Skip to main content

AVID200 Improves Platelet Counts in Patients with Myelofibrosis After Discontinuation of Ruxolitinib

Conference Correspondent

AVID200, a TGFβ;1/3 inhibitor, has previously demonstrated positive effects against TGFβ;-mediated responses in multiple cell types involved in myelofibrosis (MF). TGFβ; is a cytokine that regulates bone marrow fibrosis (BMF), prolonging dormancy in normal but not malignant hematopoietic stem cells, inhibition of normal megakaryocyte proliferation, and production of collagen by mesenchymal stromal cells (MSCs). In MSCs, AVID200 significantly reduced growth, phosphorylation of SMAD2 which mediates TGFβ; function, and collagen expression. In megakaryocytes that produce platelets, AVID200 increased proliferation and decreased phosphorylated SMAD2 without affecting total SMAD2/3. Treatment of MF mononuclear cells with AVID200 also led to increased numbers of progenitor cells with wild-type JAK2 and a reduction in mutated cells. Taken together, the evidence indicates regulation of TGFβ; by AVID200 may be a viable therapeutic option for patients with MF previously treated with ruxolitinib (RUX).

Twenty-two patients with intermediate-2 or high-risk MF, grade 2/3 BMF, and resistant to/intolerant of RUX were enrolled in the phase 1b study of AVID200 (9 in the dose-escalation phase and 12 in the dose-expansion phase). At baseline, JAK2 V617F (71%) mutation was detected at the highest frequency. 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 International Working Group/European LeukemiaNet criteria after 6 cycles of AVID200. The median number of AVID200 cycles received was 6 (range, 1-17 cycles) 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. Reasons for discontinuation of AVID200 as determined by study investigators included disease progression (n = 8), lack of response (n = 5), study completed (n = 2), other (n = 2), and patient decision (n = 1). 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 more total nonhematologic events, but each was experienced by only 1 patient (epistaxis, mucositis, extraocular muscle paresis, fatigue, rash, duodenal hemorrhage, gastric hemorrhage, urinary tract infection, and syncope).

Spleen size, platelet counts, BMF, and TGFβ; were assessed at baseline. Median change in palpable spleen length was +10% (range, –70% to +150%) and total symptom score change was –50% (range, –100% to +185.7%). An increase in platelets 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 x 109/L; range, 66-263) compared with baseline (114 x 109/L; range, 28-695). There was no evidence of change in BMF score from baseline as assessed by paired bone marrow biopsy samples. Elevated levels of TGFβ;1 at baseline were reduced 21 days after the last dose of AVID200 in all patients.

The evidence suggests AVID200 is well-tolerated and improves platelet counts while reducing serum TGFβ; levels. These data indicate AVID200 can mitigate TGFβ;-mediated development of thrombocytopenia in patients with advanced MF. However, clinical responses at cycle 7 of therapy in this patient population were limited. Researchers concluded AVID200 may be most effective as combination therapy in patients with MF with TGFβ;-induced thrombocytopenia.

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.

Related Items