Nizamuddin, Imran

Abstract Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P< .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Introduction: The real-world outcomes in patients (pts) with PCALCL in the era of targeted therapies like Brentuximab Vedotin (BV) is not well defined due to lack of large multicenter studies. We conducted a multicenter retrospective analysis (RWA) to assess patient and disease characteristics, treatment patterns, survival outcomes and impact of novel therapies in this rare type of cutaneous T cell lymphoma (CTCL). Methods: The analysis included 167 adult (≥18 years) patients (pts) with PCALCL across 9 academic institutions in the United States diagnosed between 01/2012 to 06/2022. The study was approved by the Institutional Review Boards at the respective sites. Demographic and disease factors were summarized using descriptive statistics. Overall survival (OS) and relapse-free survival (RFS) were estimated using Kaplan-Meier method and compared via log rank tests. Prognostic models included factors such as age, sex, race, performance status (PS), disease stage, type of initial lesion, presence of B symptoms, previous history of lymphomatoid papulosis and prior transplant. Prognostic factors for survival were assessed using both univariable and multivariable Cox proportional hazard models. Results: The median age at diagnosis was 61 (range 18-93) years. The majority of pts were male (55%) and white (82%), with good PS as indicated by an ECOG 0-1 (71%). The initial skin presentation consisted of tumors in 62% of the pts, while 34% presented with plaques or patches. Notably, no pts presented with erythroderma. Most pts underwent PET scan for staging at initial diagnosis (83%) with the majority having early-stage (IA-IIA) disease (86%). Furthermore, palpable lymph nodes (11%) and the presence of B symptoms (4%) were rare at diagnosis, and no pts had blood involvement. The most common sites of involvement were extremities (33%) followed by the head and neck (H&N) and trunk (31% each). Immunophenotyping revealed CD4 positivity in 59% of pts and CD8 positivity in 25%. The T cell receptor (TCR) rearrangement was positive in 28% of pts, though it was not completed in the majority of cases (72%). Most common initial treatments included localized radiation (61%) and surgical excision (19%). A small subset of pts received frontline systemic chemotherapy regimens such as cytotoxic chemotherapy (11%), BV (8%) and oral methotrexate (MTX) (8%). Approximately 7% of the pts had a stem cell transplant. Overall response rate (ORR) for radiation, oral MTX, BV and cytotoxic chemotherapy were 78% (CR:78% 74/100), 42% (CR:63% 6/12) and 39% (CR:67% 6/12), 89% (CR: 88% 15/18) respectively. At a median follow-up of 3.8 years (range 0.04-10.23), the median RFS and OS were 2.7 years (95% CI:1.86, 3.43) and 12 years (95% CI:10.6- NA) respectively. The estimated 3- and 5-year RFS are 46% (95% CI:0.38, 0.55) and 37% (95% CI:0.28, 0.46) respectively. The estimated 3- and 5-year OS were 89% (95% CI:0.82, 0.93) and 82% (95% CI:0.73, 0.88) respectively. At the time of the last follow-up, 79% were alive, while 21% were deceased. The cause of death (COD) was unknown in 50% of the cases and only 10% (3/of deaths were attributed to lymphoma. Other known CODs included infection (20%) and second malignancies 7%. On univariate analysis (UVA), age (p=.007), female sex (p=.04), ECOG PS 1-2 compared to 0 (p=.007) and prior transplant (p=.009) predicted for worse RFS. On multivariate analysis (MVA), only ECOG PS 1-2 (HR 2.31, 95 CI:1.06, 1.18, p=.009) and prior transplant (HR 5.38, 95 CI:2.30, 12.57, p=.0001) had a significant impact on RFS. Age and presence of B symptoms were strong predictors of OS on both UVA (age p=<.0001; B symptoms p=<.0001) and MVA (age: HR 1.12, 95 CI:1.06, 1.18, p=<.0001; B symptoms: HR 16.48, 95 CI: 3.69, 73.60, p=.0002). However, the impact of B symptoms should be interpreted with caution as only 4% of pts presented with this at baseline. On UVA, each one-year increase in age was associated with an 8.5% rise in the risk of death. ECOG PS 1-2 was associated with worse OS on univariate analysis (HR 2.62, 95% CI 0.99, 6.93, p=.05), but was not significant on MVA (HR 1.05, 95% CI 0.368, 2.974, p=.93). Conclusions: In this large RWA of PCALCL, excellent long-term survival was observed with predominantly skin directed frontline therapies. The use of systemic treatments, including BV, was infrequent as first line therapy. Older age and poor PS were significant predictors for reduced survival.

