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Abstract Introduction: Blinatumomab (Blin), a CD19xCD3 bispecific T-cell engager, is recommended in the consolidation phase of front-line therapy for Philadelphia (Ph) negative B-cell acute lymphoblastic leukemia (B-ALL) on the basis of the ECOG-ACRIN 1910 (E1910) study. On the E1910 regimen, patients were randomized to receive consolidation chemotherapy with or without Blin if they achieved and maintained an MRD negative complete remission with three courses of BFM-like induction and intensification, with a significant survival advantage for those who received Blin. Due to toxicities of the initial chemotherapy or progression prior to the randomization, only 59% of patients were randomized. This suggests that alternative approaches to initial chemotherapy debulking of leukemia burden, and possibly earlier implementation of Blin, may be preferable. The MD Anderson Cancer Center (MDACC) also has published a regimen incorporating Blin into hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) therapy as induction and consolidation for adults with Ph neg B-ALL. We have used a modification of the hyperCVAD/Blin approach at the University of California San Francisco for adult patients and report here our initial results. Methods: A modification to the MDACC hyperCVAD/Blin regimen was used in which all patients received hyperCVAD cycles (C) and Blin courses in the following order: C1A-C1B-Blin1-Blin2-C2A-C2B-Blin3-Blin4-maintenance (POMP with quarterly blinatumomab). This approach was adopted to ensure all patients follow the same sequence and to provide exposure to Blin after no more than two chemotherapy cycles. Two doses of rituximab were included in each of the first 4 cycles of therapy when CD20 expression was identified on ≥20% of blasts at diagnosis. Intrathecal prophylaxis consisted of alternating doses of methotrexate and cytarabine, with a goal of administering 2 doses per cycle for a minimum of 8 doses. Diagnostic bone marrow biopsies were evaluated by conventional cytogenetics, ALL FISH, and NGS using Foundation One Heme. Remission was assessed by bone marrow biopsy with flow and/or NGS MRD quantification. Results: Twenty-two adult patients (median age 36, range 23-60) initiated treatment with the modified hyperCVAD/Blin regimen from July 2023 to May 2025. The population was 72% male and 64% Hispanic. High risk (HR) B-ALL (68%) was defined as genotypes including Ph-like lesions (36% of total population had CRLF2/JAK2 abnormalities), KMT2A rearrangement (9%), complex karyotype (14%), and TP53 mutations (4.5%), or therapy-related ALL (after prior treatment for multiple myeloma, 4.5%). Median follow-up for the group is 18 months (mos). The complete remission rate after C1A was 82% (53% and 7.7% MRD negative by flow and NGS, respectively), after C1B was 95% (71%/22% MRD negative by flow/NGS), and after completion of one or two cycles of Blin (cycle number dependent on timing of subsequent transplant in those selected to proceed) was 95% (100%/81% MRD negative by flow/NGS). Median RFS/OS have not been reached, with 1 year RFS 66% and OS 94%. In patients with standard risk Ph neg B-ALL, RFS remains 100% with median follow-up 21 months in that subset, with 1 of 7 having undergone CR1 alloHCT due to persistent MRD after Blin. In patients with HR B-ALL, the median RFS is 10.9 mos with median follow-up of 15 months. Eight HR patients (36%) proceeded to alloHCT in CR1 resulting in median RFS 14.8 months and OS 16.5 months. Amongst patients who could not proceed to alloHCT due to lack of adequate social support (n=6), the RFS was reduced at a median 4 months, but OS is 16.6 months with current followup. Conclusions: The addition of Blin to front-line hyperCVAD chemotherapy is associated with excellent RFS in adults with standard-risk ALL, but patients with HR genotypes remain at risk of relapse within one year of treatment initiation. This demonstrates a need for further iteration on this approach to better mitigate the risk of relapse. Because alloHCT remains the best approach to sustain long-term definitive disease control, it remains especially important to navigate patients to potentially curative transplants after achieving deep remission with the first 3-4 cycles of chemo/Blin. In adults unable to proceed to transplant in a timely manner due to limited social support, outcomes remain suboptimal and additional approaches to prevent relapse need further exploration.