Caimi, Paolo F.

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.

Multiple CD19-directed therapies are available for the treatment of relapsed and refractory (R/R) DLBCL, including CAR T cells, tafasitamab/lenalidomide (TL), and loncastuximab tesirine (lonca-T) (Sermer D., Blood Rev 2023). However, there are few data available on the efficacy of sequential CD19-directed therapies. We performed a retrospective study evaluating all patients with R/R LBCL treated consecutively with TL at 11 institutions from 8/2020 to 8/2022, identifying 178 patients. In this study, we specifically evaluate outcomes in patients who received anti-CD19 therapy prior to or after TL. The primary outcome of interest was progression-free survival (PFS) in TL recipients who previously received CD19-directed CAR T therapy, with overall response rate (ORR), complete response rate (CRR), and overall survival (OS) also evaluated. Outcomes of lonca-T and CAR T after TL therapy were evaluated. Data on CD19 expression was assessed on biopsies after TL; this was determined locally using flow cytometry or immunohistochemistry per institutional protocols. In subgroup analyses, ORR and CRR were compared using Fisher's exact test. PFS and OS were estimated using the Kaplan-Meier method, with differences tested using the log-rank test. Of 178 patients who received TL, 52 had received prior anti-CD19 CAR T therapy, at a median of 7.4 months before TL (Table 1). Median PFS was lower in prior CAR T recipients (1.6 mo, 95% CI 1.1-2.5) vs no prior CAR T (2.1 mo, 95% CI 1.8-3.2), with hazard ratio 1.46 (p = 0.04; Figure 1). Best ORR was lower in patients with prior CAR T exposure (15% vs 33%, p = 0.02) though CRR was not significantly different (15% vs 18%, p = 1.0). We specifically evaluated TL outcomes based on prior response to CAR T, given the previously identified association of refractory disease with poor TL outcomes (Qualls D et al., presented at ASH 2022). Of 19 patients who had progressive disease more than 6 months after CAR T, ORR and CRR to TL therapy were 31.6% (all responses were CRs); in 33 patients with refractory disease (less than CR or relapse within 6 months) after CAR T, ORR and CRR to TL were significantly lower, at 6.1% (p = 0.04). Median PFS after TL was shorter in CAR-refractory than CAR-relapsed disease, at 1.4 vs 3.5 months (HR 2.2, p = 0.02). Of 88 patients who received therapy after TL, 20 (23%) received lonca-T and 14 (16%) received CAR T. Data on survival and initiation of new treatment after CAR T or lonca-T was available, but response and progression data after CAR T or lonca-T therapy is pending. These data allowed an estimate of OS and event-free survival (EFS), defined as survival without initiation of a new treatment after CAR T or lonca-T. With a median 3.9 months' follow-up, median EFS after CAR T administration was 3.7 months (95% CI, 0.9 - 6.5), and median OS was 8.1 months (95% CI, 0.6 - 15.7). In patients who received lonca-T, with median 2.7 months' follow-up from initiation, median EFS was 2.8 months (95% CI, 0.9 - 4.7), and median OS was 3.5 months (95% CI, 1.2 - 5.7). When comparing CAR T and lonca-T to polatuzumab vedotin- or chemotherapy-based therapies after TL, there were no significant differences in OS or EFS. In patients who discontinued TL, 24 had a biopsy a median of 18 days after the last dose of tafasitamab. Of these, 13 (54%) were CD19-positive and 11 (46%) were CD19-negative. All samples obtained more than 21 days after tafasitamab (6/6) were CD19-positive, while 46% obtained within 21 days were CD19-positive. These time-dependent findings may reflect “epitope masking” by tafasitamab rather than CD19 loss, reflecting other recent reports (Fitzgerald K., Leuk Lym 2022; Duell J., Leuk Lym 2022). In patients receiving TL after CAR T, responses and PFS were lower than in patients without prior CAR T therapy; however, with disease that was not refractory to prior CAR T, results were similar to patients who had not had prior CAR T. This may reflect that refractory disease, regardless of prior therapy, is associated with shorter PFS, though the possibility of CD19-mediated mechanisms of resistance remains. Modest EFS and OS were seen in patients receiving CAR T therapy or lonca-T after already receiving TL, though this may also reflect the high-risk disease characteristics of this cohort. Overall, in a high-risk, real-world cohort of TL-treated patients, these data suggest that some patients may benefit from subsequent CD19-directed therapies, but better therapeutic options are needed.

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.

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.

Background SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. Methods SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. Results A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10–30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. Conclusions SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. Trial registration number NCT02376699.

Monoclonal antibody treatment initially heralded an era of molecularly targeted therapy in oncology and is now widely applied in modulating anti-cancer immunity by targeting programmed cell receptors (PD-1, PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and, more recently, lymphocyte-activation gene 3 (LAG3). Chimeric antigen receptor T-cell therapy (CAR-T) recently proved to be a valid approach to inducing anti-cancer immunity by directly modifying the host’s immune cells. However, such cell-based therapy requires extensive resources such as leukapheresis, ex vivo modification and expansion of cytotoxic T-cells and current Good Manufacturing Practice (cGMP) laboratories and presents significant logistical challenges. Bi-/trispecific antibody technology is a novel pharmaceutical approach to facilitate the engagement of effector immune cells to potentially multiple cancer epitopes, e.g., the recently approved blinatumomab. This opens the opportunity to develop ‘off-the-shelf’ anti-cancer agents that achieve similar and/or complementary anti-cancer effects as those of modified immune cell therapy. The majority of bi-/trispecific antibodies target the tumor-associated antigens (TAA) located on the extracellular surface of cancer cells. The extracellular antigens represent just a small percentage of known TAAs and are often associated with higher toxicities because some of them are expressed on normal cells (off-target toxicity). In contrast, the targeting of intracellular TAAs such as mutant RAS and TP53 may lead to fewer off-target toxicities while still achieving the desired antitumor efficacy (on-target toxicity). Here, we provide a comprehensive review on the emerging field of bi-/tri-specific T-cell engagers and potential therapeutic opportunities.