Plerixafor for the Treatment of WHIM Syndrome

Abstract

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).

Figure 1.. Hematologic Improvement during Long-Term, Low-Dose Plerixafor Treatment.

The periods of treatment with granulocyte colony-stimulating factor (G-CSF) and plerixafor are demarcated by the red and blue bars at the top of each corresponding column of graphs. The dotted portion of the red line for Patient 1 denotes the time when high-dose G-CSF treatment (300 μg subcutaneously every day) was interrupted owing to severe thrombocytopenia and the drug was given at a reduced dose (150 μg subcutaneously every other day) only during episodes of cellulitis. Horizontal dashed black lines in each graph designate the upper and lower limits of the normal range for each variable, as determined by the National Institutes of Health (NIH) Clinical Center Clinical Hematology Laboratory. Baseline values were assessed when neither drug was being taken (solid circles). All values for Patients 1 and 2 at baseline and during plerixafor treatment were determined at the NIH. Peak refers to values obtained approximately 3 hours after plerixafor administration, the time of the peak white-cell count, as defined previously. Trough refers to values obtained approximately 12 hours after a dose of plerixafor was administered. Most white-cell values for Patient 3 were determined at trough by the local provider in Germany owing to travel limitations; exceptions are designated by the peak and trough symbols in the figure key, and these values were determined at the NIH. Values during G-CSF treatment were obtained for Patients 1 and 2 at trough (defined as just before a dose was administered) by the local provider and reported to the NIH.

Figure 2.. Amelioration of Myelokathexis and Myelofibrosis during Long-Term, Low-Dose Plerixafor Treatment.

Core bone marrow–biopsy samples were obtained from Patients 1 and 3 approximately 3 days before starting plerixafor (before treatment) and 24 and 52 months after starting plerixafor (after treatment) for Patients 1 and 3, respectively. Pretreatment hematoxylin and eosin–stained biopsy samples from both patients show markedly hypercellular marrow with granulocytic hyperplasia, right-shifted myelopoiesis, an elevated myeloid-to-erythroid ratio of approximately 5:1, and abundant neutrophils consistent with myelokathexis. This pattern was found in approximately 90% of the pretreatment marrow but in only 40 to 50% of the post-treatment marrow. The post-treatment images depict areas of normocellular marrow with normal myelopoiesis and a normal myeloid-to-erythroid ratio of 2:1. The pretreatment touch preparations of bone marrow aspirate (Wright–Giemsa stain) show frequent atypical neutrophils with pyknotic nuclear segments connected by thin, wispy strands of chromatin that are characteristic of myelokathexis (red arrows). These neutrophils can still be seen in the post-treatment samples but are less frequent. Both patients had severe myelofibrosis as defined by pretreatment dense reticulin staining of bone marrow; myelofibrosis was ameliorated after plerixafor treatment. All images are at 1000× magnification.

Figure 3.. Amelioration of Skin Pathologic Conditions during Long-Term, Low-Dose Plerixafor Treatment.

Panel A shows the left medial lower leg, left foot, and right medial lower leg of Patient 1 both before starting plerixafor and after 36, 36, and 28 months of plerixafor therapy for the left, middle, and right post-treatment images, respectively. The fingers of Patient 2 are shown before plerixafor was started and after 9 months of treatment, and the hand of Patient 3 is shown before plerixafor was started and after32 months of treatment. Patient 1 had chronic eczematoid dermatitis associated with recurrent cellulitis for 6 years. The left and middle post-treatment images of this patient show resolution of inflammation, with residual areas of hyperpigmentation probably representing uncleared hemosiderin; recurrent cellulitis ceased. The right pretreatment image of this patient shows a chronic inflammatory mass centered at a site of recurrent cellulitis and saphenous-vein insufficiency that was removed surgically 6 months after plerixafor was started. The surgical wound (16×10×2 cm) healed completely (right post-treatment image). Patients 2 and 3 had a reduced cutaneous wart burden after plerixafor therapy. Both patients also received topical imiquimod, and Patient 2 received human papillomavirus (HPV) vaccination during treatment. (For photographs of the hands of Patients 2 and 3 before and after plerixafor treatment, see Fig. S4 in the Supplementary Appendix.) Panel B shows clearance of 17 HPVs and Trichodysplasia spinulosa polyomavirus in Patient 1 after 18 months of plerixafor therapy. The relative abundance of each of the viruses detected is conveyed by the arc length on the donut plot. The number in the center is the number of different HPV types plus polyomavirus species detected (see Table S1 in the Supplementary Appendix for quantitative details and virus names). Patient 1 was not given imiquimod or other treatments for HPV. He had received HPV quadrivalent vaccination before starting plerixafor and HPV 9-valent vaccination 2 years after starting plerixafor. Those vaccines do not include any HPV types recovered from the patient.