Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study.

ABSTRACT: In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.

Chimeric antigen receptor T-cell therapy for haematological malignancies: Insights from fundamental and translational research to bedside practice.

Autologous chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of lymphoid malignancies, leading to the approval of CD19-CAR T cells for B-cell lymphomas and acute leukaemia, and more recently, B-cell maturation antigen-CAR T cells for multiple myeloma. The long-term follow-up of patients treated in the early clinical trials demonstrates the possibility for long-term remission, suggesting a cure. This is associated with a low incidence of significant long-term side effects and a rapid improvement in the quality of life for responders. In contrast, other types of immunotherapies require prolonged treatments or carry the risk of long-term side effects impairing the quality of life. Despite impressive results, some patients still experience treatment failure or ultimately relapse, underscoring the imperative to improve CAR T-cell therapies and gain a better understanding of their determinants of efficacy to maximize positive outcomes. While the next-generation of CAR T cells will undoubtingly be more potent, there are already opportunities for optimization when utilizing the currently available CAR T cells. This review article aims to summarize the current evidence from clinical, translational and fundamental research, providing clinicians with insights to enhance their understanding and use of CAR T cells.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study.

Therapies that demonstrate durable, long-term responses with manageable safety and tolerability are needed for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer, demonstrated single-agent antitumor activity in the pivotal phase II LOTIS-2 study in heavily pretreated patients with R/R DLBCL. Here we present updated efficacy and safety analyses from LOTIS-2, performed for all patients and in subsets of patients with a complete response (CR), including patients with CR who were event-free (no progressive disease or death) for ≥1 year and ≥2 years from cycle 1, day 1 of treatment. Lonca was administered every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles). As of the final data cutoff (September 15, 2022; median follow-up: 7.8 months [range, 0.3-42.6]), 70 of 145 (48.3%) patients achieved an overall response. Thirty-six (24.8%) patients achieved CR, of which 16 (44%) and 11 (31%) were event-free for ≥1 year and ≥2 years, respectively. In the all-treated population, the median overall survival was 9.5 months; the median progression-free survival was 4.9 months. Among patients with CR, median overall survival and progression-free survival were not reached, with 24-month overall and progression-free survival rates of 68.2% (95% CI: 50.0-81.0) and 72.5% (95% CI: 48.2-86.8), respectively. No new safety concerns were detected. With additional follow-up, Lonca continued to demonstrate durable, long-term responses with manageable safety and tolerability in patients with CR (clinicaltrials gov. Identifier: NCT03589469).

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy.

Antibody-drug conjugates (ADC) represent one of the most successful therapeutic approaches introduced into clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19-targeting ADC in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine dimer warhead (SG3199). Based on the results of a phase II study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with levels of CD19 expression, and identified combination partners providing synergy with the ADC. Loncastuximab tesirine was tested across 60 lymphoma cell lines. It had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with the level of CD19 expression and intrinsic sensitivity of cell lines to the ADC's warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADC (coltuximab ravtansine, huB4-DGN462), although the pattern of activity across cell lines was correlated. The activity of loncastuximab tesirine was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine for use as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.

Lenalidomide maintenance following high-dose therapy and autologous haematopoietic stem cell transplantation in chemo-resistant or high-risk non-Hodgkin lymphoma: A phase I/II study.

Improved maintenance treatments are needed for patients with relapsed/refractory aggressive lymphomas after autologous haematopoietic stem cell transplantation (ASCT). Several studies with lenalidomide have been found to have activity in the treatment of relapsed/refractory aggressive lymphomas. In the present phase I/II, single-arm, open-label study, 59 patients with high-risk relapsed non-Hodgkin lymphoma received pretransplant BEAM chemotherapy and ASCT followed by 12 months of maintenance lenalidomide once daily on Days 1-21 (28-day cycles) beginning at post-transplantation Day 100. The most common histologies were mantle cell lymphoma (56%) and diffuse large B-cell lymphoma (24%). The maximum tolerated dose in the dose-finding part of the study was 15 mg, but cytopenias led to the subsequent adoption of a 10 mg dose in the final study. Sixteen patients (27%) completed 12 cycles of lenalidomide maintenance. The most common reason for discontinuation was adverse events (31%). These were primarily haematologic, and 56% of patients experienced Grade 3-4 events. Two-year PFS rates (95% CIs) were 70% (56%-80%), 45% (19%-68%) and 81% (66%-90%); 2-year OS rates (95% CIs) were 91% (80%-96%), 93% (61%-99%) and 90% (76%-96%) in all patients, patients completing and patients not completing 12-month maintenance respectively. These results do not support the use of lenalidomide maintenance in this setting.

Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma.

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3 + 3 dose escalation at 15 to 200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CRs). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved a CR. Loncastuximab tesirine had good stability in serum, notable antitumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for phase 2 was determined as 150 µg/kg every 3 weeks for 2 doses followed by 75 µg/kg every 3 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02669017.

Outcomes of limited stage primary bone diffuse large B-cell lymphoma in the rituximab era: a multicenter, retrospective study.

Primary bone diffuse large B cell lymphoma (DLBCL) is a rare variant of extranodal non-Hodgkin lymphoma (NHL) historically treated with induction chemotherapy followed by consolidative radiation therapy (RT). It remains unknown whether RT confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction in patients with limited-stage disease. We conducted a multicenter retrospective analysis of patients treated between 2005 and 2019 using rituximab-based CIT regimens with or without consolidative RT to discern whether consolidative RT adds benefit in patients with stage I-II disease that could be encompassed in one radiation field. A total of 112 patients were included: 78 received CIT and radiation (RT group), and 34 received CIT alone (no RT group). The OS at 10 years was 77.9% in the RT group and 89.0% in the no RT group (p = 0.42). The RFS at 10 years was 73.5% in the RT group and 80.3% in the no RT group (p = 0.88). Neither improved OS nor RFS was associated with the addition of consolidative RT. Subgroup analysis of patients only achieving a partial response after CIT suggests that these patients may benefit from consolidative RT.

A population level analysis of second hematological malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma survivors in the era of targeted therapies.

With improvement in survival after chronic lymphocytic leukemia (CLL) diagnosis, the real-world burden of second hematological malignancies (SHM) has not been comprehensively assessed in recent era. We analyzed risk, incidence, and outcomes of SHM in CLL patients between 2000 and 2019 using SEER database. CLL patients had greater risk for hematological malignancies than general population [SIR, standardized incidence ratio (95% CI):2.58 (2.46-2.70); p < 0.05]. The risk for subsequent lymphoma increased by 1.75 folds in 2015-2019 compared to 2000-2004. The duration, after CLL diagnosis, of maximum risk for SHM decreased as 60-119 months for time-period 2000-2004, 6-11 months for 2005-2009 to 2-5 months for 2010-2014 and 2015-2019. Incidence of SHM was 2.5% in CLL survivors (1736/70,346) with lymphoid SHM being more common than myeloid SHM, and DLBCL being the most common pathology (n = 610, 35% of all SHM). Male sex, age ≤65 years at CLL diagnosis, and chemotherapy treatment were associated with higher risk for SHM. The median gap between CLL and SHM diagnoses was 46 months. The median survival for de-novo-AML, t-MN, CML, and aggressive NHL was 63, 86, 95, and 96 months respectively. Although SHM remains rare, there is increased risk in recent era, likely due to improved survival in CLL patients, necessitating active surveillance strategies.