Messmer, Marcus

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.

The treatment landscape of B-cell lymphomas has significantly evolved in recent years with approval of novel targeted therapies. CD3 × CD20 bispecific antibodies and CD19-directed monoclonal antibodies and antibody–drug conjugates have demonstrated efficacy in relapsed/refractory follicular lymphoma (FL). Bruton tyrosine kinase (BTK) inhibitor–based regimens are emerging as effective treatment options for patients with TP53-mutated classical mantle cell lymphoma (MCL). Results from ongoing clinical trials suggest that the addition of CD3 × CD20 bispecific antibodies to chemoimmunotherapy improves outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, MCL, and DLBCL.

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.

Novel targeted therapies (small molecule inhibitors, antibody–drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton’s tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

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.

AbstractPlasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1–196), the 3‐year progression‐free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3‐year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper‐CVAD or auto‐SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.

Background: Plasmablastic lymphoma (PBL) is a rare subtype of Non-Hodgkin Lymphoma with a well-known association with HIV infection. The outcomes of PBL patients are typically described with high relapse rates and poor prognosis. (Loghavi S, J Hematol Oncol. 2015; Morscio J, Am J of Pathol. 2014; Castillo JJ, Clin Lymphoma Myeloma Leuk. 2011; Castillo JJ, Am J Hematol. 2008) There has been a paucity of data suggesting that limited stage disease (Ann Arbor stage I-II) may have a more favorable prognosis. However, due to the rarity of this disease there have been no large-scale reviews to confirm this. Thus, many patients with limited stage disease are subject to the aggressive therapy recommendations based on the poor outcomes of PBL patients as a whole. (Loghavi S, J Hematol Oncol. 2015; NCCN Guidelines, version 2.2020; Al-Malki MM, BBMT. 2014) We attempted to determine the treatment patterns and outcomes of patients with limited stage PBL. Methods: We conducted a multi-center (13 US academic centers) retrospective study of patients with limited stage (Ann Arbor stage I-II) Plasmablastic lymphoma. Determination of limited stage and diagnosis of PBL was determined by the investigators at each individual center. Patients diagnosed between 1/1/1990 and 6/1/2018 were included. Baseline demographic, clinical, laboratory, pathology, and outcomes data were extracted by retrospective chart review. Kaplan Meier was utilized for time to event analysis. Results: Baseline characteristics are included in table 1. A total of 80 patients were identified with limited stage disease. With a median follow up of 34 months the 3-yr Progression free survival (PFS) and overall survival (OS) was 71.9% and 78.7% respectively (Figure 1A and 1B). Patients that received frontline chemotherapy with (n=29) and without RT (n=36) had a 3-yr PFS and OS of 84.6% and 96.2% as compared to 64.5% and 70.8%, respectively (Figure 2A and 2B; Figure 3A and 3B). The Hazard ratio (HR) for PFS and OS for chemo (reference) vs chemo-RT was 0.47 (95% CI 0.18-1.3; P=0.131) and 0.18 (95% CI 0.04-0.84; p=0.029) respectively. The HR for PFS and OS for CHOP (n=14, reference) vs EPOCH (n=33) based regimens was 0.37 (95% CI 0.11-1.2; p=0.106) and 0.36 (95% CI 0.079-1.6; p=0.182) respectively. Patients with stage I/IE disease (n=56) had a 3-yr PFS and OS of 73.1% and 81.2% respectively. Patients with stage II/IIE disease (n=24) had a 3-yr PFS and OS of 69.3% and 73.4% respectively. Patients that received aggressive treatment (n=17) with Hyper-CVAD based regimens and/or Auto-SCT as consolidation had a 3-yr PFS and OS of 63.6% and 72.7% respectively. Patients with concomitant HIV (n=16) had a 3-yr PFS and OS of 80.8% and 77.4% respectively. Seven patients received RT alone and 6 patients had surgical resection alone as frontline therapy; 1 patient received no therapy; 1 patient received HAART therapy only and remains in CR without any other treatment for PBL 29 months after diagnosis. There were 8 deaths (10%) related to PBL, 3 deaths (4%) related to treatment of PBL (2 during frontline chemo and 1 upon relapse with salvage chemo), and 9 deaths (11%) related to other causes. The 3-yr lymphoma free survival (LFS) of the entire cohort, pts receiving chemo alone, and pts receiving chemo-RT (without including treatment related mortality (TRM) as an event) was 89.1%, 85.2%, and 100% respectively. The 3-yr LFS survival of the entire cohort, pts receiving chemo alone, and pts receiving chemo-RT (including TRM as an event) was 85.1%, 80.0%, and 96.2% respectively. Discussion: Here we report the largest review to our knowledge of limited stage PBL. Outcomes appear to be excellent with 3-yr PFS and OS of 71.9% and 78.7% respectively and a 3-yr LFS of 89.1% (85.1% when attributing TRM as an event). There was no obvious benefit to receiving aggressive therapy with H-CVAD based regimens and/or Auto-SCT. Although this is a small, uncontrolled sample size the HR for OS was improved in patients receiving frontline chemo-RT vs chemo alone 0.18 (95% CI 0.04-0.84; p=0.029). However, this did not take into account TRM with or progression while receiving frontline chemotherapy. Patients who were HIV+ had similar PFS and OS outcomes compared to the entire cohort. This retrospective study clearly demonstrates the favorable outcomes in this patient population, especially in those able to receive definitive therapy for their disease. Disclosures Hess: ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Patel:Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Nektar: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Nowakowski:Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding. Chavez:Bayer: Consultancy; AbbVie: Consultancy; BeiGene: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; AstraZeneca: Speakers Bureau; Celgene: Consultancy; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Verastem: Consultancy; Pfizer: Consultancy. Hill:Beigene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Maddocks:Pharmacyclics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Kahl:AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; OncLive: Honoraria. Lossos:Janssen Biotech: Honoraria; Verastem: Consultancy, Honoraria; Janssen Scientific: Consultancy, Other; Seattle Genetics: Consultancy, Other; Stanford University: Patents & Royalties; NCI: Research Funding. Portell:Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Takeda: Research Funding; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Speakers Bureau. Castillo:TG Therapeutics: Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding.

PURPOSE Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score–weighted (PSW) analysis were performed. RESULTS Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.