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Safety and efficacy of plerixafor in SCD patients
Table 1. Patients’ characteristics. Dose level
80 μg/kg
160 μg/kg
Age Gender Genotype yrs
33 M SS
21 F SS
29 M SS; thal(1/4) 32 M SS; thal (1/4) 34 M SS; thal (1/4) 25 F SS; thal (1/4)
Subject ID
1
Ethnicity
African- American
2
3 (1*)
4
Hispanic
5
African- American
African- American
African- American
6
7
8 (1*) 9
10
12
13
14
3 (2*)
8 (2*)
25 F SS
37 M SS 32 F SS
46 M SS; thal 38 M SS 23 F SS 27 M SS 31 M SS- thal 38 M SS
(1/4)
No HU HU 17 mg/kg HU 27 mg/kg HU 23 mg/kg No HU HU 27 mg/kg
Clinical complications (in addition to ACS)
Avascular necrosis, retinopathy
≥ 3 vaso-occlusive crises per year ≥ 3 vaso-occlusive crises per year Deep venous thrombosis, priapism Leg ulcers, retinopathy
Leg ulcers, retinal artery occlusion, retinopathy
Cerebral aneurysms (2-3 mm)
Avascular necrosis, retinopathy Avascular necrosis, iron overload, leg ulcers
Leg ulcers, priapism
Avascular necrosis, leg ulcers, priapism Avascular necrosis, retinopathy Avascular necrosis, priapism
≥ 3 vaso-occlusive crises per year Avascular necrosis, retinopathy
Treatment regimen
HU 16 mg/kg HU 26 mg/kg No HU No HU HU 28 mg/kg HU 16 mg/kg
HU 25 mg/kg
HU 27 mg/kg
Chronic transfusion
– No HU
drug-induced mobilization.23,24 However, Richard et al. showed that two of the three SCD patients whose hydroxyurea was withdrawn for 2 weeks developed painful crises following the withdrawal. Given these con- siderations, we designed a prospective phase I dose esca- lation study of both the safety and efficacy of plerixafor in patients with SCD in which the patients continued on their standard outpatient treatment used for disease con- trol. We have completed the dosing cohorts through to the standard plerixafor dose of 240 μg/kg and report the inter- im results here.
Methods
Study design
This study is conducted under FDA IND 122657, registered in ClinicalTrials.gov as NCT02193191, and approved by the Institutional Review Boards of Memorial Sloan Kettering, Weill Cornell Medical College and the New York Blood Center. The study design is a 3 + 3 dose escalation study with six levels of esca- lation: doses of 80, 160, 240, 320, 400, and 480 μg/kg. There are two primary endpoints: (i) efficacy, defined by the achievement of a HPC mobilization level of 30 CD34+ cells/μL; and (ii) safety, defined by the occurrence of serious adverse events (≥ grade 3) that are at least possibly plerixafor-related (including vaso-occlu- siveevents).
At any dose level, the occurrence of at least one grade 3 serious adverse event results in the addition of three more patients to the initial three-patient dosing cohort. The occurrence of two grade 3 serious adverse events at a particular dose-level signifies that the maximal tolerated dose has been exceeded and that the previous dose-level is the maximum tolerated dose. The trial will be stopped upon the occurrence of one grade 4 or 5 serious adverse event at least possibly related to plerixafor. Patients are followed for adverse events for 1 month after administration of the plerix- afor. This design provides the following probabilities of escalation based on the true chance of a dose-limiting toxicity at a specific dose level:
True probability of toxicity 0.10 0.20 0.30 0.40 0.50 0.60
240 μg/kg
*Indicatesfirstandsecondenrollmentsforindicatedsubject. ACS:acutechestsyndrome,;HU:hydroxyurea.
haematologica | 2018; 103(5)
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of the chemokine receptor CXCR4 and prevents binding of its ligand CXCL12 or stromal cell derived factor-1a to induce HPC mobilization.13 We hypothesized that plerix- afor’s mechanism of action would lead to less marked increases in white blood cell (WBC) counts and therefore less cell and coagulation system activation in SCD and supported this with data from a pre-clinical study involv- ing a sickle cell mouse model.14 Nevertheless, the safety of plerixafor in SCD patients remains a matter of concern because of possible activation of WBC and neutrophils which could still lead to vaso-occlusive complications and the risk of early death in SCD.15-19 As CXCR4 is expressed on most WBC and is involved in the retention of these cells in bone marrow, a standard dose of plerixafor of 240 μg/kg increases all major WBC subsets (neutrophils, lym- phocytes, monocytes) in normal donors about 3- to 4- fold.20 Notably, however, in SCD patients who received G- CSF, not all patients who had highly elevated WBC counts experienced vaso-occlusive complications, and conversely, not all patients who experienced vaso-occlusive complica- tions had highly elevated WBC counts,5 suggesting that WBC activation rather than WBC count per se may con- tribute to vaso-occlusion in SCD.
Another issue of concern is whether enough peripheral blood CD34+ cells can be mobilized in SCD patients with plerixafor. The mean and median peak CD34+ counts using plerixafor alone in normal donors are only ~25/μL.13,20 SCD patients might mobilize particularly well, in that SCD patients might have increased circulating HPC even at steady state, although more so during a crisis.21,22 Furthermore, SS and Sβ0 patients tend to be autosplenec- tomized, and data from patients with thalassemia showed that splenectomized patients mobilized about twice as many peripheral blood CD34 cells with plerixafor alone as non-splenectomized patients.23
Another consideration when using plerixafor is whether to withhold hydroxyurea, the recommended standard of care for most SCD patients. Hydroxyurea may inhibit mobilization and withholding hydroxyurea for 2 weeks leads to a degree of spontaneous mobilization that abets
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