Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia

Abstract

Acute myeloid leukemia carries a dismal prognosis in older patients. The objective of this study was to investigate the safety and efficacy of decitabine combined with the CXCR4 antagonist plerixafor in newly diagnosed older patients with acute myeloid leukemia and to evaluate the effects of plerixafor on leukemia stem cells. Patients were treated with monthly cycles of decitabine 20 mg/m2 days 1–10 and escalating doses of plerixafor (320–810 mcg/kg) days 1–5. Sixty-nine patients were treated, with an overall response rate of 43%. Adverse karyotype did not predict response (P=0.31). Prior hypomethylating agent treatment was the strongest independent predictor of adverse overall survival (hazard ratio 3.1; 95%CI: 1.3–7.3; P=0.008) and response (14% in previously treated patients, 46% in treatment naïve; P=0.002). As expected, the most common toxicities were myelosuppression and infection. Plerixafor induced mobilization of leukemia stem and progenitor cells, but did not cause clinically significant hyperleukocytosis. Reduction in leukemia stem cells appeared to correlate with duration of response. Plerixafor can be safely added to decitabine in poor-prognosis, elderly acute myeloid leukemia patients. The maximum tolerated dose of the combination was 810 mcg/kg. While mobilization of leukemia stem cells was observed in some patients, the clinical benefit of adding plerixafor was uncertain. This trial was registered at clinicaltrials.gov identifier: 01352650.

Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?

“…Importantly, the addition of GMI-1271 to standard induction chemotherapy did not result in excess toxicity and 30-day and 60-day mortality rates of 8% and 12%, respectively, appear to be comparable to those observed with 7 + 3 induction in routine clinical practice [ 114 , 115 ]. Similar preclinical and clinical results have been reported for the CXCR4 antagonist plerixafor that has been combined with both intensive chemotherapy and hypomethylating agents with an acceptable safety profile (NCT01352650, NCT01435343) [ 116 , 117 , 118 ]. However, a major concern with inhibitors of cell adhesion is the potential of worsening hyperleukocytosis as they could lead to increased mobilization of leukemic blasts from the bone marrow.…”

“…However, a major concern with inhibitors of cell adhesion is the potential of worsening hyperleukocytosis as they could lead to increased mobilization of leukemic blasts from the bone marrow. Notably, inhibition of CXCR4 did not lead to hyperleukocytosis in clinical trials [ 118 ]. VLA-4 serves as an another therapeutic target with two inhibitors (AS101 and FNIII14) having shown to promote chemotherapy sensitivity in in vitro studies leading to a phase II trial in human AML and MDS patients [ 50 , 119 ].…”

Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia

“…In elderly patients, plerixafor was tested for its potential to induce sensitization of LSC to decitabine (NCT01352650). Plerixafor triggered LSC mobilization, however, these cells persisted in the bone marrow during treatment, and patients with more than 2-fold increase in LSC at cycle 3 relative to the previous study point relapsed before completing 7 cycles of therapy (Roboz et al, 2018). Overall response rate to this treatment was 43% and overall survival was 11 months, similar to previous reports of decitabine, which makes its benefit uncertain (Roboz et al, 2018).…”

Potential Epigenetic-Based Therapeutic Targets for Glioma

“…In tumor cells, 5-aza-2′-deoxycytidine is blended with DNA in the form of phosphate, and then inhibit DNMT activity, eventually leading to the desired low methylation status to exert antitumor effects (Sun et al, 2011 ). Currently the clinical research of 5-aza-2′-deoxycytidine is limited in leukemia (Roboz et al, 2018 ) and part of solid tumors (Garrido-Laguna et al, 2013 ; Fan et al, 2014 ; lung cancer, etc., not including glioma). For glioma treatment, most of the studies with 5-aza-2′-deoxycytidine are still in pre-clinical research stage (Oi et al, 2009 ; Zhang et al, 2014 ).…”