Mantle Cell Lymphoma Pts Research Articles

Heterogeneity of TP53 Mutations in Mantle Cell Lymphoma- Challenges in Risk Stratification and Subclassification

Introduction: Somatic mutations in TP53 occur in approximately 10-20% of mantle cell lymphoma (MCL) patients (pts) at diagnosis. Eskelund and colleagues (Blood 2017) demonstrated poor survival among 20 pts with TP53-mutated MCL following intensive induction and transplant, and reported sequence-level variant data. However, TP53 mutations are heterogeneous, and few studies in MCL provide detailed sequencing data or variant allele frequency (VAF). Furthermore, the clinical impact of TP53 mutations may vary, and there is no algorithm shown to predict outcome for a given variant. We hypothesized that high VAF, or presence of a “disruptive” TP53 mutation as reported in squamous cell carcinoma (SCC; Poeta NEJM 2007), may adversely impact prognosis in MCL. To address this, we analyzed all MCL pts with available TP53 sequencing data at our center, including exact TP53 variant data and VAF, sMIPI score, and classification as disruptive vs not, and impact on survival from time of testing. Methods: Institutional records were analyzed with IRB approval, identifying 65 MCL pts who underwent sequencing for TP53 mutation from any tumor sample, as a single-gene assay or part of a panel. We analyzed VAF, type of mutation, and sMIPI score at time of TP53 testing. We classified TP53 mutations as “disruptive” or not according to method of Poeta and colleagues; these mutations result in a STOP codon, or an amino acid polarity change in the L2-L3 DNA binding domain of the TP53 protein (Poeta NEJM 2017). The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) from time of TP53 testing to death or last follow up, and the log-rank test was used to compare outcomes based on TP53 mutational status. Among TP53 mutated cases, Cox proportional analyses were performed to explore the impact of the following covariates on survival: disruptive status, VAF, sMIPI score at time of TP53 testing, and presence of complex cytogenetics. Results: Sixty-five pts underwent TP53 sequencing, and 23 (35%) had a TP53 mutation (mTP53+). mTP53+ pts had inferior PFS (p=0.03) compared to TP53 wild-type, and a trend toward inferior OS (p=0.07); median OS was 26 months (95% CI: 8.1, NA) from time of TP53 testing. Ki-67 index, blastoid histology, and age were similar between mTP53+ and wild-type status, but mTP53+ pts had a higher rate of complex cytogenetics (> 3 lesions; 48% vs 26%). SMIPI was also higher in mTP53+ pts (median score 6, interquartile range (IQR) range 4-7) vs TP53 wild-type pts (median 4, IQR range 3-5.2). MTP53+ pts were more likely to have received a BTK-inhibitor (BTK-I) (91 % vs 64%) and CAR-T therapy (39% vs 18%). Details of the mTP53+ subset are shown in Table 1; 4 pts had >1 TP53 mutation, median VAF was 40%, and 30% of pts had a disruptive mutation. Among mTP53+ pts, on univariate analysis, higher sMIPI at time of TP53 testing (p=0.003) was associated with worse OS (Table 2). In a multivariable Cox model including VAF >= 40%, presence of disruptive mutation, sMIPI, and complex cytogenetics, only sMIPI at time of TP53 testing was associated with inferior OS (p=0.02). Conclusion: TP53 variants in MCL are diverse, and in our cohort were largely unique from those reported by Eskelund and colleagues (Blood 2017). Despite now-routine application of sequencing and improvements in therapy, both of which may attenuate the negative prognostic impact of TP53 mutation, we confirmed poor outcomes in mTP53+ MCL. Among mTP53+ pts, only sMIPI predicted inferior OS on both univariate and multivariate analysis. Higher VAF and adoption of a clinical algorithm from SCC failed to discriminate among TP53 variants in terms of prognosis. Larger datasets of uniformly tested MCL pts are needed to elucidate prognosis among TP53 mutation variants, and improve understanding and management of mTP53+ MCL.

Acalabrutinib with Rituximab As First-Line Therapy for Older Patients with Mantle Cell Lymphoma - a Phase II Clinical Trial

Introduction - Previously, our group reported results from ibrutinib with rituximab in older mantle cell lymphoma (MCL) patients (pts) with an atrial fibrillation rate of 22%. To develop a chemotherapy-free combination for elderly MCL pts, we designed this phase II clinical trial to investigate the efficacy and safety of acalabrutinib with rituximab (AR) as a first line approach in MCL pts (≥ 65 yrs). Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT05214183. Pts received acalabrutinib 100 mg orally twice a day and intravenous rituximab, weekly for first 4 weeks, followed by once a month for 12 months and subsequently once every 2 months totaling 24 months. Acalabrutinib was continued. The primary objective was to assess best overall response rate (ORR) rate after AR. Responses were assessed as per Lugano response criteria. Clonoseq based minimal residual disease (MRD) assessment was performed. Adverse events were coded as per CTCAE version 5. Genomic studies are ongoing. Results - Among 50 pts, the median age was 69 years (range: 65-81). Male/female were 36 and 14 respectively. Bone marrow was positive for MCL in 45/50 (90%) and GI tract in 35/47 (74%) pts. Forty-six pts had classic morphology while three were blastoid and one was pleomorphic. Ki-67% was available in 42 pts - 13/42 (31%) had high Ki-67% and 29/42 (69%) had a low Ki-67% (< 30%). Simplified MIPI risk stratification included: low (n=4), intermediate (n=35) and high risk (n=11). TP53 aberration status (mutations or deletion) was available in 43/50 pts and 12 pts had aberrant TP53 while 31/43 did not have aberrant TP53. Thirty-nine pts had baseline next generation sequencing (NGS) on tumor tissue biopsy and 25/39 (64%) had ≥ 3 mutations. Median number of AR cycles was 12 (range: 3-24). One pt was not evaluable for response at 12 weeks. Overall, the best response was 94% ORR and 90% CR, 4% PR; 6% were non-responders. Median number of cycles to get complete metabolic response was 3 (range 2-7). Fourteen pts were MRD negative at last follow-up of the 28 evaluable pts. With a median follow up of 17 months, the median PFS and OS were not reached (2 year 92% and 96% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. Nine pts (18%) came off study - 3 for adverse events (syncope, atrial fibrillation, intolerance), 3 for disease progression, one melanoma recurrence, one pt choice and one with an unusual monocytosis. Overall, 2 pts died (1 on trial with primary progression). The most common all-grade toxicities were fatigue (82%), myalgia (64%), headache (38%), bruising (28%) and <1% were grade 3 or higher. Among 50 pts, 1 pt had recurrence of grade 2 atrial fibrillation (2%) and one pt had recurrence of grade 3 unstable angina. Conclusions -Chemotherapy-free frontline therapy with AR is highly effective and safe and induced early CR in older pts with MCL.

