistical power to demonstrate a 37.4% reduction in the hazard ratio, using stratified log-rank test with a 10% 1-sided alpha. Results: Demographics did not differ between the groups: median age 67 (range 42-90), 73% men, ECOG PS 0-1 98%, MIPI Low/Intermed/Hi 40/31/29%. Of 293 patients that registered to consolidation, the efficacy population was 276 (17 ineligible or not treated). The planned number of consolidation treatment cycles were completed in 95/140 (67.9%) LR vs 90/136 (66.2%) R; off treatment reasons were PD 11 vs 22, AEs 15 vs 7, other 19 vs 17, respectively. Estimated PFS at 2-yrs 85.8% LR (95% CI 78.6-90.7) vs 77.7% R (95% CI 69.5-84.0) (1-sided stratified log-rank p=0.416); hazard ratio for LR vs R = 0.96 (80% CI 0.75, 1.23). Of 119 PFS events (57 LR; 62 R), 29 are death without PD, 40 with PD have died, 50 alive post-PD. With median PFS follow-up of 5.8 years, median PFS estimated in the pooled arms is 6.1 years from step 2 registration. Of 74 pts not in CR post-induction, 50% (n=37) converted to CR (18 on LR & 19 on R arm). Calculating overall PFS from study registration (includes induction + consolidation), the 2-yr PFS and median PFS (years) for the 4 individual arms were BR-R (80.7%, 6.0), BVR-R (82.8%, 6.6), BR-LR (83.3%, 7.8), BVR-LR (94.2%, 7.7). Limiting the analysis to patients over age 60 (87% of patients on study) the 2 year and median PFS in each arm, starting from study registration, was BR-R (81.2%, 6.0), BVR-R (81.0%, 6.2), BR-LR (81.2%, 5.7), BVR-LR (93.2%, 7.7). Grade ≥ 3 toxicities were 87.0% LR vs 64.1% R, mostly neutropenia 58.9 vs 19.7%, with febrile neutropenia 6.8 vs 3.5%. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was lung infection/pneumonitis/URI (9.6 vs 4.2%); with 3 potentially treatment-related deaths (MI & invasive SCC on LR, MDS on R). Second malignancies by arm were: BR-R (17), BVR-R (21), BR-LR (23), BVR-LR (34) [data is from 64 unique patients; 19 patients had >1 second malignancy]. Conclusions: Lenalidomide did not significantly improve the primary endpoint of PFS when added to R as consolidation of BR-based induction as initial MCL therapy. Further follow-up continues as > ½ of pts remain alive and without progression. Each treatment arm was tolerable and deliverable to the majority of patients. The high CR rate and mPFS of 6+ years from start of BR-based induction + R-based fixed duration consolidation support this approach for 1st-line MCL therapy in individuals not appropriate for more intensive approaches, and as a platform for broader clinical trials (e.g. EA4181). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Provider Perceptions of Shine and Ibrutinib, Bendamustine, and Rituximab in the First-Line Setting

Background: According to the National Cancer Care Network guidelines, chemoimmunotherapy with bendamustine + rituximab (BR) is considered standard first-line (1L) therapy for mantle cell lymphoma (MCL), followed by autologous hematopoietic cell transplant (ASCT) consolidation. Most MCL patients who are refractory to BR therapy and/or ineligible for ASCT will relapse. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, recently received accelerated approval as a second line (2L) chemotherapy for MCL to help prevent relapse in ASCT- ineligible patients. Expanding upon the success of the ibrutinib' approval in the 2L, the SHINE trial (NCT01776840) sought to determine the efficacy of ibrutinib in combination with BR in the 1L setting as a therapy for older, ASCT-ineligible patients with stage II-IV MCL. At the American Society of Clinical Oncology (ASCO) 2022 annual conference, it was reported that the SHINE trial had satisfied the primary endpoint of improved progression-free survival. We surveyed providers' perceptions of the SHINE trial and the likelihood that they would adopt ibrutinib + BR (IBR) therapy in the 1L setting. Methods: At two live events held in June and July of 2022, U.S.