The CCL17-CCR4 axis is critical for mutant STAT6-mediated microenvironmental remodelling and therapeutic resistance in Relapsed/Refractory Diffuse Large B-cell Lymphoma.

Optimising outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains one of the greatest challenges still facing haemato-oncologists today. The SCHOLAR-1 analysis pooled trial and retrospective data (n = 636) and served to outline the bleak outcomes [median overall survival (OS) 6·3 months] for many of our patients who fail to respond to initial treatment. Poor outcomes included patients refractory to front-line potentially curative treatment (median OS 7·1 months) or relapsing within 12 months of autologous stem cell transplantation (autoSCT) (median OS 6·2 months) (Crump et al., 2017). Clear progress has been made over recent years in the field of cellular therapy, and recently for relapsed, refractory DLBCL patients. Chimeric antigen receptor (CAR) T-cell therapy harnesses patients’ own T-cell-mediated immunity to induce a CD19-directed DLBCL tumour assault. High initial efficacy and durable responses in a significant minority of patients have been demonstrated in phase-II single-arm trials of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) (predominantly DLBCL) (Neelapu et al., 2017; Schuster et al., 2018). However, as the authors of the accompanying manuscript highlight, CAR-T therapy is associated with significant toxicities (Neelapu et al., 2018), the challenge of equitable, timely administration across populations, and a substantial financial burden to health-care systems (Hernandez et al., 2018). Whilst maximising cure in the front-line setting is clearly still the preferred goal, the quest remains to find highly efficacious, non-toxic, and widely applicable therapies in patients failing front-line anthracycline-based immunochemotherapy who have otherwise failed or are unsuitable for autoSCT. Pixantrone is a novel aza-anthracenedione which is structurally similar to anthracyclines and is licenced in relapsed or refractory DLBCL and National Institute for Health and Care Excellence (NICE)-approved in the UK following the PIX301 trial (Pettengell et al., 2012). PIX301 compared 85 mg/m2 of pixantrone on days 1, 8 and 15 of a 28-day cycle for up to six cycles, with the control arm of ‘best available monotherapy’ for patients with aggressive B-cell NHL (primarily DLBCL). Seventy patients were randomized in each arm, including single-agent vinorelbine (16%), oxaliplatin (46%), ifosfamide (18%), etoposide (13%), mitoxantrone (6%) and gemcitabine (1%) in the non-pixantrone arm. End of treatment complete response (CR) and overall response rates (ORR) were superior in the pixantrone arm [ORR 37·1% (CR 20·0%) vs. ORR 14·3% (CR 5·7%); CR P = 0·021; ORR P = 0·003]. This resulted in a modest progression-free survival (PFS) advantage in favour of pixantrone (median PFS by intention-to-treat 5·3 vs. 2·6 months; hazard ratio (HR) 0·60, P = 0·005) but no OS benefit was seen. Patients were eligible for this trial if they were initially anthracycline-sensitive. Eligible patients had a documented response to prior anthracycline-based therapy of at least 24 weeks, introducing a key potential source of bias within the study design. Subsequently, a UK-wide retrospective non-trial cohort series (n = 92) demonstrated more limited efficacy (ORR 24%, CR 10%) of pixantrone monotherapy in a heavily-pretreated [median prior lines 3 (range: 2–9)], high-risk patient group (Eyre et al., 2016). Eighty-five percent had refractory DLBCL and 72% had an international prognostic index of 3–5. The median PFS in this UK cohort following NICE approval was a disappointing 2·0 months [95% confidence interval (CI) 1·5–2·4] and the median OS was 3·4 months. Unsurprisingly, patients with anthracycline-sensitive disease (relapsed >12 months from front-line treatment) had a significantly improved PFS on multivariable analysis (HR: 0·43; 95% CI 0·22–0·82;P = 0·011). In light of these data, we eagerly awaited the results of the PIX306, published in this edition of the British Journal of Haematology (Pettengell et al., 2019). Pixantrone combined with rituximab (PIX-R) was randomised 1:1 against gemcitabine plus rituximab (GEM-R) as the standard-of-care arm in this