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Clinical Trial
. 2018 Feb 27;2(4):381-389.
doi: 10.1182/bloodadvances.2017013391.

Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia

Tibor J Kovacsovics  1 , Alice Mims  2 , Mohamed E Salama  1   3 , Jeremy Pantin  4 , Narayanam Rao  1 , Ken M Kosak  1 , Peter Ahorukomeye  1 , Martha J Glenn  1 , Michael W N Deininger  1 , Kenneth M Boucher  5 , Linda M Bavisotto  6 , Gerardo Gutierrez-Sanchez  7 , Thomas P Kennedy  8 , Stephen G Marcus  9 , Paul J Shami  1
Affiliations
Clinical Trial

Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia

Tibor J Kovacsovics et al. Blood Adv. .

Abstract

Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women). Three, 5, and 4 patients had good-, intermediate-, and poor-risk disease, respectively. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had morphologic complete remission after 1 induction (CR1). Eight patients were alive at a median follow-up of 24 months (4 patients in CR1). Three patients received an allogeneic stem cell transplant in CR1. Median disease-free survival was 14.8 months. Median overall survival was not attained at the maximum follow-up time of 29.4 months. No CX-01-associated serious adverse events occurred. Median day to an untransfused platelet count of at least 20 × 109/L was 21. CX-01 is well tolerated when combined with intensive therapy for AML and appears associated with enhanced count recovery and treatment efficacy.

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Conflict of interest statement

Conflict-of-interest disclosure: T.P.K. is a stockholder in Cantex Pharmaceuticals. S.G.M. is employed by and is a stock holder in Cantex Pharmaceuticals. P.J.S. received research support from Cantex Pharmaceuticals. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Kaplan Meier curves of overall survival (OS) and disease-free survival (DFS).
Figure 2.
Figure 2.
Peak and steady-state CX-01 plasma concentrations vs time curves in 7 patients with AML during induction. Shown are averages and standard errors of the mean for each time point.
Figure 3.
Figure 3.
Surface plasmon resonance assay of the binding of CX-01 to CXCL12α. (A) BIAcore sensorgrams for the binding of 100 nM CXCL12α after preincubation with different concentrations of CX-01 (0, 1, 5, 10, 50, 100, 1000, and 2000 nM). (B) Competition assay shows the CX-01 concentration (50% inhibitory concentration = 4.7 nM or 0.055 μg/mL) that inhibits 50% of the maximum CXCL12α attachment response to immobilized heparin.
Figure 4.
Figure 4.
Effect of CX-01 on U937 cell migration toward CXCL12. The assay was conducted using a cell migration assay kit from Cell Biolabs (San Diego, CA), as detailed in the Methods section. CXCL12 was added at a concentration of 100 ng/mL in the wells. CX-01 was added at a concentration of 200 µg/mL in the wells. To investigate the direct effect of CX-01 on leukemia cells in 1 variable, CXCL12 only was added to the wells and U937 cells were pretreated for 30 minutes with 500 µg/mL CX-01 before loading them into inserts. The graph shows averages and standard errors of the mean of 2 to 3 replicate wells in each group (the media blank variable had 1 well). The legend indicates CXCL12 and/or CX-01 added to the wells or pretreatment of U937 cells with CX-01. The graph is representative of 2 separate experiments. RFU, relative fluorescence unit.
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