Genomic and Transcriptomic Profiles of Blastoid and Pleomorphic Mantle Cell Lymphoma Are Distinct from Classic Histology Mantle Cell Lymphoma

Introduction - Patients (pts) with mantle cell lymphoma (MCL) with blastoid (B-MCL) and pleomorphic (P-MCL) histology are traditionally considered as high risk; however, there is a paucity of information regarding the differences between P-MCL and B-MCL compared to classic MCL (C-MCL) histology. In this study, we present a comprehensive genomic and transcriptomic portrait of B-MCL and P-MCL. Methods - We conducted comprehensive molecular profiling using whole exome (WES) and bulk RNA sequencing (RNA seq) among the evaluable pt samples (n=260) from our center (MDA cohort) and previously reported cohorts from Bea et al ( PNAS 2013) (n=29) and Agarwal et al ( Nature Medicine 2019) (n=15) respectively. Pts with WES were (n=195) including n=151, n=29 and n=15 for MDA, Bea and Agarwal respectively while 175 pts underwent RNA sequencing (all MDA). This cohort study was conducted under an IRB approved protocol for MCL patients at our center. Patient characteristics, somatic mutation profiles, copy number abnormalities and gene expression profiles (GEP) were analysed. Lymph node, bone marrow, blood samples and any other tissue biopsies were utilized. DNA and RNA were extracted from FFPE sections from lymph nodes and non-nodal tissues. Joint WES and RNA-seq mutation calling, GEP, and transcriptomic cell deconvolution were performed using the BostonGene automated pipeline. WES and bulk RNA sequencing were performed with Illumina HiSeq4000 using a 76bp paired end configuration. Results - Among the 195 pts with WES, the distribution of tissue types was 133 nodal, 33 bone marrow, 25 blood, 4 spleen and other tissues. Mutation distribution and copy number analysis was performed for 99 C-MCL , 72 B-MCL, and 20 P- MCL pts. In the mutation profile, we found that the percentage of ATM mutations was comparable among the 3 pt groups (51%/50%/39%). The frequency of TP53 mutations was significantly lower in C-MCL (23%) compared to B-MCL (51%) and P-MCL (39%) (p < 0.001; Figure 1). NOTCH2 gain of function mutations were found in 11% of B-MCL and 4.6% of C-MCL but not detected in P-MCL. The NFkBIE Y254Sfs*13 mutation was exclusively found in B-MCL. Blastoid samples were enriched with CCND1 E36K mutations (7 of 16 CCND1 mut), while C-MCL had 2 of 16. P-MCL had a higher prevalence of SMARCA4 and DNMT3A mutations compared to B-MCL and C- MCL. We further observe that P-MCL pts exhibited higher polyploidy and aneuploidy than B-MCL and C-MCL ( p < 0.001; Figure 2), indicating that compared to C-MCL, genomic instability decreased from P-MCL to B-MCL. The most frequent arm level amplifications in P-MCL compared to B-MCL were 8q (=MYC) (38%) and 18q (=BCL2) (38%). In C-MCL and B-MCL the 3q (=BCL6) was frequently amplified (28% and 30%). MALT1, Bcl2 and CARD11 gene amplifications were highest in P-MCL. These differences were further supported when the data were compared at the gene level. Comparison of the deletion frequencies revealed that 9p (CDKN2A/B) and 17p (TP53) were frequently lost in B and P-MCL (~40%). Del8p, 6q, 10q, and 16q were frequently deleted in P-MCL compared to B-MCL. At the segmental level, mostly altered segments included del9p21.1-24.3, del13q14.2-14.3, and del17p12-13.3 that span genes like CDKN2A/B, miR15A, and TP53. Next, we performed GSEA analysis using RNA-seq data. The metabolic reprogramming pathway was upregulated in both B and P-MCL compared to C-MCL (p = 0.0096). The proportion of pts with an immune desert (D) “cold” tumor microenvironment associated with refractory disease was higher in P-MCL (50%) than in C or B-MCL. Conclusions -B and P-MCL exhibit a distinct molecular profile compared to C-MCL. P and B-MCL have the highest degree of aneuploidy and exhibit an immune cold tumor microenvironment. Further studies are ongoing to refine the molecular differences among B and P-MCL compared to C-MCL.

Six Years Follow up of Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hyper CVAD/MTX in Patients (age ≤ 65 years) with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-1 Clinical Trial

Background - We reported the efficacy and safety of using a combination of ibrutinib plus rituximab (IR) induction followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years)patients (pts) with mantle cell lymphoma (MCL), Wang M et al Lancet Oncology 2022. Here we report the long term follow up of this study. Methods - We enrolled 131 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. High risk pts received ibrutinib for 1 year and rituximab once every 2 months for 24 months after completion of part B. Results - Among the 131 pts, the median age was 56 yrs (range - 35-65). High Ki-67 (≥30%) in 58/117 (49.5%) pts, 10 pts (8%) had high risk simplified MIPI score, 15 pts (11%) had aggressive MCL (blastoid/pleomorphic) and 114 pts (87%) had initial bone marrow involvement. Fifty percent of the patients had Ki-67 (≥30%). ORR in part-A was 98% (87% CR). After completion of part A and part B, ORR was 90% (89% CR). After a median follow up of 71 months, 43 patients progressed/died. The median progression free survival (PFS) and overall survival (OS) were not reached. Overall, 30 pts (23%) relapsed after treatment, including 5 who transformed to aggressive MCL. PFS among pts with high and low Ki-67% was 42 months vs not reached (P=0.01) while no difference was observed in OS. PFS was significantly shorter in pts with aggressive histology (p=0.001) but not the OS. PFS was similar in pts who received maintenance vs no maintenance therapy. Overall, 8 pts died (4 with progression, 2 due to disease transformation, one on study due to multiple complications including splenic hematoma, cardio-pulmonary arrest and progression and the last one expired outside and came off study due to encephalitis). 50 pts came off study for various reasons [30 disease progression (including 5 transformation), 10 pt choice, 8 intolerance, 1 second cancer and 1 lost to follow up]. Long term, grade 3-4 toxicities on part A were 6% myelosuppression and 10% each with fatigue, myalgia and rashes and 2% mucositis. Maintenance therapy did not show high toxicities. Conclusions -Long term follow up of chemo-free induction with IR induced durable and deep responses in young MCL pts in the frontline setting. Short course R-HCVAD chemotherapy minimized toxicities and consolidated responses. IR maintenance improved survival outcomes. This combined modality treatment approach may significantly improve young MCL pts outcomes across all risk groups.

Ki-67 Expression of 50% Is the Optimal Cut-Off to Predict Survival Outcomes in Mantle Cell Lymphoma (MCL): A Pooled Analysis from CALGB 50403 (Alliance) and MCL Real-World Study Cohort

