AVID200 improves platelet counts among patients with advanced myelofibrosis
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AVID200 led to significant reduction in serum transforming growth factor beta levels and improved platelet counts among patients with advanced myelofibrosis, according to study results presented at ASH Annual Meeting and Exposition.
Although clinical responses at the landmark analysis of six cycles of treatment appeared limited, the findings indicate transforming growth factor beta plays “a pivotal role” in myelofibrosis leading to thrombocytopenia, researchers concluded.
“This agent has rationale in myelofibrosis and lacks a safety signal of concern,” John Mascarenhas, MD, director of the Center of Excellence for Blood Cancer and Myeloid Disorders at The Tisch Cancer Institute at Mount Sinai, told Healio. “Given the modest clinical activity as a single agent, it should be explored earlier in the disease course and in combination with other rational agents.”
Transforming growth factor beta contributes to myelofibrosis pathobiology by promoting bone marrow fibrosis. It enhances dormancy of normal hematopoietic stem cells but not myelofibrosis hematopoietic stem cells. Prior research also showed transforming growth factor beta inhibits normal megakaryocyte production.
Transforming growth factor beta-1 promotes collagen synthesis by normal human mesenchymal stromal cells.
AVID200 (Bristol Myers Squibb) — a transforming growth factor beta 1 and 3 inhibitor — has been shown to significantly reduce mesenchymal stromal cell proliferation, phosphorylation of SMAD2 and collagen expression, according to study background.
Researchers also have observed robust phosphorylated SMAD2 expression in the absence of exogenous transforming growth factor beta in normal-donor or myelofibrosis megakaryocytes. The addition of AVID200 to megakaryocytes reduced phosphorylated SMAD2 with no effect on total SMAD2/3, and also resulted in greater numbers of megakaryocytes.
Mascarenhas and colleagues conducted a multicenter phase 1B trial to assess AVID200 for patients with intermediate-2-risk or high-risk myelofibrosis intolerant of or resistant to the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi, Incyte).
“This is an urgent unmet need in which patients with myelofibrosis who have failed ruxolitinib do not do well, with at least five independent studies documenting a median OS of 12 to 15 months,” Mascarenhas said. “Non-JAK inhibitor agents are needed to improve the outcomes of these patients as either add-on strategies to the JAK inhibitor or as salvage treatments after discontinuation.”
All patients had baseline platelet counts of at least 25 x 109/L and grade 2/grade 3 bone marrow fibrosis.
Patients received AVID200 via IV on day 1 of each 21-day cycle. After six cycles, researchers assessed responses by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet criteria.
Patients who achieved at least clinical improvement or stable disease with reduction in bone marrow fibrosis of at least one grade continued treatment.
Mascarenhas and colleagues previously presented results of a dose-escalation study that showed AVID200 appeared well-tolerated with no dose-limiting toxicities.
At ASH, Mascarenhas reported updated efficacy and safety results from the two highest doses tested — 70 mg and 180 mg.
The analysis included 21 patients (median age, 73 years; range, 51-81; 81% men) treated in the dose-escalation phase (n = 9) or the dose-expansion phase (n = 12).
Most patients had intermediate-2-risk disease (66.7%), severe bone marrow fibrosis grade (81%) and JAK2V617 mutations (71.4%). Other common mutations included TET2 (29%), ASXL1 (24%) and CALR (19%).
The majority of patients had received prior ruxolitinib (90%), with a median 7.4 months (range, 0.5-59.9) since discontinuation.
Patients received a median five cycles (range, 2-13), and seven patients (33%) received more than six cycles.
At the seventh cycle, one patient who received the 70-mg dose attained clinical improvement as measured by anemia, spleen response and total symptom score.
Five patients exhibited stable disease and three had progressive disease. Two patients — one with 10% blasts at screening and another with 15% blasts at screening — developed progressive acute leukemia while on study.
Two patients completed the study. Common reasons for discontinuation included progressive disease (n = 8) and lack of response (n = 5).
Median change in palpable spleen length was 10% (range, –70% to 150%) and median change in total symptom score was –50% (range, –100% to 185.7%).
Seventeen patients achieved increased platelet counts from baseline, and two subjects achieved normalized platelet counts.
Maximum change in platelets from baseline was 63.8% (range, –15.7% to 505.5%).
Researchers reported median platelet counts of 114 x 109/L (range, 28-695) at baseline. Median platelet count among seven evaluable patients reached 215 x 109/L (range, 66-263) after the sixth cycle.
Analysis by central review of paired bone marrow biopsy pathology samples from 16 patients showed no significant changes in bone marrow fibrosis score or megakaryocyte histotopography between baseline and end of treatment.
All patients had elevated plasma levels of transforming growth factor beta-1 levels as detected by enzyme-linked immunosorbent assay, but researchers observed dramatic reductions 21 days after the final AVID200 dose.
Researchers observed no dose-limiting toxicities.
Sixteen patients (76.2%) experienced grade 3/grade 4 adverse events.
Eight patients (38.1%) experienced grade 3/grade 4 nonhematologic adverse events; these included one case each of epistaxis, mucositis, fatigue, rash, duodenal hemorrhage, gastric hemorrhage, extraocular muscle paresis, urinary tract infection and syncope.
Grade 3 or grade 4 hematologic adverse events included anemia (28.3%) and thrombocytopenia (14.3%). No fatal events occurred.
“The study ... confirmed safety in the myelofibrosis population and on-target activity — [with] reduced levels of plasma transforming growth factor beta-1 — with clinical improvements in terms of spleen and symptom burden reduction and a durable anemia response in one patient,” Mascarenhas said. “The most interesting finding —supported by the preclinical studies conducted by my colleagues Anna Rita Migliaccio, PhD, Lilian Varricchio, PhD, and Ronald Hoffman, MD — is that a subset of patients had a durable improvement in platelet count, including three patients with baseline thrombocytopenia that normalized their platelet count on treatment.
“We were surprised that we did not see reduction in bone marrow fibrosis in 16 paired samples from baseline to cycle seven of therapy,” Mascarenhas added. “This may be explained by the need for longer treatment, as well as the need to combine this agent with other active agents with mechanistic rationale that can also suppress relevant redundant pathways.”
Mascarenhas said he is optimistic about the potential of AVID200 as part of combination therapy due to the early signal of activity and the known repressive effects of tumor growth factor beta on megakaryopoiesis. Hoffman’s lab is conducting research to assess the optimal combination therapy approach.
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Mascarenhas J, et al. Abstract 142. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
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