Abstract 819: High response rates with entospletinib in patients with t(v;11q23.3);<i>KMT2A</i> rearranged acute myeloid leukemia and acute lymphoblastic leukemia
Authors: Alison R. Walker, John C. Byrd, William Blum, Tara Lin, Howland E. Crosswell, Danjie Zhang, Jie Gao, Arati V. Rao, Mark D. Minden, Wendy Stock
Journal: Cancer Research (2018)

Abstract Introduction: Targeted therapy for KMT2A (mixed lineage leukemia [MLL]) rearranged acute leukemia (AL) is lacking. KMT2A regulates leukemic stem cell transcription factors HOXA9 and MEIS1. Spleen tyrosine kinase (SYK) signaling induces MEIS1 in conjunction with HOXA9. We hypothesize that this regulatory loop may be sensitive to SYK inhibition with Entospletinib (ENTO) a highly selective, oral SYK inhibitor. In this analysis, we evaluate the efficacy of ENTO in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) with t(v;11q23.3) KMT2A/MLL gene rearrangements. Methods: Patients with KMT2A rearranged AL in two different clinical trials were included. AML patients (NCT02343939) received ENTO 400mg BID monotherapy for up to 14 days prior to and with induction chemotherapy (cytarabine 100 mg/m2 for 7 days plus daunorubicin 60 mg/m2 for 3 days) if previously untreated, or ENTO monotherapy alone if relapsed/refractory (R/R). R/R B-ALL patients received ENTO monotherapy for 7 days prior to and with vincristine and dexamethasone in a phase 1 study (NCT02404220). Results: 18 patients with KMT2A rearranged AL were treated. Untreated AML (n=10) patients had a median age of 49 years. One patient was in a morphologic leukemia-free state after ENTO monotherapy (before chemotherapy). After induction chemotherapy plus ENTO, seven patients had morphologic (CR) and cytogenetic (CRc) remission, but two of them had incomplete count recovery (CRi). The composite CR rate (CR/CRi/CRc) was 90%: 5 CRc, 3 CRi (CR/CRc with incomplete count recovery), and 1 CR. Six patients underwent allogeneic stem cell transplantation (SCT) in CR1. After median follow-up of 9.9 months one patient who achieved CR relapsed, with persistence of t (6;11) and an NRAS mutation. Median overall survival and event-free survival have not been reached. In R/R AML (n=6), patients had a median age of 48 years, with 2 median prior therapies. One had CR and one had CRi (but normal cytogenetics) and both received SCT. In all, 3 AML patients (1 newly diagnosed, 2 R/R) responded to ENTO monotherapy alone. In R/R ALL (n=2), median age was 59 years. Both patients had t (4;11) along with other cytogenetic abnormalities with 2 prior therapies. Both patients achieved CR with loss of KMT2A on cytogenetic testing, and one patient received SCT. Overall, ENTO was safe and well tolerated, even in combination with chemotherapy. Conclusions: KMT2A rearranged AL is sensitive to ENTO with CR observed on monotherapy in AML and high response rates in AL patients treated with combination therapy. This represents the first documentation of CR with small molecule monotherapy (n=3) in this genetic subgroup, which typically portends a poor prognosis. Correlative biomarker studies evaluating HOXA9/MEIS1 in patients with t(v;11q23.3) KMT2A rearranged leukemia treated with ENTO are pending. Citation Format: Alison R. Walker, John C. Byrd, William Blum, Tara Lin, Howland E. Crosswell, Danjie Zhang, Jie Gao, Arati V. Rao, Mark D. Minden, Wendy Stock. High response rates with entospletinib in patients with t(v;11q23.3);KMT2A rearranged acute myeloid leukemia and acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 819.