-based oncologists who treat MCL (n=89) were invited to hear discussions on select abstracts presented at ASCO 2022, including an abstract on the SHINE trial. The demographic profile of our participant population was collected via a pre-event survey. Participants' perceptions and reactions regarding the SHINE trial were collected in real-time using an electronic keypad. Not all participants who attended answered every survey question. Descriptive statistics were used to assess participants' perceptions and reactions. Results: Within a typical 3-month period, 35 (39%) participants reported that they are referred < 1 new patient with MCL, while 34 (37%) participants reported that they are referred ≥ 1 new patient with MCL. Seventy-three (82%) participants self-identified as community providers. Participants possessed an average of 22 years of clinical experience. During clinical hours, the median amount of time participants reported they focus on direct patient care was 90% (20%-100%). Sixty-three (71%) of participants stated that they prefer standard BR therapy as a 1L therapy for patients diagnosed with MCL. Sixty-four (72%) of the participants reported atrial fibrillation, and 54 (61%) reported bleeding 54 (61%) as the most concerning issues when considering IBR therapy. Sixty-nine (78%) participants agreed that if FDA approved, IBR would be likely adopted as their primary, 1L MCL regimen. Conclusions: Overall, our participants' perceptions of the SHINE trial data were positive. Following the presentation of the SHINE trial and data for the IBR regimen in MCL, participants were most concerned with the atrial fibrillation and bleeding adverse events, respectively. Despite these safety concerns, nearly 4 in 5 (78%) participants consider it likely that they would prescribe the IBR regimen based on the SHINE study results and assuming FDA approval, as a 1L therapy for patients diagnosed with MCL. Second generation BTK inhibitors have demonstrably improved safety and efficacy profiles, and many of our participants expressed a desire to see further studies of second generation BTK inhibitors added to the BR therapy backbone as a potential future regimen of interest.

Targeting the HSP90-MYC-CDK9 Axis to Overcome Dual Resistance to BTK Inhibition and CAR-T Therapy in Mantle Cell Lymphoma

Targeting the HSP90-MYC-CDK9 Axis to Overcome Dual Resistance to BTK Inhibition and CAR-T Therapy in Mantle Cell Lymphoma

Mutations of ATM Confer a Risk of Inferior Survival in Patients with TP53-wild Type Mantle Cell Lymphoma

Background: Despite improved approaches to prognostication in mantle cell lymphoma (MCL), the impact of specific genomic aberrations is not well-described beyond TP53, which is well recognized as a high-risk marker across malignancies and widely assessed at time of diagnosis. However, since outcomes in patients without TP53 aberrations can be highly variable and difficult to predict, additional molecular markers are needed to identify patients who are at high risk for early relapse and inferior OS (Bond et al, Blood Adv 2021). In this study, we used comprehensive whole exome and transcriptome sequencing to genomically assess the prognostic impact of recurrent abnormalities in patients with MCL with and without TP53 aberrations. Methods: The Atlas of Blood Cancer Genomes (ABCG) project is a worldwide effort to systematically profile the genetic alterations and expression changes in all blood cancers. We recruited MCL patients with detailed clinical data available and subjected their tumors to whole exome and transcriptome sequencing. TP53-aberrant cases were identified from the genomic and diagnostic data. Progression-free survival (PFS) and overall