Mobilization of Leukemic Cells Using Plerixafor as Part of a Myeloablative Preparative Regimen for Patients with Acute Myelogenous Leukemia Undergoing Allografting: Assessment of Safety and Tolerability

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myelogenous leukemia (AML); however, a major cause of treatment failure is disease relapse. The purpose of this single-center Phase I study was to determine the safety and tolerability of administration of the CXCR4 inhibitor plerixafor (Mozobil; Sanofi Genzyme) along with myeloablative conditioning in patients with AML undergoing allogeneic HCT. The rationale was that plerixafor may mobilize leukemic stem cells, making them more susceptible to the conditioning chemotherapy (registered at ClinicalTrials.gov; identifier NCT01141543). Three patients were enrolled into each of 4 sequential cohorts (12 patients total). Patients in the first cohort received 1 dose of plerixafor (240 mg/kg s.c.) before the first dose of fludarabine and busulfan, and subsequent cohorts received injections before 2, 3, and 4 days of conditioning chemotherapy. The median age at HCT was 49 years (range, 38 to 58 years). All patients engrafted following HCT, with an absolute neutrophil count .5 £ 10 9 /L observed at a median of 14 days (range, 11 to 18 days). Adverse events possibly related to plerixafor were transient and not severe. Main adverse events following the injection were nausea and dizziness in 4 patients (33%) and fatigue in 4 patients (33%). Among the 12 patients, 2 patients (17%) relapsed post-HCT and 6 (50%) were alive at the last follow-up. The median followup of survivors was 67 months (range, 53 to 82 months). In conclusion, plerixafor administration is safe and well tolerated when included in a myeloablative conditioning regimen for allogeneic HCT for AML. Further study in a larger cohort is warranted for the investigation of the impact of plerixafor on post-allogeneic HCT outcomes.

Role of CXCR4 in the progression and therapy of acute leukaemia

“…Six patients died due to infection (n = 3), relapse (n = 2), or chronic GVHD (n = 1), and the remaining patients maintained continuous CR. 149 Thus, the addition of CXCR4 antagonists in conditioning was well-tolerated and associated with increased myeloid chimerism.…”

Targeting CXCR4 in AML and ALL

“…In follow-up correlative studies, a negative correlation between survival and the percentage of AML blasts before and after conditioning was reported ( 122 ). The second trial included 12 adults with AML in first remission who underwent allogeneic HCT after receiving conditioning with plerixafor, busulfan, fludarabine, and 400 cGy total body irradiation (NCT01141543) ( 120 ). Plerixafor was administered 6 h before fludarabine and busulfan for up to 4 consecutive days (days−5 to −2 pre-HCT).…”

“…Plerixafor was administered 6 h before fludarabine and busulfan for up to 4 consecutive days (days−5 to −2 pre-HCT). Of the 12 patients enrolled, only two experienced disease relapse post-transplantation and six were alive at a median follow-up of 67 months ( 120 ). In the third trial, plerixafor was included as part of a myeloablative conditioning regimen for 12 pediatric patients with rrAML undergoing a second allogeneic HSCT (NCT01068301) ( 121 ).…”

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

“…At present, CXCL12-CXCR4 inhibitors are explored in preclinical and clinical studies. Among those, clinical trials with Plerixafor are the most promising, as this CXCR4 antagonist efficiently mobilizes leukemic cells from BM to peripheral blood, thereby making them better targetable by conventional chemotherapy [54][55][56][57][58].…”