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RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis.Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region. Patients were aged ≥18 years with histologically confirmed DLBCL and received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients enrolled in the observational and L-MIND cohorts were matched using propensity score-based 1:1 nearest-neighbor matching, balanced for six covariates. Tafasitamab+lenalidomide was compared with polatuzumab vedotin+bendamustine+rituximab (pola-BR), rituximab+lenalidomide (R2), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and progression-free survival.From 200 sites, 3,454 patients were enrolled in the observational cohort. Strictly matched patient pairs consisted of tafasitamab+lenalidomide versus pola-BR (n = 24 pairs), versus R2 (n = 33 pairs), and versus CAR-T therapies (n = 37 pairs). A significant OS benefit was observed with tafasitamab+lenalidomide versus pola-BR (HR: 0.441; p = 0.034) and R2 (HR: 0.435; p = 0.012). Comparable OS was observed in tafasitamab+lenalidomide and CAR-T cohorts (HR: 0.953, p = 0.892).Tafasitamab+lenalidomide appeared to improve survival outcomes versus pola-BR and R2, and comparable outcomes were observed versus CAR-T. Although based on limited patient numbers, these data may help to contextualize emerging therapies for R/R DLBCL.Clinical trial registrationNCT04697160 (January 6, 2021)

Tafasitamab is an Fc-modified monoclonal antibody that binds to CD19, a cell-surface antigen that is broadly expressed on various types of B-cell non-Hodgkin’s lymphoma (NHL). Antibody-dependent cellular cytotoxicity (ADCC), a key mode of action of tafasitamab, is mediated through the binding of tafasitamab’s Fc region to FcγRIIIa receptors on immune effector cells and results in antitumor activity. Despite the proven clinical activity of tafasitamab in combination with lenalidomide in the treatment of diffuse large B-cell lymphoma (DLBCL), a higher number of immune cells in cancer patients may improve the activity of tafasitamab. Here, we characterized two ex vivo-expanded FcγRIIIa receptor—expressing cell types—γδ T and MG4101 natural killer (NK) cells—as effector cells for tafasitamab in vitro, and found that in the presence of these cells tafasitamab was able to induce ADCC against a range of NHL cell lines and patient-derived cells. We also explored the concept of effector cell supplementation during tafasitamab treatment in vivo by coadministering MG4101 NK cells in Raji and Ramos xenograft models of NHL. Combination treatment of tafasitamab and allogeneic MG4101 NK cells in these models demonstrated a survival benefit compared with tafasitamab or MG4101 monotherapy (Raji: 1.7- to 1.9-fold increase in lifespan; Ramos: 2.0- to 4.1-fold increase in lifespan). In conclusion, adoptive cell transfer of ex vivo-expanded allogeneic NK or autologous γδ T cells in combination with tafasitamab treatment may potentially be a promising novel approach to increase the number of immune effector cells and enhance the antitumor effect of tafasitamab.

CD19-targeted therapies, including monoclonal antibodies, antibody–drug conjugates, and chimeric antigen receptor (CAR) T-cell products, have significantly improved outcomes in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Despite their clinical efficacy, resistance and antigen modulation pose substantial challenges, especially in patients requiring sequential therapy. This review provides a comprehensive overview of CD19 biology and its relevance as a therapeutic target. We examine mechanisms of resistance such as antigen loss, epitope masking, and T-cell exhaustion, as well as the implications of tumor microenvironmental immunosuppression. Future efforts should prioritize the integration of real-time diagnostics, such as flow cytometry, immunohistochemistry, and transcriptomic profiling, and AI-assisted predictive models to optimize therapeutic sequencing and expand access to personalized immunotherapy.

Abstract Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 24% of new cases of B-cell non-Hodgkin lymphoma in the US each year. Up to 50% of patients relapse or are refractory (R/R) to the standard first-line treatment option, R-CHOP. The anti-CD19 monoclonal antibody tafasitamab, in combination with lenalidomide (LEN), is an NCCN preferred regimen for transplant-ineligible patients with R/R DLBCL and received accelerated approval in the US (July 2020) and conditional marketing authorization in Europe (August 2021) and other countries, based on data from the L-MIND study. The recommended dose of tafasitamab is 12 mg/kg by intravenous infusion, administered in combination with LEN 25 mg for 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. Tafasitamab + LEN is associated with durable responses in patients with R/R DLBCL. The majority of clinically significant treatment-associated adverse events are attributable to LEN and can be managed with dose modification and supportive therapy. We provide guidelines for the management of patients with R/R DLBCL treated with tafasitamab and LEN in routine clinical practice, including elderly patients and those with renal and hepatic impairment, and advice regarding patient education as part of a comprehensive patient engagement plan. Our recommendations include LEN administration at a reduced dose if required in patients unable to tolerate the recommended dose. No dose modification is required for tafasitamab in special patient populations. It is important for clinicians to understand the optimal use of tafasitamab + lenalidomide and how treatment-emergent toxicities may be managed in the broader population to prevent early treatment discontinuation. This review provides a practical clinical guide for the management of patients with relapsed/refractory diffuse large B-cell lymphoma treated with tafasitamab + lenalidomide in routine clinical practice.