Introduction The Ki-67 index has been previously shown to be prognostic, wherein the cut-off of 30% was associated with inferior survival outcomes (Determann O et al, Blood 2008) in newly diagnosed MCL patients (pts). However, this cut-off determination was made in pts treated with CHOP/R-CHOP as the first-line treatment, controlled only for MIPI, and predates the advent of novel agents. Short diagnosis to treatment interval (DTI ≤ 14 days) was recently shown to be prognostic in newly diagnosed MCL but its association with Ki-67 is unknown. We sought to determine the optimal Ki-67 cut-off in MCL and its prognostic relevance in the modern era. Methods This is a pooled analysis of 2 large datasets, one prospective (CALGB 50403) and one retrospective (MCL real world study [MCL-RWS]). CALGB is now part of the Alliance for Clinical Trials in Oncology. CALGB 50403 is a phase II randomized study wherein newly diagnosed MCL pts received intensive induction chemoimmunotherapy (IIC) followed by autologous transplant, and posttransplant rituximab. The MCL-RWS included adult pts (≥18 years [yrs]) with MCL treated from 2000 to 2017 at 12 participating US sites. Pts from sites in the MCL-RWS that enrolled on CALGB 50403 were excluded. Ki-67 was scored by central review in 10% increments in the CALGB 50403 and per institutional standard in the MCL-RWS. We assessed Ki-67 as a continuous variable and used a restricted quadratic spline fit to find an optimal cut-off. We looked at the associations between Ki-67 and other known/ established MCL prognostic markers including MIPI and DTI. The outcome parameters were PFS and OS. Time-to-event endpoints were evaluated by Kaplan-Meier and Cox proportional hazard methods. Results Among the 793 pts (n=666, MCL-RWS and n=127, CALGB 50403) in the pooled analysis, Ki-67 was available in 385 pts (311 from MCL-RWS and 74 from CALGB 50403). The median OS (mOS) and PFS (mPFS) in the entire cohort (n=793) was 11.8 years and 4.7 years, respectively. The two groups (gps), those with and without Ki-67 data, were well balanced including MIPI and DTI. The median age was 62 yrs (range, 32-88), 81% males, 94% with ECOG performance status (PS) 0-1 and 84% with stage 4. We found a Ki-67 cut-off of 50% to be optimal as the relative hazard of death rises after 50%. Pts in the Ki-67 >50% gp had significantly higher proportion with short DTI (36% vs 17%, p<0.001), ECOG PS ≥2 (12% vs 5%, p=0.02), elevated LDH (58% vs 39%, p=0.005), and MIPI ≥6.2 (38% vs 20%, p=0.007) compared to Ki-67 of ≤50%. Ki-67 >50% was associated with significantly inferior PFS with a hazard ratio (HR) of 2.10 (95%CI 1.50-2.92) compared to Ki-67 ≤50% with a mPFS of 2.1 vs 5.3 yrs, respectively, regardless of the age (young [≤65 yrs], 2.6 vs 5.3 yrs or old [>65 yrs], 1.1 vs 5.4 yrs) or receipt of IIC (2.2 vs 5.9 yrs). Figure 1 shows the statistically significant difference in PFS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% remained prognostic for PFS in multivariable analysis (MVA) after adjusting for significant variables in univariable analysis (UVA) including short DTI, ECOG PS ≥2, stage 4, elevated LDH, and MIPI ≥6.2 with adjusted HR (aHR) 2.19, 95%CI 1.38-3.48, p <0.001. Ki-67 >50% was associated with significantly inferior OS with a HR of 2.10 (95%CI 1.33-3.32) compared to Ki-67 ≤50% with a mOS of 9.4 yrs vs not reached (NR), respectively, regardless of the age or receipt of IIC. Figure 2 shows the statistically significant difference in OS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% was not prognostic for OS in MVA after adjusting for significant variables in the UVA (MIPI and sex), aHR 1.79, 95% CI 0.92-3.49, p=0.08. Similar findings were seen in multivariable analysis with Ki-67 >30%, which showed no prognostic significance (aHR 1.46, 95%CI 0.82-2.58, p=0.19). Because of disparate datasets, we performed sensitivity analysis looking at the prognostic relevance of in individual datasets (CALGB 50403 and MCL-RWS) and found Ki67 >50% was prognostic for PFS and OS in both of the datasets consistent with the primary analysis. Conclusions This study evaluating the optimal Ki-67 cut off for pts with newly diagnosed MCL in the modern era found that Ki-67 > 50% was prognostic for PFS but not OS in MVA. A potential reason for the lack of prognostic relevance for OS in this more recent dataset is the availability of effective options at relapse. We also found that short DTI was associated with high Ki-67 gp which is a novel finding.

Minimal Residual Disease (MRD) Testing By Next Generation Sequencing (NGS) after Two Cycles (CY) of Non-Intensive Chemoimmunotherapy Is Predictive of Remission Duration and Need for Maintenance Therapy (MT) in Previously Untreated Mantle Cell Lymphoma (MCL): A Wisconsin Oncology Network Study

Introduction: Despite the variable course of MCL, limited prospective markers exist to identify more indolent disease. MCL is often diagnosed in older patients (pts) less able to tolerate intensive approaches. Bendamustine/rituximab (BR) is a standard non-intensive regimen for MCL, and use of MT remains controversial. Emerging data in MCL suggest a correlation between achieving MRD negativity (MRD-) and progression-free survival (PFS). The GALLIUM study (Marcus R, et al, N Engl J Med 2017) previously showed improved PFS with a bendamustine/obinutuzumab (BO) induction compared with BR in follicular lymphoma, and we postulated this benefit may be observed in MCL. Using MRD testing, we predicted that MT may be omitted in pts achieving MRD- status after induction BO chemoimmunotherapy for MCL. Methods: Adult pts ≥18 years (yrs) with previously untreated MCL who were ineligible for more intensive therapies (including transplant) were enrolled. Pts received 4-6 CY of BO induction intravenously (IV) every 28 days (D) with B 90 mg/m2 IV D1 & 2 every 28D for 6 CY concurrent with O IV (cycle 1 = 100 mg D1, 900 mg D2, and 1000 mg D8 & 15; then 1000 mg D1, CY 2-6). Peripheral blood (PB) MRD was obtained using NGS (ClonoSEQ®) after cycle 2 BO as an exploratory endpoint. Consolidation O (CO) 1000 mg IV weekly for 4 doses was initiated ≤12 weeks after the final dose of BO. Restaging and MRD testing of PB and bone marrow aspirate (BMA) was done ≤30 days after CO completion. For pts with complete response (CR) radiographically and MRD- in PB/BMA, maintenance O (MO) was omitted. For pts without CR or persistent MRD positivity (MRD+) in the PB or BMA, MO was given with 1000 mg IV D1 of a 56-day cycle for 8 CY. Pts were followed for ≥2 years from therapy completion. The primary endpoint is PFS from D1 of BO induction. Secondary endpoints are MRD status, concordance rate of PB/BMA in predicting MRD status, response rates and overall survival (OS). Results: Twenty-one pts (of planned 32) enrolled beginning 2/2018, with follow-up through 6/1/2023. The study closed prematurely due to slow enrollment. Median age is 70 yrs with 3 pts >80 yrs; majority were men (76%). Median MIPI score is 6.11 and median ECOG performance status 0. Twenty pts (95%) have stage IV disease. Twenty pts completed 4 (n=1) or 6 CY BO. Ten pts received MO; 10 did not receive MO per protocol due to radiographic CR and MRD- PB/BMA post-CO. Six pts did not complete MO for reasons of progressive disease (n=4), infection (n=1) and new carcinoma (n=1). After cycle 2 BO, PB analysis was MRD+ in 7 pts and MRD- in 13. Concordance rates between post-CO MRD testing in PB and BMA was 70% (14/20). Of non-concordant values, all had PB MRD- but BMA MRD+. Best responses in 20 assessable pts are: CR 75% (15/20), partial response 20% (4/20), and stable disease 5% (1/20). Most common grade 3/4 toxicities were: neutropenia (10/21), leukopenia (6/21), infections (5/21) and infusion reactions (2/21). One pt had grade 5 cardiac arrest with sepsis during BO. Most common grade 3 infections were abdominal/colitis (n=3) and pneumonia (n=2). Most common grade 1/2 toxicities were nausea (14/21), diarrhea (10/21), constipation (8/21), dysgeusia (6/21), fatigue (8/21) and dry skin/rash (12/21). After a median duration of follow-up of 43.9 months (mos) (95% confidence interval [CI] 28.3-60.1), PFS at 2-yrs and 3-yrs is 66.0% (95% CI 41.6-82.2) and 58.7% (95% CI 33.2-77.3), respectively; and median PFS is 46.5 mos (95% CI 16.4-∞). MRD- status after the exploratory endpoint post-C2 BO was predictive of 2-year PFS (Figure 1a), 83.3% (95% CI 48.2-95.6) for MRD- vs. 42.9% (95% CI 9.78-73.4) for MRD+, with hazard ratio [HR] 0.34 (95% CI 0.09-1.39), p value 0.133. Evaluation of PFS by MRD status post-CO showed similar outcomes regardless of receiving MO (Figure 1b): 2-year PFS is 77.8% (95% CI 36.5-93.9) in MRD- pts post-CO vs 60.0% (95% CI 25.3-82.7) in MRD+ pts; HR 0.45 (95% CI 0.10-1.91, p value 0.278. Median OS is 46.5 mos (95% CI 35.1-∞). Conclusion: Omission of MO in pts achieving MRD- status after induction/CO did not result in worsening PFS. Observed PFS and toxicities with BO induction and CO appears comparable with other data sets utilizing a BR-based induction +/- MT in older, less fit MCL pts. Correlation between PFS and PB MRD testing after C2 induction therapy represents a potential new prognostic marker of MCL behavior, and may be an important early disease indicator in development of risk-adapted therapies.

