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M. Steurer et al.
tribution and metabolism of olaptesed pegol were inde- pendent from disease and combination partner. Rapid increases in CLL cell numbers were observed, with a peak at 24 h, which were maintained for at least 72h. Interestingly, CXCR4 expression on CLL cells gradually increased during the intravascular circulation of CLL cells, also peaking at 24 h. The mobilization efficiency was maintained throughout the cycles with an up to 3-fold increase in CLL cell numbers above mean baseline level in
A
cycle 4. The observed CXCR4 increase that accompanied mobilization reflects the extended circulation of CLL cells in the periphery as described by Calissano et al.5 and rep- resents a pharmacodynamic biomarker for the sustained blockade of CXCL12 by olaptesed pegol. Of note, contin- uous circulation of CLL cells ultimately leads to apoptosis, a phenomenon also called ‘death by neglect’20 due to the fact that CLL cells need to regularly receive their survival signals from the protective niches.5
B
C
Figure 3. Mean lymphocyte counts, chronic lymphocytic leukemia to leukocyte ratio in cycle 1 versus cycle 4 and lym- phadenopathy evaluation. (A) Mean lymphocyte counts (x 103/μL peripheral blood) evaluat- ed at different time points during the pilot phase for ten patients (Pilot) and cycle 1 to cycle 6 for all 28 patients are depicted. (B) The chronic lymphocytic leukemia (CLL) cell to leukocyte ratio evalu- ated at cycle 1 and cycle 4 is depicted for each individual patient. (C) Lymphadenopathy at the end of treatment was assessed in 24 patients who pre- sented with enlarged lymph nodes at screening. *For patients who discontinued treatment before cycle 6 the value at the end of cycle 3 is depicted. PD: progressive disease; PR: partial response; CR: complete response.
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haematologica | 2019; 104(10)