Tafasitamab is a novel humanized anti-CD19 monoclonal antibody, designed for the treatment of B-cell malignancies. Our study aims to enhance the direct, non-immune-mediated, activity of tafasitamab (TAFA) with the combination of metronomic chemotherapy (mCHEMO), including vinorelbine (mVNR) and etoposide (mETO), in preclinical models of diffuse large B-cell lymphoma (DLBCL). In vitro , the 144 h exposure of thrice-weekly mVNR, daily mETO, and single-dose TAFA significantly inhibited the viability of human CD19 + DLBCL cell lines (i.e., Toledo, OCI-LY3, and SU-DHL10) in a concentration-dependent manner. In all cell lines, the concomitant treatment with TAFA and mVNR or mETO showed a marked synergism, except for TAFA + mETO on SU-DHL10 cells. The TAFA + mCHEMO treatments promoted apoptosis, and the TAFA + mVNR combination significantly inhibited, already after 24 h, the phosphorylation of GSK3α/β, mTOR, p70S6K, RPS6, and TSC2 proteins in DLBCL cells. TAFA significantly increased the VNR and ETO intracellular concentrations in all DLBCL cells after 24 h, except for ETO levels in SU-DHL10. The TAFA + mCHEMO treatment strongly reduced the ABCB1 , ABCG2, and c-MYC gene expression in SU-DHL10 cells. In vivo, the TAFA + mVNR combination was well tolerated, significantly reduced the volumes of subcutaneous DLBCL masses, and increased the overall survival of mice affected by systemic DLBCL. We report additional mechanisms to enhance the direct activity of TAFA with mCHEMO synergistically in DLBCL cells in vitro and in vivo, suggesting the use of this combination schedule into future clinical trials.

IntroductionSeveral CD19 targeted antibody-based therapeutics are currently available for patients with diffuse large B-cell lymphoma (DLBCL), including the Fc-modified antibody immunotherapy tafasitamab. This therapeutic landscape warrants the evaluation of potential sequencing approaches. Prior to a subsequent CD19-targeted therapy, CD19 expression on tafasitamab-treated patient biopsy samples may be assessed. However, no standardized methods for its detection are currently available. In this context, selecting a tafasitamab-competing CD19 detection antibody for immunohistochemistry (IHC) or flow cytometry (FC) may lead to misinterpreting epitope masking by tafasitamab as antigen loss or downregulation.MethodsWe analyzed a comprehensive panel of commercially available CD19 detection antibody clones for IHC and FC using competition assays on tafasitamab pre-treated cell lines. To remove bound tafasitamab from the cell surface, an acidic dissociation protocol was used. Antibody affinities for CD19 were measured using Surface Plasmon Resonance (SPR) or Bio-Layer Interferometry (BLI).ResultsWhile CD19 was successfully detected on tafasitamab pre-treated samples using all 7 tested IHC antibody clones, all 8 tested FC antibody clones were confirmed to compete with tafasitamab. An acidic dissociation was demonstrated essential to circumvent CD19 masking by tafasitamab and avoid false negative FC results.DiscussionThe current study highlights the importance of selecting appropriate CD19 detection tools and techniques for correct interpretation of CD19 expression. The findings presented herein can serve as a guideline to investigators and may help navigate treatment strategies in the clinical setting.

BackgroundDespite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects.MethodsAntibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).ResultsThree different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling, which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model.ConclusionThis study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo .

Peripheral nervous system involvement in lymphoproliferative diseases, often due to direct nerve infiltration (neurolymphomatosis, NL), is mostly seen in aggressive B-cell lymphoma. We report the case of an 88-year-old man with stage IVA DLBCL, who achieved the first complete response after six R-miniCHOP21 cycles. One year post-treatment, he developed severe neurological symptoms, and PET-CT revealed widespread relapse with extensive neural involvement. Treatment with tafasitamab and lenalidomide led to a complete morpho-metabolic remission and full neurological recovery, with minimal side effects. This case underscores for the very first time the efficacy and tolerability of this regimen in treating NL, highlighting its potential for frail patients unfit for more intensive therapies.

The outcomes of Relapsed/Refractory (R/R) Diffuse Large B-cell lymphoma have been historically poor. The recent development of several novel therapies including CD19 directed agents has improved the prognosis of this disease significantly. Chimeric antigen receptor (CAR) T-cell therapy has drastically changed the treatment of R/R DLBCL, but it is still associated with significant barriers and limited access. Tafasitamab (an anti-CD19 engineered monoclonal antibody), in addition to lenalidomide, has shown significant efficacy with exceptionally durable responses in patients with R/R DLBCL who are ineligible for autologous stem cell transplantation (ASCT). Tafasitamab-lenalidomide and certain other therapies (ie, antibody-drug conjugates and bispecific antibodies) are important treatment options for patients who are ineligible for CAR-T due to co-morbidities or lack of access, and patients with rapid progression of disease who are unable to wait for manufacturing of CAR-T. This review will thus discuss currently approved and recently studied targeted treatment options for patients with R/R DLBCL with an emphasis on CAR-T alternative options, particularly Tafasitamab-lenalidomide.

Overall, around 40% of patients with diffuse large B-cell lymphoma (DLBCL) have refractory disease or relapse after the first line of treatment. Until relatively recently, the prognosis of patients with relapsed or refractory DLBCL was very poor and treatment options were very limited. In recent years, several novel therapies have been approved that provide more effective options than conventional chemotherapy and that have manageable toxicity profiles. CAR-T cell therapy has become the new standard treatment for patients with refractory or early relapsed DLBCL, based on the positive results of the phase 3 ZUMA-7 and TRANSFORM clinical trials. This review addresses the role of CAR-T therapy and autologous stem cell transplantation in the treatment of these patients and other approved options for patients who are not candidates for transplant, such as the combinations of polatuzumab vedotin with bendamustine and rituximab, and tafasitamab with lenalidomide.