Sawalha, Yazeed

Primary mediastinal B-cell lymphoma (PMBCL) is a rare form of large B-cell lymphoma (LBCL) with around 90% of patients cured with frontline treatment. For relapsed or refractory (R/R) disease, the optimal treatment is unclear. CD19 chimeric antigen receptor-T cell (CAR-T) has been established as the preferred second line (2L) treatment for primary refractory or early relapsing LBCL based on the overall survival benefits observed in the landmark phase III trials. However, PMBCL patients were underrepresented on these pivotal studies. This study evaluated outcomes of 252 patients treated with 2L therapies for R/R PMBCL at 14 US institutions between 2001 and 2025. Platinum-based salvage with intent to proceed to high dose therapy and autologous stem cell transplant (HDT/ASCT) (platinum cohort) and CD19 CAR-T (CAR-T cohort) were given as 2L therapy in the real-world setting in 157 and 26 patients, respectively. Overall response rate (ORR), complete response (CR) rate and median progression-free survival (PFS) were significantly higher in the CAR-T cohort compared with the platinum cohort (ORR: 91.3% vs 44.2%, p <0.001; CR 65.2% vs 14.7%, p<0.001; median PFS not reached vs 3.5 months, hazard ratio (HR) 0.28, 95% CI 0.15-0.54, p=0.001). No significant difference was observed in overall survival. This study demonstrated superior response rate and PFS of CD19 CAR-T over platinum-based salvage with intent to proceed to HDT/ASCT as 2L treatment for R/R PMBCL.

Abstract Introduction: Primary mediastinal B-Cell lymphoma (PMBCL) is a rare form of large B-Cell lymphoma (LBCL) with around 90% of patients (pts) cured with first line (1L) treatment. For pts with relapsed or refractory (RR) PMBCL, the optimal treatment is unclear. Prior retrospective analysis in the rituximab (R) era have shown high response rates to platinum salvage and high-dose chemotherapy followed by autologous stem cell transplant (HDT/ASCT) in second line (2L) RR PMBCL (Bakos et al. ASH 2023 and Dumke et al. ASCO 2024). The pivotal phase III LBCL trials in early relapsing pts that compared CD19 chimeric antigen receptor-T cell (CAR-T) with HDT/ASCT as 2L treatment had few PMBCL pts: none on ZUMA-7 and 17 PMBCL on TRANSFORM, of whom only 8 were randomized to 2L CAR-T. This study aims to evaluate outcomes of 2L therapies for RR PMBCL, including pts treated with 2L CAR-T. Methods: We performed a multicenter retrospective study in pts with RR PMBCL treated between 2001 and 2025. Clinical and pathologic characteristics, treatment regimens, and efficacy outcomes were collected and analyzed. Results: 139 pts were included with 43% male, 69% Caucasian, 7.9% Black, 8.6% Asian and 79% Non-Hispanic. R-EPOCH (64%) and (32%) were the most common 1L treatments and all pts received R. Consolidative radiation was used in 21 pts (15%) as part of 1L therapy, 28% after RCHOP. Primary refractory disease with relapse ≤6 month (mo), or early relapse ≤12 mo, occurred in 83% (N = 115) and 93% (N = 129 pts), respectively. At relapse, median age was 34 years (yrs), 44% had advanced stage disease, 31% had bulky disease (≥ 7.5cm). CNS relapse occurred in 8.6% of pts. Overall and complete response rate (ORR and CR) to any 2L treatment was 44% and 27%, respectively. At median follow-up of 40 months (mo) from the start of 2L treatment, median PFS of the entire cohort was 3.2 mo with a 3 yr OS of 70%. For 2L treatment, N=93 (67%) pts were treated with platinum salvage with intention to proceed with HDT/ASCT. Most commonly used platinum salvage regimens were ICE± R (n= 53, 38%), R-DHAP (n=23, 17%), R-GemOx (n= 5, 3.6%), and GDP ± R (n= 10, 7.2%), and the majority (95%) of pts received R with 2L therapy. ORR and CR to platinum salvage was 46% and 15% respectively. With a median follow up of 30 mo from start of 2L therapy, median PFS was 2.6 mos, and 3 yr PFS and OS was 15% and 64%, respectively. Of the 93 pts treated with platinum salvage, only 25 pts (27%) proceeded with HDT/ASCT- of whom, N = 17 (68%) achieved a CR after ASCT. In patients that proceeded to ASCT, relapses occurred in 10 pts (40%) with a 3 yr PFS and OS 56% and 83%, respectively. CAR-T was used as 2L in 20 pts (14%)- most commonly either axi-cel (N =7) or liso-cel (N = 8). ORR and CR to CART was 89% and 55% respectively, median PFS and OS was NR after CAR-T infusion and 3 yr PFS and OS was 55% and 95%, respectively. Other 2L treatments included pembrolizumab (N =3), brentuximab vedotin (BV) + nivolumab (N= 4) or single agent BV (N=2). Radiation was given as part of 2L treatment in 25.9% of pts. 2L CAR-T therapy was associated with improved ORR (OR 7.60, 95% CI 1.68 – 34.55, p = 0.002), improved CR rate (OR 4.15, 95% CI 1.49 – 11.53, p = 0.008) and improved PFS (HR 0.18, 95% CI 0.06 – 0.57, p = 0.004) compared to pts treated with 2L platinum salvage. There was no difference in OS between pts treated with platinum salvage or 2L CAR-T. A total of 96 patients progressed on 2L therapy, and 92 pts (95.8%) received third-line (3L) treatment. Third line treatments included chemoimmunotherapy +/- HDT/ASCT (N= 23), CD19 CAR-T (N = 35), clinical trial (N=7), check point inhibitor-based regimen (N= 11), BV based regimen (N= 8), allogeneic stem cell transplant (N = 3) or other (N = 5), with 7 pts receiving radiation as part of 3L therapy. Median PFS and OS from start of 3L therapy was 6.7 mo and 6.4 mo, respectively. Conclusions: We report the largest cohort of pts with RR PMBCL treated in the rituximab era and the largest number of PMBCL pts treated with 2L CAR-T. This is the first analysis, to our knowledge, to show a statistically significant benefit in PFS, ORR and CR rate of CAR-T compared to platinum salvage followed by HDT/ASCT as 2L treatment in a study of exclusively RR PMBCL pts. Our dataset was largely (93%) compromised of pts with primary refractory or early relapsing disease and provides support for using CAR-T as 2L treatment in this high-risk subset of RR PMBCL patients.

Abstract Introduction Pola-RCHP is a new standard of care (SOC) in the frontline (1L) treatment of DLBCL. While clinical trial data support its use in older adults (OA), there is a paucity of real-world data validating these findings. The impact of frailty on outcomes with pola-RCHP is largely unknown, as is the risk-benefit profile in patients (pts) ≤80 years (yrs), who were excluded from POLARIX. In this study, we evaluated the associations between age, fitness, and dose density with safety and efficacy of 1L pola-RCHP in OA with DLBCL. Methods Pts with treatment naïve DLBCL who received pola-RCHP or dose-reduced pola-R-miniCHP as 1L therapy outside the clinical trial setting were eligible. This multicenter retrospective study included pts from 17 US centers. Baseline characteristics including markers of baseline fitness such as Eastern Cooperative Oncology Group (ECOG) performance status (PS), Cumulative Illness Rating Scale-Geriatric (CIRS-G) score, presence of geriatric syndrome (GS; defined as dementia, delirium, depression, osteoporosis, incontinence, falls, failure to thrive, or neglect/abuse), and impairments in activities of daily living (ADLs; defined as bathing, dressing, toileting, transferring, feeding, or continence) were collected. Primary