A phase 1 trial of ibrutinib and azacitidine for higher risk myelodysplastic syndromes (University of California Hematologic Malignancies Consortium Study 1503).

Despite the use of hypomethylating agents (HMA), outcomes remain poor for patients with higher-risk myelodysplastic syndromes (HR-MDS). Ibrutinib (IBR) is a Bruton's Tyrosine Kinase (BTK) inhibitor that can exert anti-myeloblast activity through inhibition of NF-kB signaling. IBR also has immunomodulatory activity through binding to interleukin-2-inducible kinase (ITK). We conducted a multicenter Phase 1b trial (NCT02553941) to evaluate the safety, tolerability, and preliminary efficacy of the combination of IBR and azacitidine (AZA) in patients with HR-MDS. Patients received standard AZA in combination with IBR at two dose levels (DL), 420 mg (DL1) and 560 mg (DL2). Twenty-one patients were enrolled, including 17 with high- or very high-risk disease and six with prior HMA therapy. No dose-limiting toxicities were observed in the dose escalation cohorts. The most common grade 3 or higher adverse events included thrombocytopenia, neutropenia, anemia, and febrile neutropenia. Bleeding events occurred in 14 patients (67 %), with a grade 3 event in one patient. The overall response rate was 48 %, including 3 (14 %) complete remissions (CR) and 4 (19 %) marrow CR. Responses were seen in patients with TP53 mutations or deletions. CD34 positive bone marrow mononuclear cells (BMMC) BTK and peripheral blood MC (PBMC) ITK occupancy by IBR demonstrated on-target activity in relevant target cells. In patients with HR-MDS, the combination of IBR and AZA is safe, tolerable, and active, including responses in patients with TP53 aberrations and with prior HMA therapy. Further study in a larger, randomized trial is necessary to assess efficacy of this regimen for patients with HR-MDS.