Introduction: Scant data exist on prognostic factors, survival and treatment (Tx)-related outcomes in SCNSL. We conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis (de novo), or after frontline Tx (1L) either with (concomitant) or without (isolated) systemic (syst) relapse. Methods: This study collected data from patients (pts) treated between 2001-2023 at 35 centers. Overall (OS) and progression-free survival (PFS) were calculated from SCNSL diagnosis to first event (death for OS, relapse/death for PFS) or last follow-up. Uni- (UVA) and multivariable (MVA) Cox analyses were performed to assess prognostic factors; Kaplan-Meier method was used to estimate survival. Results: 1173 (US: 863, UK: 273, Canada: 37) pts with SCNSL were included. Baseline characteristics were median age: 62 years (interquartile range 52.5-69), male sex: 58.7%, elevated LDH: 71.1%, stage III/IV: 88.6%, HIV: 3%, transformed LBCL (tLBCL): 13.8%, non-germinal center B-cell like (non-GCB) subtype: 52.3%, double expressor (DE): 40%, MYC rearrangement (MYC-R): 28.3%, MYC/BCL2 double hit: 16.6%, MYC/BCL2/BCL6 triple hit (TH): 6.1%. Among 522 pts with de novo SCNSL, 84.2% had involvement of a single CNS compartment (44.7% brain parenchyma; 40.4% leptomeningeal [lepto]). 1L regimens included 36.2% R-CHOP with high-dose methotrexate (HD-MTX), 12.5% MARIETTA-type, and 9.8% R-CODOX-M/IVAC; 54.6% received intrathecal chemotherapy. Consolidation Thiotepa-based autologous stem cell transplant (TT-ASCT) occurred in 15.3%. The majority of pts who underwent TT-ASCT had previously achieved CR or PR in syst (92.5%) and CNS (72.5%) compartments. At median follow-up 25.7 months (mos), subsequent relapse was observed in 27.5% TT-ASCT recipients: 36.3% had isolated CNS, 27.4% syst, and 36.3% concomitant. 588 pts presented with SCNS after 1L (66.2% isolated, 33.8% concomitant). Brain parenchyma involvement was observed in 56.8%, lepto in 22.6%. Tx included 31.6% HD-MTX combination (eg, R-MPV, MTR); 18.4% HD-MTX +/- rituximab; 16.2% MARIETTA-type; and 9.4% platinum-based regimen. Consolidation TT-ASCT occurred in 22.4% (n=132), and 13.8% (n=81) received CAR-T cell therapy (excluding subsequent relapses in de novo group). Syst (65.1%) & CNS (69.1%) responses (CR/PR) were higher before TT-ASCT compared to CAR-T cell (49.5% & 54.5%, respectively). After TT-ASCT, 52 pts (39.3%) relapsed, mainly in the CNS (n=30, 57.7%), with only 4 (7.7%) concomitant. After CAR-T, 48 pts (59.3%) relapsed: 15 (31.2%) isolated in CNS and 15 (31.2%) concomitant. 12-month cumulative incidence of relapse (with death as competing risk) was 21.1% after TT-ASCT and 55.8% after CAR-T. In 63 pts (5.4%), the first CNS event occurred >2 lines of Tx. With median follow-up of the entire cohort of 24.6 mos, median PFS and OS were 11 and 21 mos, respectively. mPFS and mOS were significantly better in pts with de novo SCNSL (13.4 & 47.4 mos) compared to SCNSL after 1L (10.4 & 14.2 mos) and >2 lines of Tx (6.5 & 9.7 mos); P<0.0001. Factors associated with significantly shorter OS in UVA across all presentations were age >60, male sex, GCB subtype, MYC-R, tLBCL, DE, TH, elevated LDH, ECOG PS ≥2, SCNSL after 1L (vs. de novo), and failure to achieve syst/CNS response to 1L. Of these, age >60, male sex, MYC-R, ECOG PS ≥2, and failure to achieve response to 1L remained significant in MVA. In de novo cases, age >60, DE, ECOG PS≥2, and failure to achieve syst/CNS response to 1L were associated with poorer OS; for pts with SCNSL after 1L, age >60, GCB subtype, and ECOG PS ≥2 were significant. Pts treated with HD-MTX-based regimens after 1L experienced longer OS than those treated with platinum regimens or high-dose cytarabine. In de novo cases, TT-ASCT was significantly associated with longer OS (HR=0.58; P=0.025) in MVA after adjusting for significant factors, 1L type, and response. For SCNSL at relapse, TT-ASCT (HR=0.34; P<.0001) and isolated SCNSL presentation (vs. concomitant HR=0.70, P=0.007) were associated with longer OS, adjusting for significant factors, type of second-line Tx, & site of CNS relapse. Conclusions: This study represents the largest analysis of SCNSL inclusive of all modes of presentation. Concomitant SCNSL at relapse was associated with poor outcomes, while TT-ASCT consolidation was associated with improved OS in de novo & relapsed disease. Despite advances in LBCL SCNSL remains an unmet therapeutic need.