Fixed Duration Mosunetuzumab Plus Polatuzumab Vedotin Has Promising Efficacy and a Manageable Safety Profile in Patients with BTKi Relapsed/Refractory Mantle Cell Lymphoma: Initial Results from a Phase Ib/II Study

Background: New treatment options are needed for patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially for pts with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. Outcomes for R/R MCL pts with PD after the BTKi ibrutinib are very poor, demonstrated by a median overall survival of 2.9 months (Martin et al. Blood 2016). While chimeric antigen receptor (CAR) T-cell therapies are approved for pts with R/R MCL; treatment is associated with high toxicity and difficulty with accessibility. Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that engages and redirects T cells to eliminate malignant B cells. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that inhibits cell division and induces apoptosis in B cells. This ongoing Phase Ib/II study (NCT03671018) is investigating Mosun in combination with Pola (M-Pola) in pts with R/R B cell non-Hodgkin lymphoma. Here, we report initial safety and efficacy data from an ongoing Phase II expansion cohort of pts with R/R MCL who had received prior BTKi therapy. Methods: Eligiblepts had histologically confirmed R/R MCL and had received ≥2 prior regimens (including an anti-CD20 agent, BTKi, and anthracycline- or bendamustine-based therapy). Mosun was administered subcutaneously (SC) by step-up dosing on Days (D) 1 (5mg), 8 (45mg), and 15 (45mg) of Cycle (C) 1, then 45mg on D1 of every cycle from C2D1, every 3 weeks for a total of 17 cycles. Pola (1.8mg/kg intravenous [IV] infusion) was administered on D1 of C1-6. All pts received corticosteroid premedication prior to C1 of treatment. From C2, premedication was optional for pts who did not experience cytokine release syndrome (CRS) in the previous cycle. Response was assessed by investigators using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Results: As of October 27, 2022, 20 pts had received M-Pola (n=10 active on treatment, n=1 completed treatment, n=9 discontinued Mosun treatment). Median age of all pts was 68.0 (range: 44-82) years, 75% were male, 95% had Ann Arbor stage III/IV disease, and 40% had a MIPI score ≥6 at study entry. Median number of prior lines of therapy (LOT) was 3 (range: 2-9). All pts had received prior BTKi therapy; 7 pts (35%) had received prior CAR T-cell therapy; and 85% (17/20) of pts were refractory to their last LOT. Median time since last LOT was 1.6 (range: 0-39) months. The proportions of pts with high-risk MCL factors at baseline were: 65% of pts with Ki-67 proliferation index ≥50%; 50% with blastoid/pleomorphic variants; and 20% with TP53 mutation. The overall median time on study was 7.2 (range: 0.4-17.5) months. The most common (≥25%) Mosun and/or Pola-related adverse events (AEs) in all pts (n=20) were CRS (50%), injection site reaction (50%), fatigue (45%), dyspnea (35%), paresthesia (30%), diarrhea (30%), myalgia (30%), infusion-related reaction (25%), and nausea (25%). Two (10%) Grade (Gr) 5 AEs occurred, both of which were due to COVID-19 pneumonia; neither were deemed treatment-related by the investigator. Ten pts (50%) experienced CRS events; 9 pts experienced Gr 1 events, and 1 pt experienced a Gr 2 event, which was managed with tocilizumab and low-flow oxygen. One pt was managed with corticosteroids and no pts required pressors or ICU admission. All CRS events resolved by the data cut-off. Treatment-related neurologic AEs, potentially consistent with ICANs, occurred in 3 pts (15%; Gr 1 confusional state and Gr 2 amnesia, 1 pt; Gr 1 agitation, 1 pt; and Gr 2 memory impairment, 1 pt). Neuropathy occurred in 3 pts (15%); all events were Gr 1. Four pts (20%) had AEs leading to treatment discontinuation: 1 pt with Gr 3 uveitis (related to M-Pola); 1 pt with Gr 3 pneumonitis (related to M-Pola); and 2 pts with Gr 5 COVID-19 pneumonia (both unrelated to M-Pola). Overall response rate (ORR) and complete response (CR) rates were 75% and 70%, respectively (Figure). Best ORR and CR rates were generally consistent in high-risk MCL subgroups (Figure). Median duration of CR was not evaluable (NE; 95% confidence interval: 3.8-NE). Conclusions: Fixed-duration Mosun SC in combination with Pola IV induced high CR rates in pts with R/R MCL who had previously received BTKi therapy, including those in high-risk subgroups and those who had received prior CAR T-cell therapy. CRs were observed early and persisted during the follow up period. M-Pola had a manageable safety profile, and all CRS events were low grade.

Pirtobrutinib in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Patients with Prior cBTKi: Safety and Efficacy Including High-Risk Subgroup Analyses from the Phase 1/2 BRUIN Study