phase-III multicentre trial of 312 patients with relapsed aggressive B-cell NHL deemed ineligible for autoSCT. Briefly, there were no significant differences in median PFS [7·3 (95% CI 5·2–8·4) months with PIX-R vs. 6·3 (95% CI 4·4–8·1) months with GEM-R (HR: 0·85; 95% CI 0·64–1·14; P = 0·28)] or indeed median OS [13·3 (95% CI 10·1–19·8) months with PIX-R vs. 19·6 (95% CI 12·4–31·9) months with GEM-R (HR: 1·13; 95% CI 0·83–1·53)] between the treatment arms. No patient subgroups could be identified for whom PIX-R was statistically more beneficial in terms of survival. The PFS was longer in the control arm than the investigators expected; the initial statistical calculations assumed a median PFS of 2·8 months with GEM-R. The improved PFS was likely due to the exclusion of patients with refractory DLBCL from an otherwise ‘trial-fit’ population. Ultimately this is a negative trial and showed that PIX-R is broadly equivalent in terms of efficacy and survival to GEM-R in patients with aggressive B-cell NHL enriched for DLBCL. Despite this, the authors are to be strongly congratulated for conducting this large international collaborative effort; one of the very few randomised controlled trials in relapsed, refractory aggressive B-cell NHL and the only published phase-III trial to date in exclusively autoSCT-ineligible aggressive B-cell NHL patients. Despite the disappointing outcome of the PIX306 trial, hope remains elsewhere for our patients. The antibody–drug conjugate polatuzumab vedotin targeting the CD79b component of the B-cell receptor, in combination with bendamustine and rituximab (BR), has recently received Food and Drug Administration (FDA) approval for the treatment of adult patients with relapsed or refractory DLBCL for whom autoSCT is not suitable. Approval was based on a small randomised phase-II trial where this combination showed an improved ORR (PET CR: 40% vs. 18%; P = 0.026), PFS (HR: 0.34; P < 0.0001) and OS (HR: 0.42; P = 0.0023) compared to BR (Sehn et al., 2018). This combination seems to represent a step forward in this setting, although no randomised phase-III trial is planned. We do, however, eagerly await the results of the randomised phase-III POLARIX trial (NCT03274492) comparing front-line polatuzumab vedotin plus R-CHP versus R-CHOP. Ongoing clinical trials in the field of relapsed, refractory DLBCL continue to investigate targeted agents of promise. CD19 monoclonal antibodies such as the Fc-engineered tafasitamab in combination with lenalidomide are undergoing active investigation (Salles et al., 2019). This combination has shown interesting efficacy in a phase-II trial (L-MIND; NCT02399085) of relapsed (not refractory) DLBCL. The antibody is currently being tested in a randomised phase-III clinical trial in combination with bendamustine (B-MIND; NCT02763319) and the final results of both studies are awaited with interest. Bi-specific T-cell engagers such as mosunetuzumab or CD20-TCB (RG6026) engage T cells by co-targeting CD3 and a B-cell surface marker (typically CD19 or CD20) and are a drug class of great potential, with impressive efficacy in early phase-I–II trials (Budde et al., 2018; Dickinson et al., 2019). Antibody–drug conjugates such as loncastuximab tesirine (Lonca), which comprises a humanized anti-CD19 antibody conjugated to a potent pyrrolobenzodiazepine dimer toxin, have displayed early efficacy signals. Lonca at ≥120 μg/kg has substantial anti-tumour activity in relapsed, refractory DLBCL (ORR 43.3%) displaying equivalent efficacy in refractory patients compared to those with relapsed disease (Radford et al., 2019). Finally, the novel combination of rituximab, lenalidomide and ibrutinib has shown encouraging activity (ORR 65%) in relapsed or refractory non-germinal centre type DLBCL in response-evaluable patients (Goy et al., 2019). Despite the genuine interest in these newer agents with novel mechanisms of action, continuing to demand the testing of agents demonstrating efficacy in early-phase single-arm trials in large, well-designed randomised clinical phase-III trials such as PIX306 must remain the focus of the international treating community. Only then will we truly understand the value of novel agents of promise in relapsed or refractory DLBCL.

