PF668 RESULTS FROM ONGOING PHASE 1/2 CLINICAL TRIAL OF TAGRAXOFUSP (SL‐401) IN PATIENTS WITH INTERMEDIATE, OR HIGH RISK, RELAPSED/REFRACTORY MYELOFIBROSIS
Authors: N. Pemmaraju, H. Ali, V. Gupta, A. Yacoub, G. Schiller, S. Lee, M. Talpaz, E. Wang, M. Taparia, M. Sardone, H. Wysowskyj, S. Shemesh, J. Chen, C. Brooks, E. Poradosu, P. McDonald, N. Rupprecht, A. Pardanani, A. Tefferi, S. Verstovsek, J. Khoury, M. Patnaik
Journal: HemaSphere (2019)

Background: Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the US FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. Moreover, CD123 + plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor‐promoting role. 1,2,3 Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor, associated with rapid disease progression and shortened survival, suggesting an accelerated disease phase in MF. 4 As such, tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, including patients with monocytosis. Aims: Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with MF who were relapsed, refractory, or unable to tolerate JAKi. Methods: This multicenter, open‐label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), 28 days (cycles 5–7), and 42 days (cycles 8 + ). In Stage 2 (expansion), patients are receiving the RP2D (12 mcg/kg). Results: 23 patients with MF received tagraxofusp, including 12 patients who received ≥ 3 prior lines of therapy. Median age 69 years (range 55–81), 61% were female, and 30% had baseline monocytosis (≥ 1x10 9 /L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate‐1, 12 patients (52%) with intermediate‐2, and 10 patients (44%) with high‐risk. At study entry, the median platelet count was 59 K/uL with 71% of patients had baseline platelets &lt;100 K/uL, of which 8 patients had platelets &lt;50 K/uL. 87% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin [LCM]). Most common treatment‐related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, alanine aminotransferase increased and thrombocytopenia. The most common ≥ grade 3 TRAE was thrombocytopenia (8%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 14 evaluable patients with baseline splenomegaly, 57% had spleen size reductions: 43% (6/14) had reductions of &gt; 25%, of which 3 patients had reductions of ≥ 45%. In 5 patients with baseline splenomegaly and monocytosis, 80% (4/5) had reductions of &gt; 25%, of which 2 had reductions of ≥ 45%. Six patients, including 3 patients with monocytosis and 5 patients with platelets &lt;100 K/uL, had treatment duration of 6 months or more. Summary/Conclusion: Tagraxofusp demonstrated single agent activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor, both constituting potential areas of unmet medical need. Enrollment continues, and updated trial data will be presented. Registrational trial designs are being evaluated. Trial information: NCT02268253.