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and 46 weeks, respectively.3 Similar results have been achieved in other single-center trials using single-agent decitabine in a 10-day schedule, including at our own cen- ter.4,5 Still, since most newly-diagnosed AML patients treated with decitabine generally relapse within 6-18 months, and overall median survival is less than one year, a variety of potentially synergistic agents are under inves- tigation.
Acute myeloid leukemia originates from a rare popula- tion of leukemia stem cells (LSCs) that are capable of self- renewal, proliferation, and differentiation into malignant blasts. LSCs and leukemic blasts can persist after treatment and contribute to disease relapse.6 Drugs that release LSCs and blasts from their protective microenvironment may leave them more vulnerable to therapy, as they are strongly dependent on the bone marrow niche for proliferation and survival.7 CXCR4, the chemokine receptor for stromal cell- derived factor 1 (CXCL12/SDF-1), is a critical component of the bone marrow niche and is expressed on both normal stem cells and AML blasts. The CXCR4/SDF-1 axis in AML promotes leukemic cell homing to the marrow, as well as in vivo growth.8,9 Plerixafor, a small molecule antag- onist of CXCR4, is commercially available as a stem cell mobilizing agent and is approved by the US Food and Drug Administration (FDA) for use in combination with granu- locyte-colony stimulating factor (G-CSF) for patients with multiple myeloma or non-Hodgkin lymphoma undergoing autologous stem cell transplantation (Mozobil, Sanofi- Aventis). Plerixafor blocks CXCR4-mediated signaling and significantly decreases the survival of AML cells in vitro. Plerixafor has been safely combined with cytotoxic chemotherapy in several studies of patients with relapsed/refractory AML.10-12 While mobilization of leukemic blasts was achieved, these trials were not ran- domized and, thus, the impact of plerixafor on clinical out- comes was unclear. The objective of this investigator-initi- ated clinical trial was to investigate the safety and efficacy of adding plerixafor to decitabine in newly diagnosed older patients with AML. Extensive correlative scientific studies were performed to determine the effects of plerixafor on the mobilization of LSCs and leukemic progenitor cells.
Methods
This trial was registered at clinicaltrials.gov identifier: 01352650 and was approved by the Institutional Review Board of Weill Cornell Medical College. The study was performed in accordance with the Declaration of Helsinki, and all subjects provided written informed consent.
as per the FDA package insert for plerixafor.
The trial was designed as an open-label, phase I feasibility study
to optimize mobilization of leukemia stem and progenitor cells using a fixed dose and schedule of decitabine combined with esca- lating doses of plerixafor. Based on previous data, it was expected that patients would require between 1-4 10-day cycles of decitabine to achieve clinical response. Plerixafor was adminis- tered during alternating treatment cycles, which allowed each patient to serve as his/her own “control” for measurements of mobilization and other correlative scientific studies. Half of the patients received plerixafor during odd-numbered treatment cycles, and half during even-numbered cycles, as the optimal tim- ing of plerixafor administration was unknown.
Treatment schedule
Patients were treated according to the schedule in Figure 1. Ninety-three patients were screened and 69 were enrolled onto the trial. Prior to protocol treatment, patients were treated with hydroxyurea to reduce the total white blood cell count to <30 x109/L. Up to 4 induction cycles of decitabine, with or without the addition of plerixafor, were permitted, with 28-56 days between the starting days of each cycle. Decitabine was administered as an intravenous infusion of 20 mg/m2 over 1 hour (h) on days 1-10 of every treatment cycle. Plerixafor was administered 4 h prior to decitabine, during alternating treatment cycles: schedule A patients received plerixafor during even-numbered cycles and schedule B patients received plerixafor during odd-numbered cycles. There were three dosing cohorts of plerixafor. Cohorts 1, 2 and 3 received 320, 540, and 810 μg/kg of plerixafor intravenous- ly on days 1-5, respectively, during alternating treatment cycles. All patients in all groups were treated with decitabine at the same dose and schedule. Patients with evidence of clinical benefit from treatment, including improved blood counts, reduced transfusion requirements, and/or improved performance status were eligible for treatment with ongoing monthly maintenance cycles of five days of decitabine, with plerixafor administered during alternate cycles according to the same dose and schedule as during induc- tion. Patients were treated with antibiotics, transfusions, and other supportive care measures as per institutional guidelines. The use of erythropoietic growth factors was not permitted. GSCF was permitted at the discretion of the investigator, but could not be administered on the same days as plerixafor. Plerixafor was provided by Genzyme Inc., which was later acquired by Sanofi Oncology.
Safety assessments
Patients were hospitalized for daily laboratory and clinical mon- itoring, as per institutional practice. Adverse events were reported using the National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) v.4.0. A data and safety monitoring board (DSMB) was established as per the guidelines of Weill Cornell Medical College, and assessments of dose-limiting toxicity (DLT) were made in conjunction with the Data and Safety Monitoring Board.
Response assessments
Responses were determined using the International Working Group criteria.15 Complete remission (CR) was defined as a decrease in bone marrow blasts to less than 5% and absence of blasts in the peripheral blood, coupled with recovery of the absolute neutrophil count (ANC) to ≥1.0x106/mL and platelet count to ≥100x106/mL. Patients who met all criteria for CR except ANC or platelet recovery were defined as CR with incomplete peripheral blood count recovery (CRi). Partial response (PR) was defined as a ≥50% reduction in bone marrow blasts.
Patient selection and study design
The study population included patients ≥60 years old with newly diagnosed, pathologically confirmed AML, as defined by World Health Organization criteria.13 Patients with an antecedent hematologic disorder or therapy-related myeloid neoplasm were included, but those with acute promyelocytic leukemia or favor- able risk cytogenetics according to the European LeukemiaNet (ELN) criteria were excluded from participation.14 Patients with a history of prior treatment with either decitabine or plerixafor, and those undergoing active treatment for a concomitant malignancy were also excluded. There were no mandatory requirements for organ system function or performance status, but patients with a calculated CrCl of ≤50 mL/min using the Cockcroft-Gault formula had a dose reduction of plerixafor by one-third during that cycle,
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Decitabine and plerixafor in elderly AML
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