survival (OS) were measured from the date of diagnosis until date of progression/relapse or death (PFS) or death (OS) using the Kaplan-Meier method and statistical comparisons by the logrank test. Results: Whole exome and whole transcriptome sequencing was performed successfully for 252 patients with MCL. Consistent with previous descriptions of the disease, median age at diagnosis was 65 years (range: 32-96), and 73% of patients were male. Seventy-five percent of patients had stage IV disease, and MIPI score was high, intermediate, or low in 34%, 34%, and 32% of patients, respectively. Ki67 proliferative index was ≥30% in 48% of patients with available data (n=115). Most patients received commonly used MCL therapies. Of the 185 patients for whom first-line treatment was known, 28% received bendamustine-containing regimens, 42% received cytarabine-containing regimens, and the remaining 30% received other regimens. Twenty-one percent of patients underwent autologous stem cell transplant consolidation as part of first-line therapy. Seventeen percent of patients had blastoid or pleomorphic histology, and 3% had leukemic non-nodal type MCL. Median PFS for the entire cohort was 41 months, and median OS was 138 months. As expected, patients with a confirmed TP53 abnormality (n=39) had inferior median OS compared to TP53-WT patients (n=84; 39 months vs 138 months, p<0.001). Recurrent mutations identified in TP53-aberrant and TP53-WT patients are presented in Figure 1. Among TP53-WT patients, the following genes were mutated in ≥10% of cases: ATM (45%), KMT2D (23%), PTPN13 (13%), NOTCH1 (13%), NSD2 (11%), and SPEN (10%). Incidence of ATM mutations in TP53-aberrant patients was 21% and was less common in patients with TP53 mutations (14%) rather than deletions (30%). Presence of an ATM mutation (median variant allele frequency 43%; range 15-96%) in TP53-WT patients was associated with inferior median PFS (38 months vs 138 months for ATM WT, p=0.023) (Figure 2); median OS was also shorter in patients with ATM mutations (104 vs 138 months, p=0.035). Although the incidence of ATM mutations was lower in TP53-aberrant patients, there was no significant association between ATM mutation and PFS or OS in that subgroup. Conclusions: To our knowledge, this study represents the largest genomic characterization of clinical outcomes in MCL patients. These findings suggest a pathogenic role for ATM mutations in patients with TP53-WT MCL and provide molecular insights into their heterogeneous outcomes. Although ATM mutations have been previously shown to be mutually exclusive with TP53 mutations (Mareckova et al, Leukemia & Lymphoma 2019), to our knowledge this is the first study that shows prognostic differences by ATM mutation status among TP53-WT patients. Our data indicate that ATM mutations are a significant prognostic factor and should be assessed at diagnosis along with TP53. Further clinical investigation of ATM mutations in TP53-WT MCL patients will be important to determine how this molecular marker may inform risk stratification and treatment approaches. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Development of a Potent DNA Damaging Agent LP-284 for Treatment of Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is a rare and aggressive type of non-Hodgkin lymphoma that is characterized by the hallmark t(11;14) translocation and subsequent deregulation of expression of the Cyclin D1 (CCND1) gene. Immunochemotherapy followed by autologous stem cell transplantation and/or maintenance therapy remains the most common frontline choice for eligible individuals. Additionally, the introduction of bruton's tyrosine kinase inhibitors (BTKi), anti-CD19 chimeric antigen receptor T-cell therapy, and targeted therapies have advanced the treatment of r/r (relapsed/refractory) MCL. Unfortunately, not all patients are eligible for these therapies and durable remission is rare. Alternative therapies with novel mechanisms of action and increased efficacy are urgently needed for MCL patients. LP-284 is a novel small molecule and DNA damaging agent being developed for the treatment of MCL. The DNA lesions induced by LP-284 are repaired by transcription-coupled DNA repair and can trigger apoptosis in tumors with DNA damage repair deficiencies. As LP-284 DNA lesions block transcription, we hypothesize that LP-284 directly starves transcriptionally addicted tumors such as those with actively transcribing onco-fusion genes such as CCND1. We previously reported that LP-284 shows nanomolar potency across 6 MCL cell lines, including cells resistant to BTKi, bortezomib (Btz.), and venetoclax. Here we report LP-284's efficacy in MCL xenograft mouse models and its ability to induce ATM and subsequent gamma-H2AX phosphorylation, transcriptomic response in MCL cell lines, and preliminary toxicological profile in dogs. Methods and Results: In JEKO1-derived MCL xenograft mice, LP-284 (2 or 4 mg/kg; i.v.) was tested to evaluate its survival benefits and efficacy compared to ibrutinib (Ibr.; 50mg/kg; oral) or Btz. (1 mg/kg; i.p.). LP-284 significantly (p< 0.001; n=7 or 8 per group) increased the overall survival of these mice from 20 days in the vehicle control group to 41 days (LP-284, 2 mg/kg) and 48 days (LP-284, 4 mg/kg). Additionally, LP-284 at either concentration showed significantly increased tumor growth inhibition (TGI) compared to Ibr. or Btz. At day 17 post treatment, 113% TGI was observed in the 4 mg/kg LP-284 arm and 63% TGI was observed in the 2 mg/kg LP-284 arm, whereas Ibr. or Btz. only resulted in 8% and 22% TGI, respectively. We also tested if LP-284 (4 mg/kg) could rescue tumors that grew after treatment of Ibr. or Btz. Our data showed that LP-284 treatment resulted in near complete TGI in tumors pretreated by and grew resistant to Ibr. or Btz. No tumor regrowth nor animal death was observed 15 days after the last dose of LP-284. Additionally, we performed western blot and RNAseq on JEKO1 and REC1 cells treated by LP-284 or the vehicle for 24 hours. LP-284 treatment resulted in increased phosphorylation of ATM and gamma-H2AX in JEKO1, indicating the formation of double-strand DNA breaks. Differential gene expression analysis indicated that LP-284 reduced the expression of CCND1 by ~2 fold and there was a significant down-regulation of the MYC pathway targets. The toxicological profile of LP-284 was evaluated in a non-GLP repeat-dose toxicity study in dogs. LP-284 was administered i.v. once a day on days 1, 8, and 15 and at 0.3, 0.6, or 1.2 mg/kg/doses. Adverse effects in body weight, clinical pathology and pathology were only observed at ≥0.6 mg/kg/dose. LP-284-related changes in hematology were noted at ≥0.3 mg/kg/dose. At the microscopic level, 0.3 mg/kg/dose LP-284-related hematological changes were considered non-adverse based on the small magnitude and no associated changes in clinical hematology compared with the control animals. Therefore, under the condition of this study, the No Observed Adverse Effect Level (NOAEL) was determined to be 0.3 mg/kg/dose. Conclusions: Taken together, our results demonstrated that LP-284 has significantly increased efficacy over Ibr., Btz., and vehicle treated MCL animal models. In addition, Ibr./Btz. resistance could be overcome by LP-284. We also demonstrated that LP-284 reduced the expression of the onco-fusion gene CCND1 and the MYC pathway, which are both genes and pathways implicated in MCL. LP-284's strong potency in in vivo MCL tumor models, novel mechanism of action, and the progress in toxicological studies are in favor of further development of LP-284 as a novel MCL therapy.

