Patients with Relapsed Large B-Cell Lymphoma after 12 Months Have a Similarly Poor Prognosis As Patients with a Relapse before 12 Months

Recently, ZUMA-7 study patients with early relapsed LBCL (<12 months after first-line immunochemotherapy) who were treated directly with CAR T-cell therapy in second-line instead of third-line, had a significantly better overall survival (OS) compared to patients who were treated with standard salvage treatment consisting of high-dose chemotherapy followed by autologous stem-cell transplantation (HDT-ASCT). Despite non-protocolled cross-over to CAR T-cell therapy in third-line for 57% of patients in the HDT-ASCT arm, a significant difference in OS of 9% remained, suggesting that patients benefit if the most effective therapy is applied at an early stage.

On the basis of these results, the paradigm of HDT-ASCT shifted to CAR T-cell therapy as second-line therapy for patients who have refractory or early relapsed disease <12 months. However, patients with a late relapse (>12 months) are still unable to receive CAR T-cell therapy until the third-line. A main argument is that late relapsed LBCL is considered to be still chemo sensitive and therefore these patients would have a better OS following HDT-ASCT salvage. The aim of this study was to compare the responses of LBCL patients with an early (<12 months) versus a late (>12 months) relapse onset, to see whether this argument is justified in real world.

All patients diagnosed with LBCL between 2005 and 2020 in the province Friesland, The Netherlands, were included (n=877). Detailed patient characteristics and outcomes of patients in first-line, relapsed setting and beyond were analyzed. OS was calculated from relapse onset.

Median follow-up was 7.0 years from diagnosis (range 0.01-15.6). In the first line, 729 patients (83.1%) were treated with curative intent. Early relapse (refractory and <12 months after first-line therapy) and late relapse (>12 months) occurred in 120 (16.4%) and 70 patients (9.6%), respectively. Patients with an early relapse show a 2-year and 5-year OS of 21.5% and 18.3%. Compared to early relapse, patients with a late relapse show a slightly favorable OS of 36.1% at 2 years, yet an almost similar OS at 5 years of 19.6%. Main cause of death for both groups were lymphoma, including treatment related complications (93.9% in early and 82.6% in late relapse).

Second-line salvage therapy, consisting of HDT was initiated in 53 patients (44.2%) with early and 22 patients (31.4%) with late relapsed disease. Of these, only 16 patients (30.1%) with an early relapse and 11 patients (50%) with a late relapse obtained a sufficient response and maintained an acceptable clinical performance to undergo ASCT. Patients who completed ASCT, had a 5-year OS of 73.3% (early relapse) versus 49.2% (late relapse). In contrast, early and late relapsed patients who initiated salvage HDT but did not reach ASCT showed a 5-year OS of only 8.3% and 18.2%, respectively. This OS was comparable to the 67 patients (55.8%) with an early relapse who were upfront ineligible to start salvage HDT (5-year OS 10.2%). For HDT-ineligible patients with a late relapse (n=48, 68.6%) OS was similarly disappointing with a 5-year OS of 14.6%

In conclusion, these real-world data contradict the argument that LBCL patients with a late relapse (>12 months) have an advantage over patients with early relapse (<12 months) in their potential to reach a long-term remission and survival with HDT-ASCT. This supports the evaluation of early application of CAR T-cell therapy in second-line, also for DLBCL patients who relapse beyond 12 months.