Integration of cell therapies and bispecific antibodies into the treatment pathway of relapsed diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL) representing 30–40% of all cases. 1 It is a heterogeneous B-lymphoid neoplasm that consists of subtypes distinguished by clinical, cytogenetic, and molecular features, with variable outcomes when treated with upfront immunochemotherapy. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is the current standard for first-line immunochemotherapy for DLBCL, with 60–70% of patients being cured by this approach. However, 10–15% of patients have primary refractory disease and a further 20–30% relapse after first-line treatment. 2 The International Prognostic Index (IPI) and age-adjusted IPI are risk stratification tools used since 1993 to identify individuals that will respond poorly to doxorubicin-containing chemotherapy regimens based on clinical variables; age, performance status, tumour stage, number of extranodal sites, and serum LDH level. 3 This prognostic scoring system remains valid in the rituximab era. Biological features of the disease also have prognostic relevance including the cell-of-origin (germinal centre B-cell and activated B-cell, as identified by gene expression profiling),4–6 genetic rearrangements in c-MYC in addition to BCL2 and/or BCL6 (double/triple-hit lymphoma)7–10 and expression of c-myc and Bcl2 in the absence of underlying genetic changes (double expressor lymphoma; Green et al, JCO 2012; Johnson et al, JCO 2012; Horn et al, Blood 2013). The current standard of care for relapsed/refractory disease for eligible patients remains non cross-reacting relapse therapy with platinum-based or ifosfamide-containing regimens, incorporating an anti-CD20 monoclonal antibody2,11 followed by autologous stem-cell transplantation (ASCT).2,11 Results of the prospective CORAL study, evaluating the efficacy of R-ICE compared to R-DHAP as salvage regimens, demonstrated that only 50% of relapsed/refractory patients were able to undergo ASCT largely due to failure to adequately respond to second line therapy. This was more common among patients with higher secondary age-adjusted IPI score, prior rituximab treatment, and refractory disease/relapse less than 12 months after diagnosis. 11 Other reasons for ineligibility for aggressive approaches include advanced age, comorbidities, and less commonly, failure to collect stem cells. Failure of response to first-line salvage treatment or relapse post ASCT results in extremely poor outcomes. 12 For those patients who could not proceed to ASCT in the CORAL study, median overall survival was 4.4 months from failing response. 13 The curability of these patients with second-line relapse regimens is limited; nevertheless, a minority of relapsed/refractory patients will respond to third-line regimens and may be considered for allogeneic stem cell transplant.13,14 For transplant-ineligible patients with relapsed/refractory disease median overall survival remains very poor at less than 4 months. 15 Treatment options include conventional chemotherapy with or without rituximab, localized radiotherapy, supportive care, or enrolment in clinical trials. Table 1 demonstrates response rates in the trial setting for recently approved therapies in relapsed/refractory and transplant-ineligible patients. These include antibody-drug conjugates: Polatuzumab vedotin and loncastuximab tesirine, tafasitamab (CD19-targeting monoclonal antibody), and selinexor (oral nuclear export inhibitor). Polatuzumab vedotin (targeting CD79b, a B-cell receptor component) combined with Bendamustine and rituximab (BR) has been licenced in some countries based on superior progression free and overall survival results in a randomized phase II trial compared with BR alone, 16 while the results of the POLARIX trial where it is used in the first-line setting alongside R-CHOP are eagerly awaited. The FDA granted accelerated approval of tafasitamab plus lenalidomide, selinexor and more recently loncastuximab tesirine for adult patients with relapsed/refractory DLBCL based on high and durable overall response rates.17–19 Enrolment in clinical trials of novel approaches, including cellular therapies and bispecific antibodies, are becoming increasingly important in targeting this unmet need. Table 1. Response rates in the trial setting for recently approved therapies in relapsed/refractory and transplant-ineligible patients.