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

Tibor J. Kovacsovics, Alice Mims, Mohamed E. Salama, Jeremy Pantin, Narayanam Rao, Ken M. Kosak, Peter Ahorukomeye, Martha J. Glenn, Michael W. N. Deininger, Kenneth M. Boucher, Linda M. Bavisotto, Gerardo Gutierrez-Sanchez, Thomas P. Kennedy, Stephen G. Marcus and Paul J. Shami

Article Figures & Data

Figures

  • Figure 1.

    Kaplan Meier curves of overall survival (OS) and disease-free survival (DFS).

  • 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.

    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.

    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.

Tables

  • Table 1.

    Patient Characteristics and Outcomes

    PatientAgeSexKaryotype and molecular findings% Marrow blasts at diagnosisDay 14 bone marrowInduction outcomePostinduction therapy and outcome
    100263M+8, t(9:11), FLT3 TKD93<5% cellularity; NEDCRThree cycles of IDAC consolidation off study followed by allogeneic stem cell transplant in CR1.
    100346Mt(12,13)6.4<5% cellularity; NEDFailureAllogeneic transplant after salvage therapy.
    100474Madd(8) t(8,19) FLT3 TKD64Suboptimal; NEDCRTwo cycles of IDAC consolidation and relapse 6 mo after diagnosis.
    Postrelapse therapy on an experimental protocol and died of cerebral hemorrhage.
    100546MXY (SNP array)26Suboptimal; serous atrophy; NEDCRFour cycles of HiDAC + CX-01 consolidation on study.
    Relapse 16 mo after diagnosis. Underwent salvage therapy and allogeneic transplant. Had extramedullary relapse posttransplant and underwent salvage therapy and donor lymphocyte infusion.
    100671Finv(3) FLT3 ITD59<5% cellularity; serous atrophy; NEDCR MRDTwo cycles of IDAC consolidation off study followed by allogeneic stem cell transplant in CR1.
    Relapse 9 mo after diagnosis, received further therapy on an experimental protocol and died of infectious complications.
    100758Minv(16) +8, +22, +2151<5% cellularity serous atrophy; NEDCR MRDFour cycles of HiDAC consolidation off study because of incomplete induction cycle.
    100954MXY - NPM1+3710% cellularity; NEDCRThree cycles of consolidation with HiDAC + CX-01 on study
    One cycle of consolidation with HiDAC alone after withdrawing from study.
    101052MXY - FLT3 ITD30<5% cellularity serous atrophy; NEDCRDeveloped line-associated deep vein thrombosis and went off study after induction. –
    Two cycles of HiDAC consolidation off study followed by allogeneic stem cell transplant in CR1.
    200154Mt(6,9) - FLT3 ITD70Not doneCRReceived 2 d of induction and relapsed 7 wk after diagnosis.
    Underwent salvage therapy and allogeneic stem cell transplant. Subsequently died of transplant-related complications.
    300122FXX - NPM1 +21<10% cellularity; NEDCROne cycle of HiDAC + CX-01 consolidation on study and was lost to follow-up after withdrawing study.
    Relapsed 13.5 mo after diagnosis, received salvage therapy and underwent allogeneic stem cell transplant in second remission.
    300267Mdel(20) (q11.2) - FLT3 ITD (tested at relapse)50Hypocellular; NEDCRThree cycles of consolidation therapy off study.
    Relapsed 11.5 mo after diagnosis. Underwent salvage therapy with transient response and relapse followed by allogeneic stem cell transplant.
    300325FXX69<20% cellularity; NEDCRTwo cycles of HiDAC + CX-01 consolidation on study.
    Relapsed 6 mo after diagnosis and underwent salvage therapy and allogeneic stem cell transplant. Subsequently relapsed again and underwent salvage and second allogeneic stem cell transplant and died of transplant-related complications.
    • HiDAC, high-dose cytarabine; IDAC, intermediate-dose cytarabine; MRD, minimal residual disease; NED, no evidence of disease.