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

Adaptive Manufacturing of LV20.19 CAR T-Cells for Relapsed, Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by the presence of t(11;14) and bright CD20 expression. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL is limited by both relapse and high rates of Grade 3+ cytokine release syndrome (CRS) and ICANS with 15% and 31% patients (pts) experiencing such toxicities, respectively. To improve outcomes we utilized dual targeted lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T-cells with an adaptive manufacturing (MF) process to optimize the final CAR product as part of a Phase 1/2 clinical trial in R/R MCL. Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. We report results of MCL pts from a fully enrolled Phase I safety run-in and Phase II efficacy cohort. The primary outcome for the Phase II cohort was day 90 complete response (CR) rate. The Phase II cohort utilized an adaptive 8/12 day MF process to enhance the percentages of T-SCM (stem cell-like memory) and T-CM (central memory) CAR T-cells in the final product by shortening culture time. CAR T-cells were harvested either on day 8 of MF or extended to a 12-day MF process depending on achieving target cell dose in culture. Fludarabine/cyclophosphamide lymphodepletion was started during MF to facilitate fresh infusion in eligible pts. Descriptive statistics were utilized for demographic data and the Kaplan Meier methodology for survival analysis. Results: In total 17 pts with R/R MCL received LV20.19 CAR T-cells (Phase 1=3 pts and Phase 2=14 patients). All pts achieved target cell dose. 13 pts received an 8-day product while 4 received a 12-day product. 14/17 pts received a fresh (non-cryopreserved) infusion. 8-day products were enriched for T-SCM/CM phenotype cells with significantly lower number of terminally differentiated effector memory (EMRA) T-cells in the CD4 compartment (p<0.05) than 12-day products. The median age was 63 (50-74 years) and 15 (88%) were cisgender male. The median number of lines of therapy was 4 (3-8). p53 deletions or mutation were present in 7 pts. Day 28 overall response rate (ORR) was 100%; CR rate=76% and partial response (PR) =24%. Initial ClonoSEQ MRD assay performed within the first 90 days of LV20.19 CAR T (n=13) was negative in 10 pts (77%). Among Phase II patients with day 90 results available (n=12) the ORR was 100%, CR rate=92% and PR rate=8% exceeding the Phase II efficacy threshold. Two pts have relapsed to date, +8 months and +2 years after infusion. There were two non-relapse mortality (NRM) events that occurred beyond day 28: gram negative rod sepsis & COVID19 infection resulting in a 1-year NRM rate of 12%. The 1-year progression free survival (PFS) was 77%, 1-year duration of response (DOR) was 92%, and 1-year overall survival (OS) of 84%. Median PFS/DOR/OS have not been met with median follow-up of 14 months of surviving pts (Figure 1). In terms of safety, 94% (n=16) experienced CRS, all grade 1-2. 18% (n=3) had ICANS in the first 28-days, 2 pts with Grade 3 toxicity. There were two pts with late (>day 28) episodes of Grade 1 neurological toxicity. Both pts had immense expansion of lymphocytes in the CSF (total nucleated cell count of 386/µLand 1005/µL) with CAR+ T cells present. Both received only a single dose of intrathecal hydrocortisone (no systemic steroids) with resolution of neurotoxicity within 24 hours of administration. Conclusions: Bispecific LV20.19 CAR T-cells with adaptive MF process is feasible, safe, and efficacious for R/R MCL with ORR 100%, no Grade 3+ CRS and low rates of Grade 3+ ICANS (12%). Adaptive MF enriched the final product with higher percentages of T-SCM/T-CM CAR cells and allowed most pts to receive CAR-T cells within 8 days of apheresis. Dual targeting of CD20 and CD19 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL.

Pirtobrutinib in covalent BTK-inhibitor (cBTKi) pre-treated mantle cell lymphoma (MCL): Updated results and subgroup analysis from the phase 1/2 BRUIN study with >3 years follow-up from start of enrollment.

7514 Background: Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory (R/R) MCL and more than 3 years follow-up from start of enrollment. Methods: Pts with cBTKi pre-treated R/R MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in the prespecified primary efficacy cohort that comprised the first 90 enrolled pts who had measurable disease, had received a prior cBTKi, and had no known central nervous system involvement. The primary endpoint was overall response rate (ORR) as assessed by independent review committee. Secondary endpoints included duration of response (DOR) and safety. A data cut of 29 July 2022 was utilized. Results: Among MCL pts who received a prior cBTKi (n=90), median age was 70 years (range, 46-87), median prior lines of therapy were 3 (range, 1-8), 82% discontinued a prior cBTKi due to disease progression, and 78% had intermediate/high risk sMIPI score. Of samples available, 17/36 (47%) had TP53 mutations and 25/34 (74%) had Ki67 ≥30%. The ORR was 57% (95% CI, 46-67), including 19% complete responses (n=17) and 38% partial responses (n=34). At a median follow-up time of 13 months, the median DOR among the 51 responding pts was 17.6 months (95% CI, 7.3-27.2). The 12- and 18-month estimated DOR rates were 58% (95% CI, 41-72) and 45% (95% CI, 27-61), respectively. ORR and DOR by subgroups are shown in the Table. The median progression-free survival was 7.4 months (95% CI, 5.3–13.3). The median overall survival was 23.5 months (95% CI, 15.9-NE). In the MCL safety cohort (n=166), the most frequent treatment-emergent adverse events (TEAE) were fatigue (31%), diarrhea (22%), and anemia (17%). The most common Grade ≥3 TEAE was neutropenia (15%). Grade ≥3 TEAE of hemorrhage (3%) and atrial fibrillation/flutter (2%) were infrequent. Only 5 (3%) pts discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib continues to show durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. Responses were observed in pts with high-risk disease features including pts with blastoid/pleomorphic variants, elevated Ki67 index, and TP53 mutations. Clinical trial information: NCT03740529 . [Table: see text]

PIRTOBRUTINIB IN COVALENT BTK‐INHIBITOR PRE‐TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS, SUBGROUP ANALYSIS FROM BRUIN WITH >3 YEARS FOLLOW‐UP FROM START OF ENROLLMENT

PIRTOBRUTINIB IN COVALENT BTK‐INHIBITOR PRE‐TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS, SUBGROUP ANALYSIS FROM BRUIN WITH >3 YEARS FOLLOW‐UP FROM START OF ENROLLMENT

Mutation Spectrum, Characteristics and Impact of Mutation Profiling on Prognosis, Outcome and Treatment Responses in Patients (pts) with Mantle Cell Lymphoma

