Abstract

The microenvironment emerged as an attractive therapeutic target for chronic lymphocytic leukemia (CLL) given increasing evidence of its essential role in CLL cell survival. Plerixafor, a small molecule inhibitor of the CXCR4 receptor, is responsible for homing CLL to the microenvironment via a concentration gradient of its cognate ligand CXCL12 and has been safely tested in CLL patients. Lenalidomide is an immunomodulatory small molecule with efficacy in CLL, though monotherapy responses are typically partial and delayed. The combination of plerixafor with lenalidomide offers a novel non-cytotoxic alternative to improve clinical activity. Laboratory correlatives were designed to improve understanding of the effects of individual and combination therapy on the biology of CLL, assess for CLL mobilization from the microenvironment, and discover targetable drug resistance mechanisms to improve therapeutic efficacy.

In this single institution phase I clinical trial, subjects were dose escalated on lenalidomide before initiation of plerixafor (Fig. 1). Primary safety response assessment was after one month of combination therapy. After four cycles of combination therapy, the primary response assessment was performed. Peripheral blood was collected for correlates and included an extended CLL phenotype panel (CLL cell-surface markers, CD184/CXCR4, sIgM, CD38, CD40, CD52, CD80, CD86, CD95) by flow cytometry with analysis of CLL subpopulations by CXCR4 expression levels. Phosphoprotein analysis was performed by phosphor-flow cytometry (phosflow).

Fifteen subjects were enrolled with 10 subjects initiating plerixafor. Subjects included 4 females with a median 62 years of age and 4 prior lines of therapy. Two dose limiting toxicities (neutropenia, thrombocytopenia) occurred in plerixafor dose level two. Four patients reached primary response assessment. One patient had a PR and three patients had SD, however, all assessed patients derived improvement in nodal mass and disease symptoms. Phenotyping demonstrated a statistically significant decrease in CD20 and an increase in CD40 and CD95 for subjects initiating plerixafor. For the four subjects completing to end of study (EOS), the statistically significant decline in CD20 continued and CD95 and CD52 declined significantly. In all subjects, the proportion of CLL expressing high CD184/CXCR4 decreased significantly by four hours after plerixafor administration (Fig. 2). Phosflow for subjects initiating plerixafor revealed significant increases in phosphorylation of p-Akt, p-Mek, and p-Erk with decreases after plerixafor addition. For subjects reaching EOS, there was a significant decline in p-Syk from time of plerixafor addition but an increase in p-Akt.

Lenalidomide plus plerixafor is a novel non-cytotoxic therapeutic alternative with an acceptable safety profile in heavily pretreated CLL patients. Grade 3/4 toxicities (and DLTs) were predominantly related to myelosuppression. Though the study is ongoing, the first two patients of cohort 3 have reached safety response assessment without a DLT; therefore a minimum total of 5 subjects were safely treated at dose level one (plerixafor 0.24mg/kg) and it was identified as the MTD. Plans are to proceed to a phase II trial to evaluate efficacy. Early responses among patients able to escalate lenalidomide to 10mg target dose are encouraging given the duration subjects remained on trial without progression. Correlates support mobilization of CLL from the microenvironment with decreases in CXCR4 expression and downstream signaling. Increases of CD40, CD80 and CD86 on lenalidomide monotherapy suggest immunomodulatory actions. Ongoing study will confirm observed trends, and improve understanding of response and resistance mechanisms for translation into optimized treatment strategies.

Disclosures:

Brander:Celgene: Research Funding, Research Fund provided to lab but not author Other. Off Label Use: Lenalidomide and Plerixafor are being studied in this Phase I clinical trial but have not been FDA approved for the indication of CLL. Allgood:Celgene: Research Funding. Lanasa:Celgene: Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.