Introduction: DH/THL also classified as high-grade B cell lymphomas (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements have higher risk of progression after initial treatment and poor response to salvage therapies compared to diffuse large B cell lymphoma (DLBCL), NOS. Recently, CART cell therapy has shown encouraging responses in treatment of relapsed refractory (R/R) DLBCL. In this retrospective study, we evaluated whether survival of (R/R) DH/THL is improved in the CART era. Methods: In this multicenter retrospective study, adult pts (pts) with R/R DH/THL after anthracycline-based therapy were included. Demographic and clinical variables were obtained from electronic health records. Study objectives was overall survival (OS) at 2 year landmark. We utilized full propensity score matching to compare progression free survival (PFS) and OS of CART with 2 nd line chemoimmunotherapy. Results: 278 DH/THL pts treated between 2010-2020 were included. Median age was 63 years (range 52-74), 163 (58%) were male, 119 (43%) were classified as DLBCL and 116 (42%) as HGBCL; 40 (14%) were transformed from follicular lymphoma. 225 (82%) had advanced stage, 161 (67%) had elevated LDH, 85 (33%) had bulky disease, 74 (59%) had B symptoms. 105 (38%) pts treated for relapsed disease before 2018 were included in the pre-CART era cohort. 168 (60%) pts treated from 2018 onwards were included in the CART era cohort. 102 (60%) pts in CART cell era received CART cells, 40 (14%) received polatuzumab vedotin (pola), 10 (3.5%) received loncastuximab tesirine, tafasitamab and bispecific antibody each. Characteristics at relapse were similar in both groups. Median follow up was 8.9 (0.2-146) months. 2-year OS estimate was 36% (CI 95: 30-42%) in entire population. Patients treated in CART cell era had significantly higher OS (2 yr OS: 43% [CI 95: 35-53]) compared to pts treated in pre-CART cells era (2-year OS: 24% [CI 95: 16-34], p=0.0006) (Figure 1). In multivariable analyses, increasing age (HR = 1.02 (CI 95: 1.01, 1.04), p=0.003), extranodal disease (HR = 1.41 (CI 95: 1.00, 1.99), p<0.001), elevated LDH (HR = 1.57 (CI 95: 1.11, 2.24), p=0.01) were associated with inferior OS. Increasing time to relapse (HR = 0.98 (CI 95: 0.97, 0.99), p<0.001) was associated with superior OS. BCL6 rearrangement did not affect OS. When adjusted for these factors, treatment with CART cells was associated with higher 2 yr OS (HR = 0.33 (CI 95: 0.22, 0.49), p<0.001). Treatment with polatuzumab (HR = 1.07 (CI 95: 0.71, 1.6), p=0.07) was not significantly associated with OS in univariable analysis. 102 pts underwent CART cell therapy at any point for relapse; 94 (93%) were refractory to prior chemotherapy. 62 (60%) responded and 52 (50%) had CR after CART cells. 2-year PFS and OS after CART cell therapy were 28% (CI 95: 19-40) and 40% (CI 95: 30-53), respectively. Increasing time to CART was associated with inferior OS (HR: 1.02 (CI 95: 1.0-1.03, p=0.03) but not PFS (HR: 1.02 (CI 95: 0.99-1.04), p=0.2). 219 (79%) pts received curative intent salvage chemotherapy for 2 nd line. 2-year PFS and OS were 15% (CI 95: 11-20) and 38% (CI 95: 31-45), respectively. 21 pts received CART cell therapy for 2 nd line. 2 year PFS and OS in this small number of pts were 52% (CI 95: 35-79) and 70% (CI 95: 52-94), respectively. Due in part to the small number of pts who received CART cells in 2 nd line, we utilized full propensity score matched analysis to compare each patient in CART cell group to all possible matched controls in salvage chemotherapy group. Variables matched were age, LDH, extra nodal disease and time to relapse. In propensity score matched analysis, pts who received CART cells had significantly higher 2 year PFS (HR: 10.5 (CI 95: 3.4-17.5), p=002) and 2 year OS (HR: 7.5 (CI 95: 1.4-13), p=0.01). Conclusions: Survival of r/r DH/THL appears to have improved in the era of CART cell therapy. About 2/3 of pts refractory to chemotherapy respond to CART cells, and in multivariable analysis, receipt of CART cells was associated with improved OS. Increasing time to CART cells was associated with inferior survival. In a propensity score matched analysis utilizing full matching, CART cell therapy in 2 nd line was associated with significantly higher 2 year PFS and OS compared to curative intent salvage therapy. Other CD 19 and CD 20 targeting agents approved after CART cell therapy might contribute to favorable survival, effect of these agents could not be assessed because of small numbers.

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

AbstractCheckpoint inhibitor (CPI) therapy with anti–PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post–CAR-T outcomes.