Background: Genomic profiles of mantle cell lymphoma (MCL) are associated with clinical outcomes. BTKi Resistance in MCL can be predicted with mutation profile. Identifying these patients (pts) early can help guide therapy decisions and predict outcomes. We describe results from a clinical NGS based assay with a customized 162-gene panel in routine work-ups of MCL pts. Materials and Methods: We reviewed data from MCL patients who underwent CLIA approved lymphoma gene panel testing at MDACC from October 2020 until the end of June 2022. Data on treatment response, outcomes, and patient characteristics were collected. Mutation panel testing was conducted on various patient samples. Genomic DNA was isolated from fresh bone marrow (BM) aspirate, formalin-fixed paraffin-embedded (FFPE) tissues, fine needle aspirate (FNA) and peripheral blood (PB) specimens. Sequencing was performed using the Illumina NextSeq platform (Illumina, San Diego, CA). Variant calling was performed using Agilent SureCall software v4.1 and post-variant call analysis and annotation were performed using an in-house bioinformatics pipeline (OncoSeek v 1.1). Analytical sensitivity of the assay was established at 2% using a per base coverage cut-off of 200x. The assay was performed in cases with >10% lymphoma cells in the sample. Results: We included 227 MCL pts in this study: 129 treatment naïve and 97 with prior therapies. The distribution of patients according to the sample type included: BM (n=107), FFPE (n=50; 24 lymph node, 20 GI tract, and 6 miscellaneous tissues), FNA from involved nodal and non-nodal tissues (n=50) and PB (n=20). Baseline pt features included a median age of 67 years (range, 38-88 years). There were 164 men and 63 women. Histomorphology was classic in 165 pts, blastoid in 31, pleomorphic in 19 and blastoid/pleomorphic in 2. Ten pts had unclear histomorphology. Ki-67% in involved tissues was evaluable in 180 pts (in 47 pts Ki-67% was not available). Ki-67% was high (>=30%) in 98 and low in 82 biopsy specimens. Among the 97 previously treated pts, 47 had BTKi refractory disease. Twenty-three pts were treated with standard of care brexucabtagene autoleucel (CART). The spectrum of gene mutations is depicted by both previously untreated and pts with prior therapy in figure-1A. The most common mutated genes were: ATM (51.5%), TP53 (29.5%), KMT2D (21.1%), CCND1 (19.3%), BIRC3 (16.2%), NSD2 (11.4%), SMARCA4 (10.1%), UBR5 (9%), NOTCH1 (8.3%), CARD11 (7%), SAMHD1 (7%), NFKB1E (6.6%), SP140 (6.6%), S1PR1 (6.6%), DNMT3A (6%), NOTCH2 (6%), IGLL5 (6%), TRAF2 (5%), TET2 (5%). Unlike chronic lymphocytic leukemia, mutations of BTK (n=5; 2%) and PLCg (n=4; 2%) were rare. BTK mutations included missense mutations: C481Y, C481R, T474I and 2 with L528W. All patients with BTK mutations were resistant to prior BTKi and 4/5 died with refractory disease. Additional mutations of prognostic interest in other lymphomas were detected at very low frequency (<3%) and included CDKN2A, CD79b, MYD88, MEF2B, MAP3K14, Rb1, PAX5, SPEN, SF3B1, DIS3. We also evaluated pt survival from the date of gene panel testing and noted that TP53 mutant MCL pts had significantly inferior survival. We further divided the pts based on >=3 mutations (n=77) vs < 3 mutations (n=150) and identified that pts with a higher number of mutations had inferior survival, P <0.0001 (Figure 1C). Pts with SMARCA4 and TRAF2 mutations also demonstrated shorter survival compared to those which were wild type (not shown). Twenty-three pts received CART therapy and 7 had progressed and 16 have not. The distribution of mutations before CART in the two groups was not significantly different. Among the 47 BTKi refractory MCL, the frequency of certain mutations was higher: TP53 (49%), ATM (55%), KMT2D (31%), CCND1 (23%), 10% each for SMARCA4, NSD2 and SP140. Currently, we are utilizing this test to evaluate and include pts with high risk MCL on our clinical trials in MCL and treat with risk stratified treatments. Conclusion: The clinical NGS-based assay for MCL pts at our institution has proven to have prognostic significance. Resistant MCL pts exhibit a preponderance of mutations involving TP53, epigenetic modifier and chromatin regulator genes. Comprehensive risk stratification of pts early on and during therapy is very useful and improves patient care, helps design next generation clinical trials and improves our understanding of the biology of resistant MCL in the BTKi and CART era. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Results from a Phase 1/2 Study of Tandem, Bispecific Anti-CD20/Anti-CD19 (LV20.19) CAR T-Cells for Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with variable clinical course. The disease is characterized by presence of t(11;14) and bright CD20 expression. While frontline immunochemotherapy plus autologous hematopoietic cell transplant (HCT) has improved progression-free survival, invariably MCL patients (pts) relapse. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL provides durable disease control but is limited by high rates of Grade 3+ cytokine release syndrome (CRS) and neurological events with 15% and 31% of pts experiencing such toxicities. We hypothesized that bispecific, tandem, lentiviral CAR-T cell targeting both CD20 and CD19 B-cell antigens (LV20.19 CAR) with 4-1BB co-stimulatory signaling will improve clinical outcomes in R/R MCL and that expansion in IL7 and IL15 would produce less "exhausted” CAR product with more durable clinical activity. Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. We report below outcomes from a Phase 1/2 cohort of MCL pts. LV20.19 CAR T-cells were manufactured onsite in the CliniMACS Prodigy device with IL7+15 for cell expansion with goal of fresh infusion at varying lengths of manufacturing (8 vs 12 days). After safety run-in, we opened a 14 patient single stage Phase II arm with flexible 8/12-day manufacturing with fresh infusion for MCL pts. Descriptive statistics were utilized for baseline characteristics and survival analyses were calculated utilizing the Kaplan-Meier method and differences between groups were evaluated via log-rank test. Results: To date, 10 MCL pts have received LV20.19 CAR T-cells at the specified dose of 2.5x10e6 cells/kg (Phase 1=3 pts and Phase 2=7 pts). 8 of 10 pts received 8-day manufactured CAR-T cells whereas two pts received a 12-day product in the Phase 1 cohort. Manufacturing was successful in 100% of pts and all received a fresh (non-cryopreserved) product. Median age was 62 years and median prior lines of therapy were 4 (range: 3-8). Three pts progressed after prior autologous HCT and 2 pts progressed after prior allogeneic HCT. Eight of 10 pts had progressed on a Bruton's Tyrosine Kinase inhibitor (BTKi) and 4 of these pts had additionally progressed on a non-covalent BTKi (pirtorbrutinib) administered on a clinical trial (Table 1). LV20.19 CAR T-cells produced in the CliniMACS Prodigy with IL-7/IL-15 had robust expansion with mean 5.4x10e8 CAR T-cells obtained on Day 7 of manufacturing. CAR T-cells from pts mostly consisted of central-memory and effector-memory phenotype T-cells with robust in-vivo expansion typically starting Day +4 after infusion. The Day 28 ORR was 100% (CR=60% and PR=40%). 7 of 9 pts with MRD assessed between Day 28-60 post CAR were negative. No patient has relapsed with a median follow-up of 18 months of among surviving pts. Regarding toxicity, all 10 pts (100%) had Grade 1-2 CRS (no grade 3+ events). Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 2 pts with one patient experiencing Grade 2 and the other Grade 3 toxicity. The patient with Grade 3 ICANS experienced a non-relapse mortality event due to gram negative sepsis after Day 28 evaluation. At 1-year the cumulative incidence of relapse and NRM were 0% and 10%, respectively while the 1-year PFS and OS were 90% each (Figure 1). Conclusions: Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R MCL with ORR 100%, no relapses with a median follow-up of >1.5 years, and no Grade 3+ CRS and low rates of Grade 3+ ICANS (10%). All pts on the Phase II arm had CAR T-cells manufactured on-site utilizing an 8-day platform with fresh CAR T-cell infusion and lymphodepletion starting during manufacturing. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Waveline-001: Updated Results from a Phase 1 Dose Escalation and Cohort Expansion Study of Zilovertamab Vedotin (MK-2140) in Non-Hodgkin Lymphoma