Favorable Overall Survival Following First and Second Relapse of MCL with Availability of Novel Therapies: Results from the Lion Prospective Observational Registry

Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma (NHL) associated with a high rate of relapse following frontline treatment, but with expanding treatment options for relapsed/refractory (RR) disease. Historically, outcomes for RR MCL have been unfavorable compared with indolent NHL subtypes, however survival data with more recently approved therapies is less well characterized. We report survival data following 2nd and 3rd line therapy for RR MCL in a large contemporary prospective cohort. Methods: We included patients (pts) with RR MCL enrolled in the Lymphoma Innovations ORIEN Network (LION) prospective observational registry at one of seven participating centers. The LION Cohort is a 7-center cohort project which enrolls patients with relapsed/refractory NHL. All patients signed written consent. Clinical data were abstracted from medical records using a standardized protocol. Event free survival was estimated using the method of Kaplan-Meier and defined as time from start of 2nd (EFS2) or 3rd (EFS3) line treatment until progression, subsequent treatment, or death censoring pts alive and without further treatment or relapse at last follow-up. Overall survival was estimated using Kaplan-Meier and defined as time from start of 2nd (OS2) or 3rd (OS3) line treatment until death, censoring pts alive at last follow-up. Comparisons of EFS and OS were performed using the log-rank test. Results: A total of 128 eligible pts with RR MCL consented between 2/5/2020 and 7/8/2022. Pts received 2nd line treatment between 2002- 2021; 84% (107/128) after November 2013. Baseline characteristics included male sex in 95 pts (77%), stage III/IV disease in 110 pts (91%), progression within 24 months (mo) of initial treatment (POD24) in 43 pts (34%). Median age at first relapse was 65 years. Second line treatments included BTK inhibitors (BTKi) in 61 pts (50%), bendamustine based therapy in 14 pts (12%), lenalidomide and/or bortezomib based therapy in 14 pts (12%), venetoclax in 3 pts (3%), and other classes of treatment in 30 pts (25%). After a median follow-up of 45 mo, the estimated median EFS2 was 26 mo (95% confidence interval [CI] 15-38), with a 24-month estimated EFS2 of 51% (95% CI 41-60) and 5-year estimated EFS2 of 24% (95% CI 14-34). The estimated 24-month OS2 was 91% (95% CI 84-96) and 5-year estimated OS2 was 84% (95% CI 74-90). Third line treatments included BTKi in 36 pts (47%), chimeric antigen receptor T-cell (CAR-T) in 10 pts (13%), bendamustine based therapy in 5 (7%), venetoclax in 3 (4%), lenalidomide and/or bortezomib in 3 (4%), and other treatments in 20 (26%). After a median follow-up of 34 mo from 2nd relapse, the estimated median EFS3 was 19 mo (95% CI 12-49), with a 24-month EFS3 of 47% (95% CI 34-58) and 5-year EFS3 of 29% (95% CI 16-43). The estimated 24-mo OS3 was 84% (95% CI 72-91) and 5-year estimated OS3 of 73% (95% CI 57-84). POD24 was associated with inferior EFS2, with estimated median EFS2 9.7 mo (95% CI 5.1-23.6) vs 34.4 mo (95% CI 18.4-45.9) for non-POD24 pts (p=0.0025). POD24 from frontline treatment was also associated with inferior EFS3 among pts with indexed third line therapy with median EFS3 15.6 mo (95% CI 8-37) for POD24 and 49.1 mo (95% CI 11-84) for non-POD24 pts (p=0.04). No significant differences were observed in EFS2 between pts treated with BTKi, with median EFS2 21 mo (95% CI 10-34), compared with other classes of second-line treatment with median EFS2 of 35 mo (95% CI 14-46, p=0.37). Likewise, EFS3 was not significantly different between patients treated with third-line BTKi with estimated median EFS3 of 54 mo (95% CI 11-not reached) compared to CAR-T with estimated median EFS3 of 9 mo (95% CI 3-19), compared to other third line treatments with median EFS3 of 20 mo (95% CI 10-49, p=0.4). Conclusions: We observed a median EFS2 of 26 mo and median EFS3 of 19 mo in a contemporary prospective cohort of pts with RR MCL. We did not observe an association between class of treatment received and EFS2 or EFS3, but observed inferior EFS2 and EFS3 for patients with POD24 following frontline therapy compared with patients with later first relapse highlighting the higher risk nature of this population. The observed OS2 and OS3 outcomes in this prospective cohort exceed historical estimates for relapsed MCL prior to availability of newer therapies, provide context for interpreting single arm trial results, and may inform future clinical trial design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Outcomes and Toxicities of Outpatient R-CHOP/R-DHAP in Patients with Mantle Cell Lymphoma Eligible for Autologous Stem Cell Transplant

