TGFβ-Regulated Progression of Thrombocytopenia Reduced in Patients with Advanced Myelofibrosis Receiving AVID200 Therapy

JAK inhibitors such as ruxolitinib (RUX) have proven effective in treating intermediate- or high-risk myelofibrosis (MF), but therapy discontinuations are commonly seen due to development of limiting thrombocytopenia. TGFβ is a cytokine that promotes quiescence in normal but not cancerous hematopoietic stem cells, as well as inhibition of normal megakaryocyte proliferation and decreased production of collagen by mesenchymal stromal cells (MSCs), both of which augment bone marrow fibrosis.

AVID200, a TGFβ1/3 inhibitor, targets TGFβ-mediated responses in multiple cell types involved in MF in that it significantly reduces mitotic activity in MSCs as well as the activity of SMAD2, a TGFβ regulator, and collagen expression. In megakaryocytes, AVID200 increased proliferation and decreased phosphorylated SMAD2 without affecting total SMAD2/3. These findings indicate that TGFβ modulation by AVID200 may fill a treatment gap for patients with MF previously treated with RUX. This phase 1b study enrolled 22 patients with intermediate-2 or high-risk MF and grade 2/3 bone marrow fibrosis (BMF) who were resistant/intolerant to RUX.

At baseline, the JAK2 V617F mutation was detected in 71% of cases. Additional mutations in these patients included TET2 (29%), ASXL1 (24%), and CALR (19%). Median time after RUX discontinuation was 7.4 months (range, 0.5-59.9 months). Twenty-one patients were administered AVID200 intravenously on day 1 of a 21-day cycle. Response was assessed by the International Working Group/European LeukemiaNet criteria after 6 cycles of AVID200. The median number of AVID200 cycles received was 6 (range, 1-17), and 7 patients received >6 cycles. International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria indicated limited clinical responses at cycle 7 of therapy. Discontinuation of AVID200 was primarily attributed to progressive disease (n = 8) and lack of response (n = 5), as determined by study investigators. Grade 3/4 hematologic and nonhematologic (n = 8) adverse events were observed in 16 (76.2%) patients. Hematologic events were anemia (n = 6) and thrombocytopenia (n = 2). There were 9 nonhematologic events, each being experienced by only 1 patient (epistaxis, mucositis, extraocular muscle paresis, fatigue, rash, duodenal hemorrhage, gastric hemorrhage, urinary tract infection, and syncope).

Median change in total symptom score was –50% (range, –100% to +185.7%) and change in palpable spleen length was +10% (range, –70% to +150%). An increase in platelet counts from baseline during treatment was observed in 9 patients, and 2 patients’ platelet counts were normalized. Maximum changes in platelets from baseline across all cycles was +63.8% (range, –15.7% to +505.5%). In 7 evaluable subjects, median platelet count increased after cycle 6 (215 × 109/L; range, 66-263) compared with baseline (114 × 109/L; range, 28-695). Bone marrow biopsies did not reveal any change in the degree of BMF from baseline but levels of TGFβ1 which were elevated at baseline had decreased 21 days after the last dose of AVID200 in all patients.

In conclusion, AVID200 can improve TGFβ-regulated progression of thrombocytopenia in patients with advanced MF. Since clinical responses at cycle 7 of therapy in this patient population were limited, AVID200 may be more applicable in the context of combination therapy in MF patients with thrombocytopenia mediated by TGFβ.

Source: Mascarenhas J, Kosiorek HE, Bha R, et al. Treatment of myelofibrosis patients with the TGF-β 1/3 inhibitor AVID200 (MPN-RC 118) induces a profound effect on platelet production. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 142.

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