A Phase I/II Trial of Ruxolitinib with Chemotherapy for Patients with Relapsed and/or Refractory Philadelphia-like Acute Lymphoblastic Leukemia

Background: Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) represents a high-risk subtype of B-ALL. The disease is driven by a range of kinase-activating mutations, resulting in a similar gene expression profile to that of Ph-positive ALL, and one which may be targetable by JAK- or ABL-directed kinase inhibition. Patients and methods: We conducted a phase I/II trial to explore the safety and efficacy of ruxolitinib or dasatinib in combination with Hyper-CVAD chemotherapy for patients ≥ 10 years of age with relapsed and/or refractory Ph-like ALL (clinicaltrials.gov/NCT02115295). Results: A total of 11 patients were enrolled (ruxolitinib cohort, n = 10; dasatinib cohort, n = 1) with a median age of 24 years. The median number of prior lines of treatment was 3. Genetic aberrations included CRLF2 overexpression (n = 8), HMBOX1-JAK2 fusion (n = 1), IGH-EPOR fusion (n = 1), and NUP214-ABL1 (n = 1). We observed no dose-limiting toxicities in the first 2 cohorts of patients receiving ruxolitinib (15 mg BID, n = 5 and 20 mg BID, n = 3), however enrollment of the third cohort (25 mg BID, n = 2) was terminated early due to slow accrual. The most common ≥ grade 3 adverse events were related to infectious complications. We observed overall low efficacy with 1/10 patients receiving ruxolitinib achieving complete remission with incomplete platelet count recovery. Conclusion: Continued efforts should focus on identifying optimal treatment strategies for this high-risk group of patients.