Preliminary Evidence That ODSH (2-O, 3-O Desulfated Heparin) Is Safe and Enhances Count Recovery in Patients Treated with Intensive Therapy for Acute Myeloid Leukemia – Results of a Pilot Study

Introduction

Intensive treatment of acute myeloid leukemia (AML) is associated with severe pancytopenia. Thrombopoietic agents have so far failed to mitigate treatment-associated thrombocytopenia. Platelet factor 4 (PF4) is a potent negative regulator of megakaryopoeisis and its levels correlate with platelet transfusion requirements in children treated for acute lymphoblastic leukemia. Anti-PF4 antibodies diminish chemotherapy-induced thrombocytopenia in mice. ODSH (2-O, 3-O Desulfated Heparin), a heparin derivative with low anticoagulant activity, is a potent inhibitor of PF4, mitigates heparin-induced thrombocytopenia and, like other heparins, may inhibit the CXCL12/CXCR4 axis. The purpose of this pilot study was to obtain preliminary data on the effect of ODSH when combined with intensive AML treatment.

Methods

Adult patients with newly diagnosed untreated AML (excluding acute promyelocytic and acute megakaryoblastic leukemia) were enrolled. Induction therapy consisted of cytarabine (100 mg/m² as a continuous 24-hour infusion on days 1 – 7) and idarubicin (12 mg/m² by intravenous bolus on days 1 – 3). During induction cycles, ODSH was given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 7. Patients 60 or older received further post-induction therapy off study. Patients younger than 60 received consolidation therapy with high dose cytarabine (3 g/m² every 12 hours on days 1, 3, and 5) along with ODSH given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 5. Patients received transfusion and antibiotic support per standard guidelines. Patients did not receive growth factor support during induction cycles.

Primary endpoints were to determine the safety and tolerability of ODSH combined with intensive AML therapy, and to obtain preliminary data on the effect of ODSH on platelet count recovery. Secondary endpoints included obtaining preliminary data on the effect of ODSH on complete remission rate and tolerability of chemotherapy. Data presented here are for induction cycles. Data for consolidation cycles will be presented at the meeting.

Results

Ten patients were enrolled. Two patients did not complete the full induction cycle due to complications unrelated to ODSH therapy and are not included in the analysis. The median age of the 8 patients (3 women) who completed the full induction cycle and were analyzed was 55 (range: 22 – 74). There were no ODSH-associated adverse events. Based on cytogenetic, molecular, or antecedent hematologic disorder, 1, 5, and 2 patients fell into the better, intermediate, and poor risk categories, respectively. Day 14 bone marrow biopsies were obtained on all 8 patients and were aplastic without detectable leukemia in all. Seven out of 8 patients who completed induction had evidence of a morphologic complete remission upon count recovery using IWG criteria. One of the 7 patients in morphologic remission had evidence of minimal residual disease by flow cytometry and cytogenetics. It is noteworthy that the 2 patients who did not receive a full course of induction therapy (treatment discontinued on Day 3 and Day 5 of the induction cycle, respectively) achieved a complete remission upon count recovery using IWG criteria with evidence of minimal residual disease by molecular testing.

All 8 patients who received a full course of induction therapy were evaluable for platelet count recovery. Among those patients, the median day to obtain a sustained platelet count above 20,000/ml without transfusion was day 20 (range: 16 – 22). Five of the 8 patients who received a full course of induction therapy were evaluable for neutrophil count recovery. Among those patients, the median day to a neutrophil count above 1,000/mL was day 23 (range: 21 – 27).

Conclusion

We conclude that ODSH is well tolerated when combined with aggressive therapy for the treatment of AML. Results from this pilot study show that ODSH may enhance count recovery and treatment efficacy. These results justify further study of this strategy in a randomized trial.