A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

Abstract

• Plerixafor can be given safely to WHIM syndrome patients twice daily for a 6-month period and appears promising as a treatment.Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G proteincoupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1-to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. However, long-term safety and long-term hematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which 3 adults with WHIM syndrome self-injected 0.01 to 0.02 mg/kg (4% to 8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785. (Blood. 2014;123(15):2308-2316

Molecular Pathways: Targeting the CXCR4–CXCL12 Axis—Untapped Potential in the Tumor Microenvironment

“…Another phase I study demonstrated a durable increase in circulating leukocytes, fewer infections, and improvement in warts in combination with topical imiquimod in 3 patients with WHIM syndrome who self-injected a low dose of plerixafor (4% to 8% of the FDA-approved dose) s.c. twice daily for 6 months (26). However, despite the fact that B cells and T cells were mobilized to blood, and that na€ ve B cells underwent class switching in vitro, no improvement was seen in Ig levels or vaccine responses (26). Thus, it appears that alternate dosing regimens or a more longlasting CXCR4 antagonist will be required to achieve more durable activity that may in turn provide more stable levels of immune cells in the blood to enhance adaptive immune function.…”

How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome

“…31,32 More recently, a phase 1 study of subcutaneously selfinjected plerixafor at 0.01 mg/kg twice per day in 3 WHIM patients for 6 months appeared to be both safe and efficient. 33 In particular, this treatment led to durable increases in the leukocyte and lymphocyte counts, even though the leukocyte and lymphocyte counts oscillated during the treatment and exhibited large differences between the peak and trough values. Although the monocyte and neutrophil counts were less variable, both results were likely related to the rapid pharmacokinetics of plerixafor (T1/2 5 5 hours).…”

“…Recently, preliminary results with plerixafor seem promising in terms of controlling the risk for infections, including respiratory events. 33 Meanwhile, the prompt diagnosis and antibiotic treatment of any bronchial infection is strongly recommended. When bronchiectasis is present at diagnosis, treatment may be centered on the prevention of exacerbations, prompt management of pulmonary infections, guidance by sputum culture results, and optimization of the clearance of airway secretions with regular chest physiotherapy.…”

“…Although the monocyte and neutrophil counts were less variable, both results were likely related to the rapid pharmacokinetics of plerixafor (T1/2 5 5 hours). 33 Notably, plerixafor received the orphan drug designation status by the European Medicine Agency.…”

“…47 Encouraging results have recently been obtained by McDermott et al in their phase 1 clinical trial based on the long-term (6 months) administration of low doses (0.01 to 0.02 mg/kg, subcutaneously and twice daily) of the anti-CXCR4 plerixafor, which, in combination with imiquimod, resulted in effectively improving warts. 33 The frequent and aggressive evaluation by a dermatologist is strongly recommended for any suspicious skin lesion in WHIM patients of any age.…”