endpoint was progression-free survival (PFS) in OA (age ≤70 yrs) with DLBCL. Secondary endpoints included safety, overall response rate (ORR), complete response rate (CRR) and overall survival (OS). Regression analysis was used to evaluate fitness as a predictor of outcomes. Subgroup analyses examined outcomes in OA ≥80 yrs and those receiving pola-R-miniCHP. Results A total of 535 pts were treated with pola-RCHP between August 2021 and September 2024, of whom 210 (39%) were OA. Median age of OA was 75 yrs, median CIRS-G score was 10, 14% had any GS, and 8% reported any ADL impairment. OA tended to have worse ECOG PS (≥2; 23%, p=0.009) and IPI score (3-5; 77%, p<0.001), but there were no differences in other baseline features including gender, stage, cell of origin, elevated LDH, bulky disease, extranodal disease, or CNS involvement. OA received pola-R-miniCHP more frequently (18% vs 1.5%, p<0.0001) and had similar rates of treatment completion (85%, p=0.2) as pts <70 yrs. Median follow up was 11.3 months. ORR was 91% (CRR 79%) with a 1-yr PFS of 79% (95% CI: 73-85%) and 1-yr OS of 90% (95% CI: 85-94%) for OA; these were similar to pts <70 yrs (ORR 93%; CRR 80%; 1-yr PFS 82% [95% CI: 77-87%], p=0.18; 1-yr OS 91% [95% CI: 88-95%], p=0.53]. OA had higher rates of cardiomyopathy (6.2% vs. 1.5%, p=0.004), grade 3+ (G3+) neutropenia (38% vs. 27%, p=0.013), G3+ thrombocytopenia (22% vs. 11%, p<0.001) and hospitalization (38% vs 26%, p=0.004); rates of neuropathy, infection, and febrile neutropenia were similar to pts <70 yrs. Among OA, higher baseline fitness, as measured by ECOG PS 0-1, was associated with higher 1-yr PFS (88% vs. 63%, p<0.0001) and 1-yr OS (96% vs. 74%, p<0.0001) and a lower rate of hospitalization (30% vs. 65%, p<0.001). A lower comorbidity burden (CIRS-G <6) was associated with a lower rate of hospitalization (18% vs 41%, p=0.041), but did not impact PFS or OS. Impairments in ADLs were also associated with lower OS (78% vs 91%, p=0.03). OA receiving pola-R-miniCHP (n=38) were older (79 yrs vs. 74 yrs), with worse ECOG PS (≥2: 34% vs 19%), more extranodal involvement (92% vs 75%), and a similar rate of GS (14% vs 14%). The rate of hospitalization was higher (45% vs. 36%, p<0.05) but ORR (84% vs. 93%), CRR (79% vs. 79%), 1-yr PFS (85% vs. 78%), and 1-yr OS (87% vs. 90%) were similar. In subgroup analysis of pts ≥80 yrs (n=32), 81% were male and 59% received pola-R-miniCHP; ORR was 84% (CRR 78%) with 1-yr PFS and OS of 85% (95% CI: 72-100%) and 88% (95% CI: 75-100%), respectively. Pts ≥80 yrs had a higher rate of any grade neuropathy (23%, p=0.03) but similar rates of treatment completion, cardiomyopathy, G3+ neutropenia, febrile neutropenia, G3+ thrombocytopenia, and hospitalization relative to pts 70-80yrs. Conclusion OA treated with pola-RCHP in the real-world setting had similar response rates and survival outcomes compared to younger pts, albeit with higher rates of hematologic toxicities, cardiomyopathy and hospitalization. Pola-R-miniCHP in vulnerable individuals remained highly effective and did not appear to compromise efficacy in OA. Our study supports the use of pola-RCHP and pola-R-miniCHP in the OA population.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