Background: Zilovertamab vedotin (ZV) is a receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeting antibody-drug conjugate comprising zilovertamab, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E. ROR1 is a transmembrane protein absent in mature tissues but highly expressed in certain hematologic malignancies, making it an attractive therapeutic target. Safety and efficacy of ZV are being investigated in the phase 1 WAVELINE-001 study (NCT03833180), which is a dose escalation and cohort expansion analysis in patients (pts) with relapsed and/or refractory (R/R) hematologic malignancies. Initial results showed ZV had a tolerable safety profile and promising antitumor activity in R/R non-Hodgkin lymphoma (NHL; Wang M, et al. NEJM Evid. 2021;1[1]). Updated results, including PFS and OS for mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Richter transformation (RT), are presented. Methods: Eligible pts aged ≥18 years of age, with a histological diagnosis of MCL, DLBCL, or RT; had ECOG PS 0-2; and progression during or relapsed after prior systemic therapy, were included. WAVELINE-001 included 3 dosing schedules. Data from Schedule 1 are presented; Schedules 2 and 3 are ongoing. In Schedule 1, pts received ZV IV at a starting dose of 0.5 mg/kg on day 1 Q3W, increasing to 2.5 mg/kg using an accelerated plus 3 + 3 dose escalation design. Primary end point was determination of the maximum tolerated dose and/or recommended dosing regimen (RDR). Secondary end points included safety, ORR, DOR, PFS, and OS. Results: A total of 54 pts were enrolled in Schedule 1, of which 30 pts were treated at the established RDR of 2.5 mg/kg. At data cutoff (May 18, 2022), median follow-up was 15.3 months (range, 0.5-37.8). Median age was 70.0 yrs, 57% of pts were male, 48% had an ECOG PS of 0, 65% had received ≥3 prior therapies, 80% had NHL (FL, n=3; DLBCL, n=15; MCL, n=17; MZL, n=1; RT, n=7), and 20% had other disease (AML, n=3; CLL/SLL, n=7; mixed histology, n=1). MCL pts had received a median (range) of 4 (1-9) prior lines of therapy. All MCL pts received prior BTKi therapy, and none had prior CAR-T or CAR-NK therapy. 59% of MCL pts were Ann Arbor stage IV. DLBCL pts received a median (range) of 4 (1-7) prior lines of therapy, 67% of pts had received prior CAR-T or CAR-NK therapy; 47% of pts were GCB, and 33% were ABC subtype. Five pts (71%) with RT had the DLBCL subtype. No pts with RT received autologous stem cell transplant and received a median (range) of 3 (1-10) prior therapies. Any-cause adverse events (AEs) occurred in 52 (96%) pts. Any-grade treatment-related AEs (TRAEs) occurred in 40 pts (74%); most common (≥20%) were peripheral neuropathy (46%), neutrophil count decreased (35%), fatigue (35%), nausea (28%), and diarrhea (20%). Decreases in hemoglobin and platelet count occurred in 13% and 11% of pts, respectively. Grade 3-4 TRAEs occurred in 28 pts (52%), most commonly neutrophil count decreased (33%), platelet count decreased (11%), and peripheral neuropathy (7%). AEs of special interest regardless of causality occurred in 76% of pts; most common were hematopoietic cytopenia (56%) and peripheral neuropathy (48%). For pts experiencing peripheral neuropathy, most cases were grade 1/2 (41%); 7% were grade 3. Median (range) time to onset of first peripheral neuropathy was 49 (1-162) days. No incidences of tumor lysis syndrome or infusion reactions occurred and no grade 5 TRAEs occurred. AEs led to ZV discontinuation in 12 pts (22%) and interruption or reduction in 24 (44%). ORR was 33% (5/15; 95% CI, 12-62; 3 CR/2 PR) in DLBCL, 53% (9/17; 95% CI, 28-77; 2 CR/7 PR) in MCL, and 57% (4/7; 95% CI, 18-90; 1 CR/3 PR) in RT. No responses were seen among the other indications treated. Median DOR (range) was 4.6 months (2.9-21.5) for DLBCL, 10.0 (0-20.3) for MCL, and 2.8 (0-2.8) for RT. Median PFS (95% CI) was 3.9 months (0.5-7.0) for DLBCL, 11.4 (4.0-NE) for MCL, and 4.7 (0.7-NE) for RT. Median OS (95% CI) was 9.1 months (1.0-NE) for DLBCL, 18.0 (7.1-NE) for MCL, and 24.0 (2.7-NE) for RT. Among 12 pts with NHL (10 DLBCL and 2 RT) who had undergone prior CAR-T/CAR-NK therapy, ORR was 33% (4/12; 95% CI, 10-65). Conclusions: Updated results from WAVELINE-001 support prior analyses showing ZV had a tolerable safety profile and promising response rates, and favorable PFS and OS among heavily pre-treated pts with DLBCL, MCL, and RT, including pts who had received prior CAR-T/CAR-NK therapy.

Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL): 2-Year Safety and Efficacy Analysis

Background: Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor approved for relapsed/refractory mantle cell lymphoma (MCL). We investigated safety and efficacy of chemotherapy-free induction with combination acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive patients (pts) with MCL to eliminate intensive chemoimmunotherapy exposure and reduce associated toxicity and complications. We previously reported 90% complete response (CR) and 75% molecular response rates at 20.5 mo median follow-up (ASH 2021). We present updated safety and efficacy results at 2 y median follow-up. Methods: Adults with treatment-naive MCL received AVR in this open-label, single-arm, multicenter phase 1b study (NCT02717624). Pts received A+R for six 28-d cycles with maintenance R for up to 2 y for responders and oral A continuously until progressive disease (PD) or undue toxicity. V was started at cycle 2 with standard 5-wk ramp-up to 400 mg/d and continued for 2 y. Primary endpoint was safety. Secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Treatment response was assessed by clinical examination, computed tomography (CT), and positron emission tomography (PET) by Lugano criteria, with minimal residual disease (MRD) assessment by clonoSEQ assay in peripheral blood (at partial response [PR], CR, and PD). Bone marrow (BM) was assessed at screening and CR. Results: Twenty-one pts were enrolled (median age 66 y [51-85]; Ann Arbor stage IV disease, 90.5% [n=19]; initial BM involvement, 71.4% [n=15]; high-risk simplified MIPI score, 19% [n=4]; blastoid histology, 4.8% [n=1]; pleomorphic variant, 0%; bulky disease >5 cm or >10 cm, 33.3% [n=7] and 4.8% [n=1]; Ki-67 proliferation index ≥30%, 47.6% [n=10]). At data cutoff (March 29, 2022), 15 (71.4%) pts remained on study; 6 (28.6%) had discontinued study, due to death (5 [23.8%]) or start of new therapy (1 [4.8%]). Eleven (52.4%) pts remained on at least 1 study drug and 7 pts (33.3%) discontinued all 3 drugs: 2 due to PD and 5 due to COVID-19 death. Ten pts (47.6%) discontinued A (adverse event [AE]=5, investigator's decision [ID]=3, PD=2); 17 discontinued V (completed regimen=9, PD=2, AE=4, ID=1, other=1); and 17 discontinued R (completed regimen=10, PD=2, AE=4, ID=1) All 21 pts (100%) completed the 6 initial cycles of treatment (induction) per protocol. Most common any-grade AEs in ≥20% of pts were diarrhea (15 [71.4%]), headache (11 [52.4%]), fatigue (10 [47.6%]), and neutropenia (8 [38.1%]). Grade 3/4 AEs were reported in 12 (57.1%) pts, most commonly (>1 pt) neutropenia (7 [33.3%]) and pneumonia (3 [14.3%]). Serious AEs (SAEs) occurred in 12 (57.1%) pts. SAEs in ≥2 pts were COVID-19 (5 [23.8%]), pneumonia (3 [14.3%]), and pyrexia (2 [9.5%]). Overall, 7 pts had COVID-19; 6 (28.6%) cases were treatment-emergent (up to 30 days after last dose) and 4 (19.0%) pts died. The seventh pt with COVID-19 died outside the treatment-emergent period. Table 1 shows events of clinical interest. At data cutoff, ORR was 100% (n=21), CR rate was 90% (n=19), and PR rate was 10% (n=2) by PET/CT. By Lugano, CR rate was 71% (n=15) since 4 pts were missing BM biopsy to confirm CR. Median (range) time to initial response and best response were 2.8 (0.7-5.6) and 3.0 (0.7-18.3) mo, respectively. Median DOR was not reached even after censoring COVID-19 deaths. With a median follow-up of 25.8 (8-38.5) mo, the median PFS and OS were not reached. PFS rates at 1 y and 2 y were 90% (95% CI 65.6-97.4) and 54.4% (21.6-78.5), respectively (both were 94.7% [68.1-99.2] after censoring COVID-19 deaths) (Figure 1). OS rates at 1 y and 2 y were 95.2% (95% CI 70.7-99.3) and 74.1% (48.4-88.3), respectively (both were 100% after censoring). In total, 5 pts died, all from COVID-19. MRD data were available for 12 pts (57.1%) at cycle 6 (all MRD negative at 10-6) and 14 pts (66.7%) at cycle 12 (12 negative at 10-6; 14 negative at 10-4). Fourteen of 16 (87.5%) evaluable pts had MRD negativity (10-6) at least once during treatment. Among the 15 pts who achieved CR by PET/CT, 13 (86.7%) were MRD negative at 10-6 and 1 pt was MRD negative at 10-5 at least once during treatment; 1 pt had no follow-up MRD assessments. Conclusions: AVR combination is well tolerated and induces durable and deep clinical and molecular responses in treatment-naive MCL pts. This study strongly supports further clinical investigation of AVR for treatment-naive MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1101: PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN PREVIOUSLY TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS FROM THE PHASE 1/2 BRUIN STUDY

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent (reversible) BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. Aims: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received ≥2 prior therapies. Methods: Pirtobrutinib was dose escalated in a standard 3 + 3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in ≥10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% confidence interval 38-66; 13 complete response (CR) [25%], 14 partial response (PR) [27%], 9 stable disease (SD) [17%]), 11 progressive disease (PD) [21%] and 5 [10%] discontinued prior to first response assessment). Median follow up was 6 months (range 0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Summary/Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented.

