Outcome after relapse in older patients with Philadelphia Chromosome–Negative B-cell ALL treated with inotuzumab ozogamicin and low-dose chemotherapy in first-line therapy: A graall study

Abstract Background With the advent of immunotherapy, the prognosis of older patients with Philadelphia-negative (Ph-neg) B-cell acute lymphoblastic leukemia (B-ALL) has significantly improved these recent years. Overall survival (OS) is now around 50% at 2 years, with the consequence that is it now possible to consider the outcome of relapsing patients (pts) after a first-line therapy. Here we studied the outcome of pts who relapsed after receiving a frontline immuno-chemotherapy with inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, as part of the EWALL-INO study (NCT03249870, JCO 2024). Methods The RELAPSINO study aimed to retrospectively describe post-relapse outcome in pts included in the single arm phase 2 prospective multicenterEWALL-INO study. In this former study, InO was associated with low dose chemotherapy for 2 induction cycles. In case of complete response (CR), pts then received 6 consolidation cycles and an 18-month (m) POMP maintenance or an allogeneic stem cell transplantation (allo-SCT). At diagnosis, all pts were aged ≥ 55 years and had a newly diagnosed CD22+ Ph-neg B-ALL. A total of 131 pts were included between December, 2017, and March, 2022, and 49 relapses (incidence 38% at 2 years) were documented at last follow-up in May, 2023, including 45 in France, 2 in Finland and 2 in Czech Republic. The RELAPSINO study was approved by the Groupe Nantais d'Ethique dans le domaine de la Santé (GNEDS, reference 24-79-07-100, July 2024). For administrative reason, only French pts were included in this new study. Data regarding pts were updated until May, 2025, and analyses were performed in June, 2025. Results Since the last follow-up, 6 additional relapses have been documented among French pts. Among the 45 previous relapsed French pts, we excluded 3 pts who presented concomitant therapy-related myelodysplastic syndrome. In total, 48 French relapsed pts (male n=25, female n=23) were included in this updated analysis, of whom 60% had a high-risk cytogenetics at diagnosis. None had received an allo-SCT in CR1. At relapse, median age was 70 years (IQR, 67-74; range, 55-86) and median duration of CR1 was 15.2m (IQR 5.3-22.9). Site of relapse was bone marrow (BM) in 38 (79%) pts, extra-medullary in 4 pts (CNS n=2, testis n=1, vertebra bone n=1) and combined in 3 pts (BM + skin n=1, BM + ocular n=1, BM + CNS n=1) (missing n=3). Although none of the patients received the CD19-CD3 bi-specific T-cell engager blinatumomab before relapse, CD19 and CD22 expressions were negative at relapse in 5/41 (12%) and 9/40 (23%) of evaluable pts, respectively. A large majority of pts were re-treated (n=41, 85%) and 29/41 (71%) received blinatumomab as salvage regimen, either alone (n=14) or after low-dose (n=9) or intensive (n=6) chemotherapy. Twelve pts received chemotherapy only (low dose n=3, intensive n=9). No patient was re-treated with InO or received CAR-T cells as salvage regimen. Half of the pts (n=20/41, 49%) achieved CR2. One was consolidated with CAR-T cells and 4 with an allo-SCT. By multivariate analysis (MA), a CR1 duration > 12m (but not >15m or 18m) was the only significant factor associated with CR2 achievement (p=0.04). With a median follow-up from relapse of 30.3 months (95%CI, 25.0–NA), median event-free survival (EFS) and OS were 3.2m (95%CI 2.3-5.7) and 4.5m (95%CI 3.8-11.0), respectively. Two-year EFS and OS were respectively 15% and 19%. By MA, salvage regimen with intensive chemotherapy (p=0.01), CR1 duration >18m (but not >12m or 15m) (p=0.04), and CR2 (p<0.001) were significantly associated with better OS. Intensive chemotherapy (p=0.008) and CR1 duration >18m (but not >12m or >15m) (p=0.01) were also associated with significant better EFS. The 2-year cumulative incidence of relapse after CR2 was 53%. No predictive factor for second relapse was identified. Median LFS and OS after CR2 were 13m and 24m, respectively, with 2-year LFS and OS of 36% and 46%. In pts who did not achieve CR2, median OS was 3.8m only. Overall, 38 pts (79%) died, the main cause of death being relapse or progression (n=36, 95%). Two pts died in CR2 of unknown cause.Conclusion: Half of older Ph-neg B-ALL patients relapsing after a front-line Ino-based therapy can achieve a new remission and good survival. These encouraging results support the risk of re-treating patients, especially those with late relapse, even with intensive chemotherapy, which appears the best salvage regimen in this series.

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