LAUSR

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 singlearm 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/m 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 Correspondence: Toby A. Eyre, Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK. E-mail: [email protected] commentary