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Decitabine and plerixafor in elderly AML
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Figure 6. Leukemia stem/progenitor cells persist after treatment with decitabine; absence of increase in leukemia stem cells (LSCs) at cycle 3 in responders correlates with longer remissions. (A) Scatter plots representing the fold change in LSCs (CD34+CD38-CD123+CD90-) in the bone marrow at the end of the cycle indicated, relative to the previous time point. (B) Fold change in LSCs in the bone marrow for a subset of responders from cohorts 3A and 3B compar- ing mobilizers and non-mobilizers. (C) Fold change in LSCs in the bone marrow at cycle 3 comparing patients who relapsed before cycle 7 (C <7) to those who relapsed after cycle 8 (C >8); patients who were transplanted or off trial are shown. Each symbol represents a patient, horizontal bar represents the mean, error bars represent the Standard Error of Mean.
cohort, with the objective of using each patient as his/her own control. Mobilization may have been enhanced by additional days of dosing, or by concomitant administra- tion of G-CSF, as recommended for plerixafor’s FDA- approved indication.
The overall response rate of 43% and overall survival of 11 months are consistent with, but not significantly better, than the results from single-agent, 10-day schedules of decitabine reported by our center and others. Responses were seen in poor-prognosis, older patients with AML, including in those with particularly aggressive biological features, such as adverse karyotype, TP53 mutation, or therapy-related disease. Of interest, as has been previous- ly reported with decitabine,17 OS was longer in patients with TP53 mutations, though the small sample size pre- cluded statistical significance. While our data did not con- firm a robust clinical benefit for the addition of plerixafor to decitabine in the doses and schedules investigated, the strong scientific rationale for the combination, the sugges-
tive correlative scientific data, and the safety and feasibil- ity of the approach argue that the concept of CXCR4 blockade in AML therapy should not be abandoned. Strategies for further investigation could include mobiliza- tion with alternative CXCR4 antagonists, such as novel small molecule inhibitors and antibodies, as well as com- bination strategies with G-CSF, E-selectin antagonists, and/or BCL2-inhibitors.
Acknowledgments
The authors would like to acknowledge Genzyme/Sanofi Oncology for research support and providing plerixafor, the inves- tigational product for this trial. The authors are grateful to Wen Xie for expert technical assistance. The authors also gratefully acknowledge contributors to Leukemia Fighters. MG and GR were partially supported by LLS 6427-13, DP2 OD007399, R01 CA102031. Dr. Paul Christos was partially supported by the fol- lowing grant: Clinical and Translational Science Center at Weill Cornell Medical College (UL1-TR000457-06).
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