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M. Steurer et al.
baseline, corresponding to a 200% increase, occurred at 24 h and CLL cell mobilization was effectively maintained for at least 72 h (Figure 2A,B). Simultaneously, CXCR4 expression on CLL cells gradually increased during the intravascular circulation of CLL cells peaking at 24 h (Figure 2C). In cycle 4, mobilization was evaluated in 24 patients and, similarly to the pilot phase, CLL cells were mobilized already 1 h after olaptesed pegol treatment with 187 CLL cells/μL above baseline (mean baseline level: 224 CLL cells/μL). Mobilized CLL cell numbers grad- ually increased, peaking at 24 h with 679 CLL cells/μL on average above baseline, corresponding to a >300% increase (Figure 2D,E) accompanied by a steady CXCR4 increase on CLL cells (Figure 2F).
Safety
Olaptesed pegol was safe and well tolerated as monotherapy with no serious adverse events reported in the pilot phase. All patients were escalated to the highest anticipated dose of 4 mg/kg olaptesed pegol, which was previously established in healthy volunteers as safe and effi- cacious in terms of lymphocyte mobilization.1 Common adverse events (≥10%) observed in the trial are shown in Table 3. The most frequent adverse event observed on BR alone is neutropenia with grade 3/4 events recorded in up to 50% of the patients.14-17 The triple regimen of olaptesed pegol in combination with BR does not seem to increase the incidence of grade 3/4 neutropenia, with a 50% incidence reported in this study. The incidences of grade 3/4 anemia and thrombocytopenia were low (14.3% each). There were
very few non-hematologic grade 3/4 toxicities and these were mostly reported by single patients (nausea 3.6%, con- stipation 3.6%, abdominal pain 3.6%, pyrexia 3.6%, fatigue 3.6%, hyperuricemia 7.1% and cytokine release
Figure 1. Plasma concentration-time curves of olaptesed pegol after adminis- tration of single intravenous doses (pilot phase, monotherapy). Data are shown as geometric means.
ABC
DEF
Figure 2. Mobilization kinetics of chronic lymphocytic leukemia cells and their CXCR4 expression levels after administration of olaptesed pegol. (A) Baseline values were set to 0 and chronic lymphocytic leukemia (CLL) cell counts above baseline are depicted as mean and standard error of mean (SEM) after administration of olaptesed pegol alone to ten patients in the pilot phase. (B) Baseline values were set to 100% and CLL cell mobilization above baseline is depicted in percent after administration of olaptesed pegol alone to ten patients in the pilot phase. (C) Mean fluorescence intensity (MFI) of CXCR4 expression on CLL cells was set to 100% at baseline and changes in MFI are depicted in percent for ten patients in the pilot group. (D) Baseline values were set to 0 and CLL cell counts above baseline are depicted as mean and SEM after administration of olaptesed pegol in combination with bendamustine and rituximab (BR) for 24 patients in cycle 4. (E) Baseline val- ues were set to 100% and CLL cell mobilization above baseline is depicted in percent after administration of olaptesed pegol in combination with BR for 24 patients in cycle 4. (F) MFI of CXCR4 expression on CLL cells was set to 100% at baseline and changes in MFI are depicted in percent (whisker plots for 24 patients in cycle 4.
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haematologica | 2019; 104(10)