P366: BLINATUMOMAB ADDED TO PREPHASE AND CONSOLIDATION THERAPY IN NEWLY DIAGNOSED PRECURSOR B-ALL IN ADULTS. A PHASE II HOVON TRIAL (2022)

Background: The bispecific antibody blinatumomab (blina) is approved for patients(pts) with relapsed/refractory precursor B-cell ALL (ALL). It has also shown to be highly effective in MRD+ pts in first line treatment. TABLE - Pt characteristics Total, N(%) 71(100%) Age(y), median(range) 53(18-70) Age (y), N(%) ≤40 22(31%) 40-60 29(41%) >60 20(28%) BM blasts (%), N(%) ≤50% 4(6%) >50% 62(87%) Unknown 5(7%) Karyotype, N(%) Ph+ 26/71(37%) KMT2A 2/67(3%) Complex 23/67(34%) Hypodiploidy 5/67(7%) Aims: To evaluate whether blina added in upfront therapy to prephase and after consolidation (cons)-1 would increase MRD negativity measured by qPCR or flowcytometry at a cut-off of <10-4 (primary endpoint). Secondary endpoints included CR, EFS, OS, adverse events and treatment-related mortality. Methods: Pts, 18-70 years(y) old, with newly diagnosed CD19+ ALL (incl. Ph+), were included. Treatment was based on a pediatric inspired protocol (HOVON 70, Rijneveld et al., 2011) with reduced doses of anthracyclines, MTX, etoposide and PEG-ASP for pts ≥40y old. Prephase consisted of 10 days steroids, from day 5 combined with 14 days blina in the standard step-up dosing schedule. After cons-1 and after intensification 2, two 4-week blina courses were added irrespective of MRD. The protocol was amended twice due to toxicity. First, in 2018 the first PEG-ASP administration was omitted. Second, in 2021 doxorubicin, dexamethasone and PEG-ASP were reduced during intensification 1. Rituximab (if CD20+), prophylactic ITs and imatinib (if Ph+) were standard. AlloHSCT was offered to intermediate and high-risk pts. Trial was registered with ClinicalTrials.gov, identifier NCT03541083. Results: Seventy-one pts were enrolled. Pt characteristics are presented (Table). Fifteen pts discontinued treatment before blina cons-1 due to refractory disease (n=8), toxicity (n=7) or death (n=2). In the total study population, 55/71 pts (77%) achieved CR after (blina) cons-1. Among pts still on treatment after cons-1, 55/56 (98%) pts achieved CR, 50/55 (91%) reached MRD negativity. After prephase, CR was already reached in 63% and MRD negativity in 53%. Blina related AEs in prephase were as expected (83% of pts had ≥1 AE and 10% had ≥1 SAE (hepatotoxicity 3 pts, pain lymph node 1, CRS 1, pneumonia 1, renal insufficiency 1)). CRS was observed in 35% of pts, 32% of whom experienced grade 3 and no grade ≥4. During prephase 5 pts discontinued blina; during blina cons-1, 4 pts stopped blina. With a median follow-up of 17,6 months, the estimated 2-y EFS was 64% standard error (SE) ± 7% (≤60y 71% SE ± 9% and >60y 47% SE ± 12%). Overall, 14 (20%) pts died. OS after 2y was 73% SE ± 7% (≤60y 82% SE ± 8% and >60y 52% SE ± 14%) (Figure 1). For pts with Ph+ ALL, 2-y EFS was 88% SE ± 6%and OS also 88% SE ± 7%. For Ph- ALL, 2-y EFS and OS were 53% SE ± 9% and 68% SE ± 9%, resp. Among pts who reached CR on protocol (n=60), 5 (8%) had relapse, 6 (10%) died and 6 (10%) discontinued treatment due to toxicity. Until now, 22 pts proceeded to alloHSCT and 11 with maintenance. Image:Summary/Conclusion: Blina can safely be added to prephase of an intensified pediatric schedule for newly diagnosed ALL up to 70y of age, albeit with dose reductions for PEG-ASP, doxorubicin and dexamethasone. The combination increases CR and MRD negativity rate. The early addition of blina resulted in very early achievement of MRD negativity with 53% after prephase and 91% after blina cons-1. Further reductions of chemotherapy should be explored (especially for Ph+) if these results are maintained with longer follow-up.