The Outcome of Refractory or Relapsed but Not Refractory Diffuse Large B-Cell Lymphoma in China: Results from the Real-TREND Study

Lymphoma patients with persistent disease undergoing autologous transplantation have a very poor prognosis in the rituximab era. The addition of radioimmunotherapy to the conditioning regimen may improve the outcome for these patients. In a prospective, phase 2 study, we evaluated the safety and efficacy of the addition of (90)Y-ibritumomab tiuxetan to the conditioning chemotherapy in patients with refractory diffuse large B-cell lymphoma. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. The median age of the patients was 53 years (range, 25-67). All patients were given (90)Y-ibritumomab tiuxetan at a fixed dose of 0.4 mCi/kg (maximum dose 32 mCi) 14 days prior to the preparative chemotherapy regimen. Histological examination showed that 22 patients had de novo diffuse large B-cell lymphoma and eight had transformed diffuse large B-cell lymphoma. All patients had persistent disease at the time of transplantation, with 25 patients considered to be chemorefractory. The median time to neutrophil recovery (>500 white blood cells/μL) was 11 days (range, 9-21), while the median time to platelet recovery (>20,000 platelets/μL) was 13 days (range, 11-35). The overall response rate at day +100 was 70% (95% CI, 53.6-86.4) with 60% (95% CI, 42.5-77.5) of patients obtaining a complete response. After a median follow-up of 31 months for alive patients (range, 16-54), the estimated 3-year overall and progression-free survival rates are 63% (95% CI, 48-82) and 61% (95% CI, 45-80), respectively. We conclude that autologous transplantation with conditioning including (90)Y-ibritumomab tiuxetan is safe and results in a very high response rate with promising survival in this group of patients with refractory diffuse large B-cell lymphoma with a very poor prognosis. Study registered at European Union Drug Regulating Authorities Clinical Trials (EudraCT) N. 2007-003198-22.

Phase 1 study of MK-1045, a novel CD19xCD3 T-cell engager, in participants with relapsed or refractory diffuse large B-cell lymphoma

Real-World Outcomes in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with Standard of Care: A Cota Database Analysis

Therapies and Outcomes for Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Contemporary, Nationwide, Population-Based Study in the Netherlands

BTK Inhibitors and Chidamide-Combined Therapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma with MYC+

Characterizing the US Patient Population Receiving Rituximab with Gemcitabine and Oxaliplatin (R-GemOx) for Relapsed or Refractory Diffuse Large B-Cell Lymphoma Using Real-World Data

Preclinical Evaluation of the Oral Proteasome Inhibitor Ixazomib in Diffuse Large B-Cell Lymphoma

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Chimeric antigen receptor (CAR) modified T cells targeting CD19 hold great promise to improve the complete response rates of DLBCL patients compared with conventional therapies. Here, we conducted a clinical trial to evaluate the efficacy and safety of CAR-T cells. Five patients with relapsed or refractory DLBCL were treated with autologous T cells expressing the 19-41BBz chimeric antigen receptor (CAR) specifically targeted the CD19 antigen (IM19 CAR-T). The development of cytokine release syndrome (CRS) was observed. And the efficacy of IM19 CAR-T cell treatment was measured with positron emission tomography (PET)-computed tomography (CT). Of the four patients evaluable for response, two obtained complete responses (CRs), one obtained partial response (PR), and one had stable disease (SD). Remarkably, among the five patients, only one developed grade 2 CRS while the others only elicited grade 1 CRS. Additionally, the efficacy and safety of IM19 CAR-T cells were correlated with the peak blood level and persistence of CAR-T cells, as well as the immunophenotype of T-cell subsets. Overall, this study indicates the feasibility and effectiveness of IM19 CAR-T cells in the treatment of refractory or relapsed diffuse large B-cell lymphoma.

Outcomes of Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with R-GemOx: A Multi-Center Retrospective Cohort Study

Decitabine Can Improve the Efficacy of Second-Line Chemotherapy in Relapsed or Refractory Diffuse Llarge B Cell Lymphoma

Glofitamab in Combination with Rituximab Plus Ifosfamide, Carboplatin, and Etoposide Shows Favorable Efficacy and Manageable Safety in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Eligible for Stem Cell Transplant or Chimeric Antigen Receptor T-Cell Therapy: Results from a Phase Ib Study

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Report of the Prospective, Multicenter Phase II STORM Trial

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Results of the Part I Cohort of the STORM Trial