Introduction: The optimal induction for younger fit patients (pts) with mantle cell lymphoma (MCL) is unknown; though intensive chemoimmunotherapy (CIT) containing high dose cytarabine has been shown to prolong remission. Achieving molecular remission is an independent predictor of outcomes post induction therapy in patients with MCL. Incorporating undetectable measurable residual disease (uMRD) status into the primary endpoint may be preferable to progression-free survival (PFS), particularly when approaches following induction are varied (e.g., ASCT, maintenance treatment, observation). Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton's tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439). In 2019, the US Intergroup activated EA4181 to explore the efficacy with the addition of fixed duration BTKi, to BR or BR/CR for patients with MCL ≤ 70 years old. Patients and methods: Patients were randomized 1:1:1 (stratified by MIPI risk status) to 6 cycles of BR/CR (control arm), BR/CR-A, or BR-A. Cytarabine was dosed at 2 g/m2 Q12 hours x 4, with dose reductions based on age and creatinine clearance. Acalabrutinib was dosed at 100 mg BID continuously on BR cycles with the BR/CR-A and BR-A arms and at 100 mg BID on days 1-7 and 22-28 with CR cycles on the BR/CR-A arm to mitigate hematologic toxicity. Consolidation approaches following induction were at the discretion of the treating physician. The primary endpoint was a composite of PET/CT CMR and peripheral blood uMRD rate (< 1 in 105). ClonoSEQ (Adaptive Biotechnologies) was performed at baseline and MRD testing was obtained at the end of induction. Secondary clinical objectives included PFS and overall survival (OS) at 36 months (mo), objective response rates (ORR), and toxicity rates. With 108 patients per arm expected, there was 86% power to detect an increase in PET/CT CMR/uMRD rate from 60% in the control arm to 75% in either BR/CR-A or BR-A arms using a Z-test with a 10% alpha (1-sided). Results: Between October 2019 and March 2023, 359 participants were randomized to BR/CR (n = 128), BR/CR-A (n = 129), and BR-A (n = 102). BR-A was closed to further accrual by the DSMC based on interim futility analysis for superiority in Fall 2022. The median (range) age was 61 (25, 70), 30% were ≥ 65 years, 77% were male, 89% were white, 89% were non-Hispanic, 18%/43%/39% were low/intermediate/high risk MIPI. Baseline clonal sequence was identified in 308/326 (95%) among samples received. 281/308 were eligible and treated and 260/281 had an end of treatment MRD test result (BR/CR = 85, BR/CR-A = 98, BR-A = 77). This subset (n = 260) is the focus of the primary analysis; sensitivity analysis included 281 eligible and treated pts with trackable clonal marker. In the primary analysis subset, 94%, 91%, and 90% in BR/CR, BR/CR-A, and BR-A arms, respectively, completed 6 cycles of protocol therapy. The PET/CT CMR/uMRD rates were 82% (BR/CR), 82% (BR/CR-A; p = 0.55 vs BR/CR), and 78% (BR-A; p = 0.76 vs BR/CR). In the sensitivity analysis set, PET/CT CMR/uMRD rates were 74% with BR/CR (n = 94), 76% (p = 0.44) with BR/CR-A (n = 106), and 74% (p = 0.52) with BR-A (n = 81). ORR (CMR) rates were 94% (91%), 99% (90%), and 94% (91%) with BR/CR, BR/CR-A, and BR-A, respectively. At a median follow-up of 27.9 mo, estimated 12-mo PFS/OS were 86%/94% (BR/CR), 89%/98% (BR/CR-A) and 87%/95% (BR-A). The proportion of treatment-related grade 3 or higher adverse events (AE) was 78%/88%/73%, with neutropenia in 52%/58%/27%, anemia in 23%/32%/3%, thrombocytopenia in 55%/66%/6%, and febrile neutropenia in 11%/12%/4%; treatment discontinuation due to AE occurred in 5%/7%/8% in BR/CR, BR/CR-A, and BR-A arms, respectively. Conclusion: High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles. BR-A was found not superior and closed early by the DSMC; however, it is the least toxic arm with similar efficacy, and represents an appealing option to avoid high dose cytarabine.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.

