Plerixafor, G-CSF and Azacitidine For The Treatment Of MDS: Results Of a Phase I Trial
Authors: Schroeder Mark A. , Grillot Marcus , Reineck Teresa , Jacoby Meagan A , Romee Rizwan , Pusic Iskra , Welch John , Uy Geoffrey L. , Cashen Amanda F , Stockerl-Goldstein Keith E. , Vij Ravi , Kulkarni Shashikant , Westervelt Peter , Walter Matthew J. , Dipersio John F. 
Published: October 2019

Abstract
Azacitidine has been shown to prolong survival and delay progression to leukemia in intermediate-2 and high risk myelodysplastic syndrome (MDS) in a randomized study compared to best supportive care. The combination of G-CSF and plerixafor is synergistic in increasing the release of stem and progenitor cells from the bone marrow through disruption of critical bone marrow stromal interactions including the CXCR4 / CXCL12 axis. The interaction of bone marrow stromal cells with the MDS tumor clone may play a roll in pathogenesis and response to treatment. We hypothesized that resistance of MDS to azacitidine may be related to MDS tumor and BM-stromal cell interactions, and disruption of these interactions by treatment with plerixafor + G-CSF could enhance sensitivity to azacitidine, thus improving complete and partial response rates.
We conducted a phase I trial to investigate the safety and tolerability of plerixafor + G-CSF in combination with azacitidine in adult (18 years or older) MDS patients. Secondary objectives included response rates and biologic correlates evaluating: kinetics, phenotype, cell cycle status and kinetics of mobilization of MDS blasts compared to normal stem cells in select patients with informative cytogenetics. Major inclusion criteria included MDS defined by WHO criteria, 5 – 20% blasts on bone marrow aspirate, and at least one cytopenia in one cell lineage. Subjects receiving prior hypomethylating therapy were allowed. A standard 3+3 trial with 3 cohorts (320, 440, and 560 mcg/kg/day SC) was conducted. Dose limiting toxicity was defined as grade 3 or higher non-hematologic toxicity and hematologic toxicity of leukostasis or tumor lysis. Myelosuppression, infection, grade III nausea, fatigue, weight loss and electrolyte abnormalities were not considered dose limiting. Subjects initially received G-CSF 10 mcg/kg subcutaneous (SC) daily D1 – D8, plerixafor SC daily D3 – D8 and azacitidine 75mg/m2 SC D3 – D8, 4 hours after plerixafor administration. The trial was amended after the first 3 subjects to reduce G-CSF dose and administration to 5 days.

Results
Two of the first three subjects enrolled in cohort 1 (320 mcg/kg/d plerixafor) had leukocytosis. The trial was amended to reduce the G-CSF dose (10 mcg/kg to 5 mcg/kg) and duration (8 days to 5 days) because of this. One subject had symptoms of leukostasis with a WBC reaching nearly 100K/uL and a subsequent subject developed hyperleukocytosis (WBC = 80K/uL) without leukostasis. The trial was amended to reduce the G-CSF to 5 days concurrent with plerixafor and azacitidine along with defining dose holding parameters for G-CSF and plerixafor if the peripheral blood WBC exceeded 40K/uL or if absolute blast count exceeded 10K/uL. Since amendment of the trial, 64 subjects have been screened and 20 subjects have been enrolled and are evaluable. Subjects included 65% males, median age 67, and MDS diagnosis at study entry including 6/18 (33%) RAEB-1 and 12/18 (67%) RAEB-2. 5/18 subjects (28%) had plerixafor and G-CSF held during treatment because of leukocytosis. 9/18 subjects (50%) had received no prior treatment for their MDS. DLTs were experienced in Cohort 1 related to thrombocytosis (n =1) and in Cohort 2 related to atrial fibrillation (n = 1) with near syncope. Major non-hematologic grade 3 or 4 adverse events included epistaxis, hypocalcemia, GI bleed, headache, dyspnea, infection with neutropenia, and bone pain. The MTD was determined to be 560mcg/kg plerixafor SC with no subjects (n = 6) in this cohort experiencing a DLT. The median number of cycles completed was 3. Reasons for stopping treatment included progression to leukemia (n = 6), physician choice (n = 2), withdrawal of consent (n = 1), adverse event (n = 2). Best response in those evaluable after completing 2 cycles of treatment (n = 14) showed marrow CR in 5/14 (36%, 3 in those not previously treated for MDS), stable disease in 5/14 (36%) and progressive disease 4/14 (29%).

Conclusion
Plerixafor plus G-CSF in combination with azacitidine was well tolerated in the studied MDS patients when given over 5 days and may be associated with encouraging response rates. Correlative studies are ongoing to evaluate changes in cell cycle, apoptosis and preferential mobilization of blasts using this regimen. We are currently enrolling an expanded cohort of 7 subjects at the MTD dose to evaluate preferential mobilization of blasts with plerixafor alone in cases using informative cytogenetics.

Disclosures:
Schroeder: Celgene: Research Funding; Sanofi Oncology: Research Funding. Off Label Use: Plerixafor and G-CSF for the treatment of MDS. Welch:Eisai: Research Funding. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau.