A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia.
The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR + CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis.
Division of Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA.
Geoffrey L
GL
Uy
Michael P
MP
Rettig
Ibraheem H
IH
Motabi
Kyle
K
McFarland
Kathryn M
KM
Trinkaus
Lindsay M
LM
Hladnik
Shashikant
S
Kulkarni
Camille N
CN
Abboud
Amanda F
AF
Cashen
Keith E
KE
Stockerl-Goldstein
Ravi
R
Vij
Peter
P
Westervelt
John F
JF
DiPersio
D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001596:Benzylamines; D000080027:Cyclams; D003561:Cytarabine / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D012074:Remission Induction; D016879:Salvage Therapy; D015996:Survival Rate; D055815:Young Adult
D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D003561:Cytarabine; D005047:Etoposide; D008942:Mitoxantrone; C088327:plerixafor