Analysis of spleen volume kinetics with outcomes in patients with myelofibrosis treated with JAK inhibitors

Analysis of spleen volume kinetics with outcomes in patients with myelofibrosis treated with JAK inhibitors

Myelofibrosis (MF) is a cancer of the blood-producing cells in the bone marrow. It is characterized by low blood counts leading to increased risk of bleeding and infection as well as various other symptoms (e.g., night sweats, weight loss, fatigue, pain) that impair quality of life. Additionally, MF can progress to a more aggressive blood cancer called acute myeloid leukemia (AML) and is ultimately associated with a substantially reduced life-expectancy.Patients with MF often have mutations in the so-called JAK-STAT signaling pathway which drives the constant growth of the abnormal cancer cells and contributes to the debilitating symptoms many patients experience. However, the identification of those mutations has also enabled novel therapies targeting this JAK-STAT pathway. The oral JAK1/2 inhibitor ruxolitinib was the first agent to be approved in MF based on a significant reduction in spleen volume and symptom burden compared to placebo or best available therapy. Subsequently, several other JAK inhibitors such as fedratinib, pacritinib, and momelotinib have been shown in clinical trials to lead to improvements in symptom burden and spleen volume.While the US Food and Drug Administration has accepted a 35% reduction in spleen volume as the primary endpoint in these studies as the basis for drug approval, it remains unclear what the optimal cut-off for spleen volume reduction (SVR) is and how it correlates with other patient-centered outcomes such as progression to AML or survival. For example, many patients experience symptom relief independent of achieving this arbitrary cut-off for SVR. In this project, we hope to pool the data from multiple clinical trials of JAK2 inhibitors in MF to answer important questions such as: What is the optimal threshold for SVR that captures both symptom improvement and survival?. We hope to pool data from individual patients across clinical trials (COMFORT I & II, SIMPLIFY I & II, PERSIST I & II, JAKARTA I & II) which will make this the largest study to address this question to date and is the only way to detect correlations in small subgroups including patients undergoing a bone marrow transplant. The results of this analysis have the potential to inform endpoints for future clinical trials and to guide practicing physicians in the management of patients with MF treated with JAK inhibitors.

[{ "PostingID": 20606, "Title": "NOVARTIS-CINC424A2352", "Description": "A randomized study of the JAK inhibitor INC424 tablets compared to best available therapy in subjects with primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF)" }]