Phase 1b/2 study of axatilimab in combination with azacitidine in advanced Phase MPN, MDS/ MPN overlap and high-risk CMML

Abstract Background 20% and second-line options lacking. Prognosis is poor for pts with high-risk CMML and other MDS/MPN overlap syndromes with a median overall survival (OS) 3 yrs and dismal for accelerated phase disease with OS 1 yr. The only curative treatment is an allogeneic stem cell transplant which is not feasible in many pts due to age, comorbidities, poor performance status, or inability to achieve adequate pre-transplant disease control. Axatilimab (Axa) is a first-in-class humanized IgG4 monoclonal antibody with high affinity against colony stimulating factor-1 receptor (CSF-1R). CSF-1R is expressed on cells in the mononuclear phagocyte lineage. In vitro studies have demonstrated that Axa binds to human CSF-1R and completely inhibits macrophage viability during CSF1–mediated differentiation. Axa has demonstrated adequate tolerability and encouraging response rates in the treatment of chronic graft vs host disease (cGVHD) through inhibition of donor-derived monocytes and macrophages and is FDA approved for refractory cGVHD. Inhibition of CSF-1R–mediated signaling has shown anti-tumor activity in AML models by targeting supportive cells in the microenvironment (Edwards DK et al.Blood 2019) and may therefore represent a therapeutic strategy in other myeloid malignancies as well. Study Design 2 males/1 female; all white) including 2 with CMML and 1 with MDS/MPN-U. The primary objective of phase 2 is to evaluate the overall response rate of Axa + AZA in newly diagnosed pts using Savona response criteria (Savona MR et al. Blood 2015). The secondary objectives include evaluation of safety and tolerability of the combination with a focus on immune-related side effects from Axa and QoL assessment using the MPNSAF scores. Correlative studies will evaluate markers of myeloid differentiation, mechanisms of intrinsic and acquired resistance to the regimen by tracking morphologic, signaling and epigenetic changes over time, and biomarkers specific to CSF-1R biology.