Background: Data on the clinical activity of venetoclax (ven) in lymphoplasmacytic lymphoma (LPL) are primarily limited to a phase 2 trial of ven monotherapy for a 2-year duration in 32 patients (pts) with relapsed/refractory IgM LPL who received a median of 2 prior treatments (tx), including 16 pts with prior BTK inhibitors (BTKi) (Castillo et al, JCO 2021). Overall response rate (ORR) was 84% and median progression-free survival (PFS) was 30 months (mos). We report the clinical activity of ven and prognostic factors associated with outcomes in a larger cohort. Methods: We included pts with LPL treated with ven alone at 9 US centers. The primary outcome was ORR, which included minor response (MR), partial response (PR), very good PR (VGPR), and complete response (CR) per IWWM-7. Secondary outcomes included PFS, overall survival (OS), safety of ven, and predictors of ORR, PFS, and OS. Results: Sixty-two pts were included. Twenty pts (32%) received ven on a clinical trial. At ven initiation, median age was 65 years (range 38 - 87) , 61% were male, serum monoclonal (M) protein was IgM in 50 pts (91%) (IgG/IgA in 3 (5%), absent in 2 (4%), missing n=7), median hemoglobin (Hb) was 10.4 g/dL (range 5.7-16.4), and median serum IgM was 2580 mg/dL (range 5-9300). Mutations of MYD88 and CXCR4 were present in 52 (95%; missing n = 7) and 19 (38%; missing n = 12) pts, respectively. Median lines of tx (LOT) before ven was 3 (range 1-11, 58% ≥3) including antiCD20 monoclonal antibody n=54 (87%), BTKi n=48 (77%), proteasome inhibitor n=40 (65%), and bendamustine n=31 (50%). Pts who received ven on a clinical trial were less heavily pretreated (median prior LOT = 1.5, 20% ≥3) compared with pts treated off trial (median prior LOT = 4, 76% ≥3). ORR to prior BTKi was 71% (CR 4%, VGPR 10%, PR 35%, MR 21%) (missing n=5), with a median duration of tx of 14 mos (range 0.5-119). BTKi was stopped due to progressive disease (PD) in 60% and toxicity in 40%. ORR to most recent tx before ven was 58% (CR 3%, VGPR 8%, PR 32%, MR 15%); 21% SD, 7% PD, and 15% missing. BTKi was the most frequently used tx immediately before ven (48%). Six pts (10%) required plasmapheresis up to 30 days before starting ven. Median time from diagnosis to ven initiation was 5.9 years (range 0.3-23). Ven starting dose was 200 mg in 33 pts (55%), 20 mg in 11 (18%), and 100 mg in 10 (17%) (other n=6, missing n=2). Ten pts (17%) were admitted for ven tx initiation. Maximum ven dose was 400 mg in 16 (27%) and 800 mg in 38 pts (63%) (other n=6, missing n=2). ORR to ven (missing n=3) was 73% (95% confidence interval [CI] 63-86%) (CR 2%, VGPR 21%, PR 44%, MR 7%); 23% were refractory (SD 13%, PD 10%). Median time to best response was 4 mos (range 0.5-30). Median time to peak Hb was 5 mos (range 0.1-24) and to nadir serum M protein level was 8 mos (range 0.5-34). With a median follow-up of 21.9 mos (range 2.3-70.4), the median and 3-year PFS were 30.4 mos (95% CI 11.0-38.6) and 40% (95% CI 25-54%), respectively (Figure). Median and 3-year OS were not reached (NR) (95% CI NR-NR) and 83% (95% CI 70-91%), respectively. Lymphoma was the most common cause of death (n=8/11, 73%). In univariable analyses (UVA), tx with ven on a clinical trial was associated with higher ORR (90% vs 64%; odds ratio = 8.67, 95% CI 1.04-72.16, p=.046) and superior PFS (median 39 mos (95% CI, 28.4-NR) vs 11 mos (95% CI 6.4-NR), p=.028) without a significant difference in OS. Other factors evaluated in UVA to assess association with ORR, PFS and OS were age at ven start, response to last prior tx, prior tx with BTKi, and CXCR4 mutation status. Of these, receipt of prior tx with BTKi was associated with inferior PFS (HR=2.7, 95% CI 1.1-6.5, p=.024), whereas age >65 years at ven start (HR=8.6, 95% 1.1-67.8, p=0.042) and receipt of ≥3 prior tx (HR=12.0, 95% 1.5-95.9, p=.019) were associated with inferior OS. Four pts (7%) developed laboratory tumor lysis syndrome (TLS) including 2 (3%) with clinical TLS. TLS occurred at the 400 or 800 mg dose in 3 pts (missing n=1). Ven dose interruptions and/or reductions occurred in 39%. Three pts (5%) had febrile neutropenia. Ven was stopped due to PD in 21 pts (34%), planned tx completion in 15 (24%) (median tx duration = 25 mos, range 24-28), toxicity 6 (10%), and other 4 (6%); 16 pts (26%) remain on ven. Median duration of tx for those who stopped ven was 12 mos (range 1-33). Conclusion: Ven is an effective tx option for pts with relapsed or refractory LPL. Compared with the phase 2 study, ORR and PFS were lower in this cohort of more heavily pretreated pts.

Abstract Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.