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NAVigating New Possibilities: Addition of Navitoclax to Ruxolitinib Shows Safety, Spleen Reduction, and Early Evidence of Fibrosis Reversal

  • Advances in Hematologic Malignancies
    Issue 17, Winter 2023

    Jacqueline S. Garcia, MD

    Myelofibrosis is a rare blood and bone marrow cancer characterized by abnormal hematopoiesis and scarring (fibrosis) within the bone marrow. Common symptoms include fatigue, night sweats, bony pain, and those related to splenomegaly such as weight loss, abdominal discomfort, and nausea. Myelofibrosis is mainly driven by the constitutive activation of the JAK/STAT signaling pathway. As of October 1, 2022, there are only two FDA-approved JAK2 inhibitor drugs for the treatment of symptomatic, advanced myelofibrosis without severe thrombocytopenia, which includes ruxolitinib (Jakafi) and, more recently, fedratinib (Inrebic). When there is evidence of disease progression or relapse despite ruxolitinib therapy, current available therapies (danazol, hydroxyurea, pegylated interferon, growth factors, prednisone) may provide symptomatic support, but have minimal disease modifying capabilities. Transplantation remains an option to be considered for some. There are ongoing preclinical and clinical investigations on rationale combination regimens with ruxolitinib to overcome or address potential resistance mechanisms.

    Preclinical models of myeloproliferative neoplasms (MPNs) have demonstrated overexpression of antiapoptotic proteins including BCL-xL, including in settings of JAK-inhibitor resistance.1 Navitoclax is an investigational orally-bioavailable BCL-xL/BCL-2 inhibitor. Prior trials with navitoclax in lymphoid cancers and solid tumors showed preliminary activity, but was limited by dose-dependent thrombocytopenia due to inherent dependence on BCL-xL in older platelets. Given the recent success in targeting the anti-apoptotic pathways with oral selective BCL-2 inhibitor in acute and chronic leukemias, investigation of the safety and activity of navitoclax has been launched in other disease settings. However, using lower doses of navitoclax that is still biologically active has resulted in new opportunities for use in combination approaches.

    In a multi-site phase 2 trial for adult patients with advanced (intermediate or high-risk) myelofibrosis with progression or suboptimal response to ruxolitinib, treatment with navitoclax plus ruxolitinib demonstrated safety and efficacy (N=34).2 Platelet level of ≥ 100 (109/L) was required for study entry. Notably, although thrombocytopenia was frequent and reversible, most cases were transient with dose holds or treatment modifications, and no clinical associated bleeding was observed. Spleen volume reductions ≥ 35% (SVR35) were observed in 26.5% of patients at week 24 and in 41% of patients at any time on trial, suggesting clinical improvement may still be achieved with more time on treatment. Symptoms using validated scoring systems were improved in 30% of patients by week 24. The combination of navitoclax and ruxolitinib resulted in a bone marrow fibrosis grade reduction in 33% of patients. Importantly, patients who achieved reduction in bone marrow fibrosis grade reduction had improved overall survival compared to those who did not (not reached versus 28.5 months; 95% CI 19.6 to NE). It was noted that among patients who had both fibrosis grade reduction and SVR35 at any time, the median overall survival was not reached compared to those with SVR35 without fibrosis improvement (95% CI 19.6 to NE).3

    Overall, this very positive finding hints that the treatment may lead to disease modification, which has not been previously observed on a consistent basis with ruxolitinib monotherapy.4 Though this study is small, these initial findings led to a dose expansion which is now completed and the rapid development of two ongoing phase 3 trials evaluating frontline combination of ruxolitinib and placebo/navitoclax for advanced myelofibrosis (Transform 1, NCT04472598) and relapsed/refractory combination of ruxolitinib with navitoclax versus best available therapy for advanced myelofibrosis (Transform 2, NCT04468984) with the hopes that positive results will lead to a new standard of care option.

    In the meantime, based on the exciting clinical data in MPNs with navitoclax and the promising safety and efficacy data in MDS with venetoclax in combination with hypomethylating agents5, at Dana-Farber Cancer Institute, we launched a novel investigator-initiated trial. This phase 1 trial is for patients with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN overlap), advanced myelofibrosis in accelerated or blast phase, relapsed MDS, and secondary AML arising out of previously treated MDS/MPN; it will assess the safety and preliminary efficacy of navitoclax in combination with decitabine and venetoclax (triplet therapy) (trial open to accrual; PI: Garcia, NCT05455294). Targeting the anti-apoptotic machinery offers potential opportunity to target resistance pathways and we hope these benefits can be extended to additional myeloid disease subsets.

    References:

    1. Winter PS, Sarosiek KA, Lin KH, et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014;7(357):ra122.
    2. Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy. J Clin Oncol. 2022;40(15):1671-1680.
    3. Pemmaraju N, Garcia JS, Potluri J, et al. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. Lancet Haematol. 2022;9(6):e434-e444.
    4. Pemmaraju N, Verstovsek S, Mesa R, et al. Defining disease modification in myelofibrosis in the era of targeted therapy. Cancer. 2022;128(13):2420-2432.
    5. Garcia JS, Wei AH, Jacoby MA, et al. Molecular Responses Are Observed across Mutational Spectrum in Treatment-Naïve Higher-Risk Myelodysplastic Syndrome Patients Treated with Venetoclax Plus Azacitidine. American Society of Hematology 2021 meeting. 2021.