INTRODUCTION: Despite a significant increase in median overall survival (OS) over the past three decades, mantle cell lymphoma (MCL) remains incurable with no standard frontline therapy. The addition of R-DHAP to R-CHOP with autologous stem cell transplant (ASCT) in the European MCL Network - MCL younger trial showed significant improvement in median progression free survival (PFS), although some concerns remain regarding increased toxicity. On this basis, R-CHOP/R-DHAP was approved as first line therapy for MCL at CancerCare Manitoba (CCMB) in 2016. In contrast to the original study, R-DHAP is currently administered in an outpatient setting in Manitoba. OBJECTIVE: To assess the real-world, non-trial PFS, OS, and toxicities of patients with MCL eligible for autologous stem cell transplant receiving R-CHOP/R-DHAP, administered on an outpatient basis, as induction therapy in Manitoba. METHODS: All patients with MCL in Manitoba eligible for R-CHOP/R-DHAP induction between Jan 1, 2016 and Dec 31, 2021 were identified through the CCMB. Individual patient records were obtained and reviewed for baseline demographic data, laboratory data, treatment characteristics including response, and treatment toxicities. SPSS was then used for statistical analysis to calculate PFS and OS using the Kaplan-Meier method. RESULTS: 25 charts were identified. 5 were excluded based on duplicate data for a total of 20 patients (85% male). The mean age at diagnosis was 54.4 (range 42-67). 75% had stage IV disease and 35% had constitutional symptoms. 15% of patients had ECOG ≥2 at diagnosis. 50% had elevated LDH at diagnosis, and the mean β-2-microglobumin was 3.5mg/L (range 1.9-16.1). 10% of patient's largest nodal dimension was >=7.5cm, 20% had disease with Ki67>=40%, and 15% had high risk disease by MIPI. The median number of chemotherapy cycles completed was 6 (range 2-6), with 50% requiring modification to therapy (5% progression, 20% infection, 20% ototoxicity, 20% nephrotoxicity, 5% corneal toxicity, 5% patient preference). 70% received ASCT, with 100% complete response by PET post-ASCT. 75% of all patients received maintenance rituximab, with a median of 8 cycles completed (range 2-8). At the end of follow up, there were 3 progression events, 3 deaths, and 1 death attributed to MCL. At a median follow up of 56.8 months, median PFS and OS were not reached. CONCLUSION: Our real-world data show feasibility of administering R-CHOP/R-DHAP in the outpatient setting with comparable outcome and toxicities to original study where R-DHAP was administered as inpatient. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Statins are well-tolerated, inexpensive, and widely prescribed as cholesterol-lowering agents to treat hyperlipidemia and to prevent cardiovascular diseases through the blockage of the mevalonate metabolic pathway. These drugs have also shown promising anti-cancer activity through pleiotropic effects including the induction of lymphoma cell death. However, their potential use as anti-MCL agents has not been evaluated so far. The present study aimed to investigate the activity of simvastatin on MCL cells. We evaluated the cytotoxicity of simvastatin in MCL cell lines by CellTiter-Glo and lactate dehydrogenase (LDH) release assays. Cell proliferation and mitotic index were assessed by direct cell recounting and histone H3-pSer10 immunostaining. Apoptosis induction and reactive oxygen species (ROS) generation were evaluated by flow cytometry. Cell migration and invasion properties were determined by transwell assay. The antitumoral effect of simvastatin in vivo was evaluated in a chick embryo chorioallantoic membrane (CAM) MCL xenograft model. We show that treatment with simvastatin induced a 2 to 6-fold LDH release, inhibited more than 50% of cell proliferation, and enhanced the caspase-independent ROS-mediated death of MCL cells. The effective impairment of MCL cell survival was accompanied by the inhibition of AKT and mTOR phosphorylation. Moreover, simvastatin strongly decreased MCL cell migration and invasion ability, leading to a 55% tumor growth inhibition and a consistent diminution of bone marrow and spleen metastasis in vivo. Altogether, these data provide the first preclinical insight into the effect of simvastatin against MCL cells, suggesting that this agent might be considered for repurpose as a precise MCL therapy.

