Tafasitamab 200mg powder for solution for infusion vials

Macrophages are one of the key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD19 antibody tafasitamab, approved in combination with lenalidomide for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, antibody-dependent cellular phagocytosis (ADCP) in the tumor microenvironment can be counteracted by increased expression of the inhibitory receptor SIRPα on macrophages and its ligand, the immune checkpoint molecule CD47, on tumor cells. The aim of this study was to investigate the impact of the CD47-SIRPα axis on tafasitamab- mediated phagocytosis and explore the potential of anti-CD47 blockade to enhance its antitumor activity. Elevated expression of both SIRPα and CD47 was observed in DLBCL patient-derived lymph node biopsies compared to healthy control lymph nodes. CRISPR-mediated CD47 overexpression affected tafasitamab-mediated ADCP in vitro and increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab against DLBCL cell lines. A combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro-generated macrophages. Importantly, tafasitamab-mediated phagocytosis was elevated in combination with CD47 blockade using primary DLBCL cells and patient-derived lymphoma-associated macrophages in an autologous setting. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination treatment. Finally, combined treatment of tafasitamab and an anti-CD47 antibody resulted in enhanced tumor volume reduction and survival benefit in lymphoma xenograft mouse models. These findings provide evidence that CD47 blockade can enhance the phagocytic potential of tumor-targeting immunotherapies such as tafasitamab and suggest that there is value in exploring the combination in the clinic.

Abstract licence: CC BY-NC

Many therapies are available for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥ 2 lines of therapy, albeit with scant evidence on the comparative effectiveness of these therapies. This study used inverse probability of treatment weighting to indirectly compare treatment outcomes of epcoritamab from the EPCORE NHL-1 trial with individual patient data from clinical practice cohorts treated with chemoimmunotherapy (CIT) and novel therapies (polatuzumab-based regimens, tafasitamab-based regimens, and chimeric antigen receptor T-cell [CAR T] therapies) for third-line or later R/R large B-cell lymphoma (LBCL) and DLBCL. In this analysis, epcoritamab demonstrated significantly better response rates and overall survival rates than CIT, polatuzumab-based regimens, and tafasitamab-based regimens. No statistically significant differences in response rates or survival were found for epcoritamab compared with CAR T in R/R LBCL.

Abstract licence: CC BY-NC-ND

Potential CD19 antigen loss following CD19-directed therapy has raised concerns over sequential use of these therapies. Tafasitamab, a CD19-targeting immunotherapy, combined with lenalidomide, is approved for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) treatment in adults ineligible for autologous stem cell transplantation. This retrospective analysis examined characteristics and outcomes of adults with R/R DLBCL who received tafasitamab preceding CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in a real-world setting. Nine patients received tafasitamab and lenalidomide immediately preceding CAR-T. Median (first quartile [Q1]-third quartile [Q3]) follow-up time since tafasitamab initiation was 26.1 (18.0-28.0) and after CAR-T was 9.3 (1.9-16.7) months. Of the 9 patients, 4 had complete response, 4 had partial response, and 1 had stable disease following tafasitamab; all discontinued tafasitamab due to disease progression. Median (Q1-Q3) tafasitamab therapy duration was 11.0 (8.1-14.1) months. Three patients had CD19 testing following tafasitamab discontinuation, and all tests were positive. Median (Q1-Q3) time from tafasitamab discontinuation to CD19 testing was 7 (6-9) days. Among the 9 patients, median (Q1-Q3) time from tafasitamab discontinuation to CAR-T administration was 3.2 (2.3-3.6) months. Four patients had complete response, 3 had partial response, and 1 had progressive disease as best response to CAR-T; 1 patient had data unavailable. This small real-world analysis demonstrated disease response to CAR-T therapy and detectable CD19 expression following tafasitamab treatment, adding to literature investigating treatment outcomes associated with sequential use of anti-CD19 therapies in patients with R/R DLBCL.

Abstract licence: CC BY

Abstract 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.

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ABSTRACT: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) remains challenging to treat, especially in patients ineligible for intensive therapy or chimeric antigen receptor T cells. Tafasitamab plus lenalidomide (T/L) is an effective option based on the phase 2 L-MIND trial findings, although real-world evidence studies have not consistently confirmed these results. We aimed to describe real-world outcomes of R/R DLBCL treated with T/L in Spain. A total of 99 patients received at least 1 dose of tafasitamab (intent-to-treat [ITT] cohort), with 83 completing at least 1 full cycle of T/L (efficacy cohort). Respectively for ITT and efficacy cohorts, at a median follow-up of 19.2 and 21.6 months, the overall response rate was 51% and 61% (complete response [CR], 35% and 42%). Median duration of response was not reached, and patients achieving a CR had excellent outcomes. The median progression-free survival (PFS) was 4.9 and 10.9 months, and overall survival (OS) was 12.2 and 21.8 months, respectively for both ITT and efficacy cohorts. Neither age nor cumulative illness rating score influenced survival. Better PFS was obtained in first/second relapse but only poor Eastern Cooperative Oncology Group performance status 2 to 4, double-hit lymphoma, and those with refractory/progressing disease after the previous therapy, were independently associated with worse PFS. Treatment was generally well tolerated, with manageable toxicity. Relative dose intensity of lenalidomide significantly affected response, PFS, and OS. In summary, T/L is both well tolerated and effective, irrespective of age or comorbidities. Our findings provide valuable insights into the real-world application of T/L and reinforce its role as a key treatment option for patients with R/R DLBCL.

Abstract licence: CC BY-NC-ND

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.

Abstract licence: CC BY-NC