Background: Outcomes are poor for older patients with AML and MDS who progress on HMAs. Blocking the CXCL12/CXCR4 axis may be therapeutic as this is essential for retention of malignant stem cells in the bone marrow (BM), where they may be protected from the genotoxic stresses of chemotherapy. CX-01 is a low molecular weight heparin derivative with minimal anticoagulant activity that disrupts the CXCL12/ CXCR4 axis, and neutralizes the activity of PF4, a negative regulator of megakaryopoiesis. We hypothesized that CX-01 would re-sensitize patients with HMA-refractory AML and MDS to AZA and mitigate thrombocytopenia. Methods: Patients with HMA-refractory INT-1 or greater MDS and AML received 7 day continuous infusion of CX-01 with 7 day AZA 75 mg/m² in 28 day cycles. The primary objective was to assess the overall response rate (ORR). Results: To date, 20 patients were treated and 12 are evaluable for response with a BM biopsy after C2. The median age was 74 years. 9 patients had secondary AML, 7 had MDS INT-1, 2 had MDS INT-2, and 2 had de novo AML. 10 patients had poor risk cytogenetics and/or p53 mutations. Baseline BM showed a median 16% blasts. Patients were heavily pretreated, receiving a median of 6 cycles of prior HMA cycles (range 4-20) with 10 patients receiving > 1 prior line of therapy. Patients received a median of 2 cycles of CX-01 with AZA (range 0-5). Of the 12 evaluable patients, there was 1 complete response (CR), 3 marrow CRs (with incomplete count recovery), 7 stable disease, and 1 progressive disease for an ORR of 33%. There was no significant difference in baseline characteristics of responders and the rest of the cohort. 3 of 4 responders had hematologic improvement, 2 with normalization of platelet counts. Median duration of response is 212+ days, with 2 patients disease-free at 192 and 233 days, and all four responding patients still alive. CX-01 was well tolerated, with all severe AEs thought unlikely to be related to CX-01. Conclusions: CX-01 and AZA appears to have an encouraging response rate in HMA-refractory AML/MDS. Treatment was feasible with no instances of study related severe AEs. This trial is ongoing to evaluate the ORR and OS of all patients treated. Clinical trial information: NCT02995655