Trial in Progress: A Phase I/II Study of the JAK1/2 Inhibitor Ruxolitinib for Relapsed/Refractory Immune Bone Marrow Failure

Background: Acquired bone marrow failure (BMF) results from immune destruction of hematopoietic stem and progenitor cells (HSPCs), leading to significant cytopenia and resultant comorbidities. In severe aplastic anemia, treatment is with hematopoietic cell transplant (HCT) or ATG-based immunosuppressive therapy (IST). In other forms of immune BMF, treatment algorithms are less well defined. Development of effective medical therapies for SAA and other immune BMF remains an ongoing need. ATG-based therapies require hospital admission and can result in significant infusion-related complications making development of oral-based therapies for SAA desirable. Additionally, there is paucity of effective non-transplant options in the relapsed/refractory setting necessitating further drug development.

The JAK-STAT pathway plays an important role in immune cell development and function, including antigen presenting cells, B and T cells, and its activation leads to a cascade promoting a proinflammatory cytokine milieu. Ruxolitinib is an oral JAK1/2 inhibitor, with an established safety and efficacy profile in the treatment of myeloproliferative neoplasms and in acute and chronic graft versus host disease. Other JAK inhibitors are standard therapy for many autoimmune conditions. Use of ruxolitinib in pre-clinical data in a murine model of immune BMF achieved effective count recovery, suppressed activated T-cells, mitigated Fas-mediated apoptotic destruction of target HSPCs, and improved long-term survival.

Study Design and Methods: This is a prospective, non-randomized, single center phase I/II study (NCT05998408) in which participants with relapsed/refractory immune marrow failure will be treated with the JAK1/2 inhibitor ruxolitinib. Our hypothesis is that JAK1/2 inhibition with ruxolitinib will result in hematologic improvement. The primary objectives are to assess safety and efficacy of ruxolitinib in immune marrow failure. The primary endpoints are: (a) the primary safety endpoint will be number of participants who complete a full course of ruxolitinib without cessation required by hematologic toxicity in the 6 months following treatment initiation; (b) The primary efficacy endpoint is overall response (OR) rate at 6 months. Secondary endpoints are time to OR, OR at 3 months, development of transfusion independence at 3 and 6 months, type of response at 3 and 6 months, rate of relapse up to 3 years, rate of clonal evolution up to 3 years, 3-year overall survival (OS), and number of participants tolerating maximum ruxolitinib dose.

Patients >18 years of age with a diagnosis of relapsed or refractory immune BMF will be included in cohort by subtype: SAA (cohort 1), moderate AA (MAA; cohort 2), pure red cell aplasia (PRCA; cohort 3), T-cell large granular lymphocyte lymphocytosis (T-LGL; cohort 4), and hypoplastic myelodysplastic syndrome (cohort 5), who have received at least 1 prior therapy. Major exclusion criteria include poorly controlled infection (i.e. hepatitis B/C, HIV), history of progressive multifocal leuko-encephalopathy, active chemotherapy, poor renal function (defined eGFR <15 mL/min), active non-melanoma skin cancer, acute thrombosis (within 6 months), and PNH clone >50% if not on anticoagulation or a complement inhibitor.

Patients will receive ruxolitinib at up to 20 mg twice daily after weekly dose escalation, administered for up to 6 months. Escalation will occur weekly after careful hematologic toxicity assessment (parameters include 50% increase in transfusion burden or worsening of pre-treatment cytopenia >50%). In the case of hematologic toxicity, the dose will be decreased or held per pre-specified criteria. If relapse occurs, ruxolitinib may be re-initiated on study. A total of 145 patients will be enrolled, 29 per cohort. Each cohort will be independently assessed after the first 10 patients enroll and will be closed if there are <2 responders. Response assessment will include hematologic response (cohorts 1-5), molecular response (cohort 4) and cytogenetic response (cohort 5).

Exploratory endpoints will include: the effect of STAT mutations on response, changes in T-cell activation, dynamics and genetics of clonal evolution, RNA gene expression, and correlation of response with cytokine levels.

No relevant conflicts of interest to declare.