Results of A Phase I Study of Ruxolitinib in Patients (pts) with Relapsed/Refractory Acute Leukemia

Outcomes in the treatment of AML remain overall poor. Novel targeted approaches to therapy are warranted. Ruxolitinib is a potent JAK1 and JAK2 inhibitor recently approved in the US for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia MF, and post-essential thrombocytopenia MF and is being actively investigated as treatment for pts with acute leukemia.

To determine safety, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of ruxolitinib in treatment of relapsed/refractory acute leukemia pts (AML or ALL).

We conducted a single-center prospective phase I clinical trial (n=27) in which 3 different dose levels were tested (mg, oral, BID): 50 (n=4), 100 (n=5), 200 (n=18) as continuous daily dosing. One cycle of therapy was defined as 28 days. Inclusion criteria: Age >14 years, relapsed/refractory AML or ALL, adequate organ function (ALT and/or AST ≤1.5x upper limit of normal and serum creatinine ≤2.5mg/dL, ECOG PS 0–2, at least 2 weeks from prior leukemia therapy with exception of hydroxyurea. Toxicities were defined with CTCAE criteria, v4.0.

A total of 27 pts with acute leukemias were enrolled. All but one pt had AML (one pt with B-ALL). Median age at diagnosis was 66 years (range 25–88 years). 14 pts (52%) were male. 11 pts (41%) were PS=2 at enrollment. 5 pts had splenomegaly at baseline (range 4–21 cm). Baseline median laboratory parameters included: Hb (g/dL)= 9.2 (7.9–10.9), platelet (10⁹/L)=22(3–271), WBC (10⁹/L) =4(0.3–42.8), Blast % (PB)=23(0–97), Blast % (BM)=56 (1–99). The pt with only 1% BM blasts prior to starting therapy had persistent AML represented by extramedullary disease requiring further treatment. Baseline cytogenetics: diploid (n=9), Trisomy 8 (n=1), −5/-7/both (n=8), abnormal 11q (n=1), miscellaneous (n=8). Baseline molecular mutations: JAK2V617F (n=5), NRAS (n=3), MPL (n=1), FLT3-ITD (n=1), NPM1 (n=1), CEBPA (n=1), IDH2 (n=1), DNMT3a (n=1). Majority of pts (23 pts, 85%) were treated in salvage 2 (S2) or beyond: S2-S3 (n=11), ≥S4 (n=12). 7 pts had a prior non-leukemia malignancy (mantle cell lymphoma, breast, colon, lung, prostate, melanoma, T-cell lymphoma), all 7 of whom required prior chemotherapy, radiation, or surgery. 16 pts had prior diagnosis of either MPN or MDS. Median number of treatment cycles on protocol was 2 (range 1–4). Among 27 pts enrolled, 12 pts were found to be evaluable for DLT-assessment, responses below in Table. Only one pt required a dose reduction during study period (during cycle 3, from 200mg BID to 150mg BID in setting of drug-related Grade 3 thrombocytopenia). Most common Grade ≥3 non-hematologic event was infection (n=17)(most commonly pneumonia (n=9); most commonly occurring at 200mg po BID dosing level (8/17, 47%), followed by stroke (n=2), cerebral edema (n=1), fatigue (n=1), mucositis (n=1), elevation of alkaline phosphatase (n=1). 1 pt had CRp at 200mg po BID dosing (68 year old AML pt, received 6 prior AML therapies, Trisomy 8-positive, JAK2 mutation negative; achieved CRp after 2 cycles and was on study for total of 3 cycles). Among the 5 JAK2-positive pts, 4 were evaluable for response; median number of cycles was 1(range 1–3) and no CR/CRp were noted among this group.

In this heavily pre-treated cohort of acute leukemia pts, 1 CRp was noted at highest dosing level (200mg po BID), in a relapsed/refractory AML pt, however this response was short (1 cycle). Most common grade ≥3 non-hematologic event during study period was infection, with pneumonia being most commonly reported.

Off Label Use: Ruxolitinib off label investigational drug. Cortes:Incyte: Research Funding. Ravandi:Incyte: Research Funding. Verstovsek:Incyte: Research Funding.