Abstract Although ruxolitinib (RUX) is effective in alleviating splenomegaly and constitutional symptoms for patients with myelofibrosis (MF), it does not appear to modify underlying disease biology. RUX discontinuation rate within 5 years is approximately 40%, and patients have poor prognosis after discontinuing RUX [1]. The definition of disease modification in MF is evolving. Reversal of bone marrow fibrosis (BMF) and reduction in driver gene variant allele frequency (VAF) have been suggested as evidence of disease modification; however, clinical benefits derived from achieving these responses have not been fully elucidated. Ultimately, benefits in patient survival are requisite to claim true clinically meaningful disease modification. There is also an unmet need of effective therapies for patients with MF with high molecular risk (HMR) mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1 Q157). REFINE (NCT03222609) is a phase 2 trial evaluating navitoclax (NAV), a BCL-XL/BCL-2 inhibitor, combined with RUX, in patients with MF who progressed on or had a suboptimal response to RUX monotherapy. Here, we report the exploratory analyses assessing BMF, VAF, and HMR with respect to outcomes. As BMF improvements were often observed in patients who achieved ≥35% reduction in spleen volume (SVR35), we explored if the survival benefit observed was due to this potentially disease modification-related response. All statistics were descriptive. As of May 6, 2021, 34 patients were enrolled in Cohort 1a and received ≥1 dose of NAV plus RUX. Of these, 32 were evaluable for BMF and 12 (38%) had ≥1 grade improvement during anytime on study, 4 of whom improved by 2 grades. For driver gene VAF reductions, 26 patients (JAK2, n=19; CALR, n=7) were evaluable and 6 (23%) achieved ≥20% reduction at Week 24. Five patients achieved both BMF and VAF responses. Median overall survival (OS) for patients who had ≥1 grade improvement in BMF was not reached compared with 28.5 months for those without improvement (P <0.01). Similarly, the median OS was also not reached for patients who achieved ≥20% VAF reduction versus 28.5 months for those who did not (P=0.05). Furthermore, no deaths were observed in patients with improvements in BMF or VAF. Within the patient group who had an SVR35 response at any time, median OS was not reached in those who had improved BMF (n=9), compared with an OS of 28.5 months for patients without BMF improvement (n=6; P <0.01). Of 34 patients, 33 were evaluable for molecular risk; 19 (58%) had HMR and 14 (42%) were without (non-HMR); at the time of analysis, median OS was not reached in either subgroup; there was no statistical significance in survival between HMR and non-HMR groups. Taken together, the results of these analyses demonstrate the ability of NAV, combined with RUX, to induce BMF improvement and VAF reduction. These responses are suggestive of disease modification as they were associated with improved OS for patients. In addition, the NAV plus RUX regimen potentially improved the outcome for patients with MF regardless of HMR status. Reference 1. Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer 2020; 126(6): 1243-52 Citation Format: Naveen Pemmaraju, Jacqueline Garcia, Jalaja Potluri, Yan Sun, Jason Harb, Srinivas K. Tantravahi, Srdan Verstovsek, Claire Harrison. Addition of navitoclax to ruxolitinib mediates responses suggestive of disease modification in patients with myelofibrosis previously treated with ruxolitinib monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB108.