Real-world (RW) treatment patterns and comparative effectiveness of Bruton tyrosine kinase inhibitors (BTKi) in patients (pts) with mantle cell lymphoma (MCL).

e18727 Background: BTKi therapies, approved for relapsed or refractory (R/R) MCL, have not been comprehensively evaluated in RW populations. This study aimed to assess patient characteristics, treatment patterns and associated outcomes in RW BTKi-treated MCL pts. Methods: The retrospective multicenter chart review was conducted in the Cardinal Health Oncology Provider Extended Network. EMR data were extracted for eligible pts diagnosed with MCL who initiated any of the approved BTKi (ibrutinib [ibr], acalabrutinib [acal], zanubrutinib [zanu]) from 2018 to 2021; pts enrolled in trials were excluded. Index date was defined as the use of any of the BTKis. Pts were followed 12-mo pre-index for medical history, and from index to last follow-up or death. Descriptive analyses were conducted to assess demographic/clinical characteristics, MCL baseline features, BTKi treatment patterns, adverse events (AE), and response rates by BTKi. Multivariable logistic regression was performed to assess factors associated with response and AE. Results: The study cohort consisted of 300 MCL pts (59% male; 69% white); most (64%) pts were covered by Medicare, 34% had commercial insurance. BTKis were given mainly as monotherapy (93%) and in R/R setting (86%). Pts in zanu group were significantly older (n = 100, median age = 71, range = 50-91) than pts in ibr (n = 100, median age = 69, range = 39-87) and acal (n = 100, median age = 70, range = 51-86) groups. Significantly fewer pts in the zanu group had baseline Ann Arbor stage I-II (4%) than ibr (10%) or acal (13%), while more zanu pts had presence of B symptoms (67%) than ibr (44%) or acal (57%). Pts in the zanu group also had significantly less with ECOG of 3+ (4%) compared to ibr (8%) or acal (6%). At BTKi initiation, significantly more pts in zanu group (18%) had history of atrial fibrillation than ibr (1%) or acal (5%). Multivariable regression reported a significant association of age, gender, extranodal/splenic involvement, and timing of BTKi initiation with response and AE (Table). Conclusions: This study provides the first RW evidence on comparative effectiveness of ibr, acal, zanu in MCL pts. While pts treated with zanu were older and had more complex MCL baseline features at initiation, multivariable regression suggested a trend favoring zanu over ibr or acal for both response and AE. Frontline initiation of BTKi therapy was also associated with improved tolerability. Future RW studies are needed to discern long-term outcomes.[Table: see text]

Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

7520 Background: Zilovertamab (Zilo) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anti-cancer agents, including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), multiple doses were examined. Zilo 600 mg IV starting q2wks x3 then q4wks + Ibr qD was selected as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Zilo+Ibr vs. Ibr alone). Results: As of 18Jan2022 data cutoff, 26 evaluable RR MCL pts, including pts who received prior Ibr (5) or auto-SCT (7), and 34 evaluable CLL pts (12 TN and 22 RR) were enrolled into Parts 1&amp;2. In Part 3, 22 evaluable pts were randomized (2:1) to receive either Zilo+Ibr (15) or Ibr (7). Safety: Treatment-emergent adverse events (TEAEs) (≥30%, N = 84), regardless of relationship, included fatigue (41.7%), contusion (39.3%), and diarrhea (38.1%). Most common (≥5%) Grade ≥3 TEAEs included hypertension (10.7%), pneumonia (7.1%), atrial fibrillation, fatigue, and neutropenia (all 6.0%). Grade ≥3 neutrophil decrease observed in 9.4% or 17.6%, platelet decrease in 12.5% or 2.9%, or hemoglobin decrease in 9.4% or 0% of pts with MCL or CLL, respectively in Parts 1&amp;2. Investigators scored TEAEs as due to Ibr in 78.1% or 85.3%, or to Zilo in 15.6% or 23.5% of pts with MCL or CLL, respectively. Efficacy (MCL): Objective response rate (ORR) was 80.8% (34.6% CR, 46.2% PR). ORR for pts with prior Ibr was 80% (2CR, 2PR) and median duration of response (mDOR) was 13.7 months (M) (95%CI: 11.93, NE). ORR was 100% in pts who had prior SCT+/- CAR-T (5CR, 2PR), and mDOR was 34.1 M (95% CI 13.84, NE). Overall median PFS (mPFS) was 35.9 M (95% CI: 17.3, NE) at median follow-up of 15.0 M. For MCL pts with TP 53 aberrancy (6), Ki67 &gt; 30% (13), ≥ 3 prior lines of therapies (4), blastoid histology (3), bulky disease ≥5 cm (4), intermediate MIPIb (6), or high MIPIb (11), the mPFS (in M) was 17.3 (95% CI: 2.85, NE), Not Reached (NR) (95% CI: 2.85, NE), 35.9 (95% CI: 16.52, NE), NR (min 9.18, max 27.87), 26.6 (95% CI: 0.03, NE), 35.9 (min 8.30, max 35.9) or 16.5 (95% CI: 2.72, NE). Efficacy (CLL): In Parts 1&amp;2 ORR was 91.2% (8.8% CR, 82.3% PR/PR-L), and 8.8% had stable disease (SD). At median follow-up of 31.4 M, mDOR was 33.5 M and mPFS was NR (95% CI: 36.3, NE); the mPFS (in M) for pts with 1, 2, or ≥ 3 prior therapies was NR (min 19.3, max 41.3), NR (min 31.3, max 36.8) or 36.3 (95% CI: 15.7, NE). At median follow-up of 21.1 M in Part 3, mPFS was NR for TN or RR in both Zilo+Ibr and Ibr arms. Conclusions: Zilo+Ibr is well-tolerated. Striking responses were observed in MCL pts, with mPFS of 35.9 M (95% CI: 17.3, NE) and CR of 34.6%, which compares favorably to mPFS of 12.8 M (95% CI 8.5, 16.6) and CR of 20% reported for single agent Ibr (Rule 2017). For CLL, ORR and PFS compare very favorably to Ibr monotherapy data (Byrd 2019). Clinical trial information: NCT03088878.

Safety and Efficacy of CD37-Targeting Naratuximab Emtansine PLUS Rituximab in Diffuse Large B-Cell Lymphoma and Other NON-Hodgkin'S B-Cell Lymphomas - a Phase 2 Study

Safety and Efficacy of CD37-Targeting Naratuximab Emtansine PLUS Rituximab in Diffuse Large B-Cell Lymphoma and Other NON-Hodgkin'S B-Cell Lymphomas - a Phase 2 Study

Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1/2 BRUIN Study

Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1/2 BRUIN Study