Real-World Practice Patterns and Outcomes Following Bruton Tyrosine Kinase Inhibitors (BTKi) in Older Patients with Mantle Cell Lymphoma (MCL): A Population-Based Analysis

Background: Although there has been population-based evidence on real-world patterns of BTKi use and early discontinuation in CLL, the experience in MCL has not been well described on a large scale. A single center study (Cheah et al, Ann Onc 2015) found many patients discontinued BTKi shortly after the initiation due to progression or intolerance; survival outcomes following discontinuation were very poor. These issues might be more challenging in the older population, given the prevalent comorbidities and frailty, and relatively limited treatment options for MCL compared to the younger group. In this population-based analysis, we used the SEER-Medicare database to examine real-world BTKi use and outcomes following discontinuation of BTKi in older patients with MCL. Methods: We selected adults ≥ 66 years old, diagnosed with MCL 2007-2017, with continuous Medicare A/B/D coverage (through 2019 or death), who received MCL therapy. We captured the regimens of 1st through 5th lines based on the outpatient claims and limited our analysis to patients who received their first BTKi (ibrutinib or acalabrutinib as a single agent or combined with other chemoimmunotherapy) during 2nd to 4th line of therapy. We described the baseline characteristics of the overall study population. We reported the median duration of BTKi use with interquartile range (IQR) and the rates of continuation of the same BTKi at 12 and 24 months (m) by applying Kaplan-Meier (K-M) method (discontinuation or death as complementary events of interest). We estimated compliance in patients who received ≥ 2 consecutive BTKi prescriptions, based on proportion of days covered (PDC), and defined good compliance as PDC ≥ 80%. We used K-M method to estimate overall survival (OS) in the overall population. Similarly, we estimated OS following the initiation of next line therapy (non-BTKi) following BTKi discontinuation and described the regimens used following BTKi. Results: We included 334 patients (median age: 74, 67% men, 95% White, 14% with Elixhauser comorbidity score ≥ 3, 19% with frailty), with 66%, 25%, and 9% receiving BTKi at the 2nd-4th line, respectively. The median follow-up was 37.3 m since the initiation of BTKi and 78.1 m since the start of first line therapy. The median duration of BTKi therapy was 4.6 m (IQR: 2.1-13.0 m). Among patients alive at 12 and 24 m after initiation of BTKi, 42% and 27% had continued BTKi, respectively. Among patients with at least two consecutive BTKi prescriptions (N=284), 88% met the criteria of good compliance. The OS since initiation of BTKi was 19.3 m. During follow-up, 188 (56%) patients discontinued their first BTKi agents and 73 patients died while being on BTKi. Following discontinuation, 132 patients received a next line of therapy, 98 received non-BTKi-based regimens (see Table for details of regimens) and the rest switched to another BTKi agent. During a median follow-up of 22.2 m, the median OS was 7.5 m following the initiation of non-BTKi-based next line of therapies (Figure). The OS was poor regardless the regimens of next line of therapy following BTKi. Patients who received BTKi for ≥ 1 year had significantly better OS (Table). Conclusions: As one of the first population-based real-world analysis on BTKi discontinuation among MCL patients, our study demonstrated that the duration of BTKi use (4.6 months) in older patients with MCL is much shorter than that reported in the clinical trial setting (8.3 months; Wang et al, NEJM 2013). Outcomes after the discontinuation of BTKi remained dismal even with other novel therapies as the next line of treatment, e.g., lenalidomide- or venetoclax-based regimens. Improvements to both real-world administration of BTKi and novel combinations are likely needed to improve real-world outcomes in older patients with MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Is There Still a Role for Transplant for Patients with Mantle Cell Lymphoma (MCL) in the Era of CAR-T Cell Therapy?

Opinion statementFor years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton’s tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies.