Warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency disorder caused by gain-of-function mutations in the gene for the chemokine receptor CXCR4. Normally, CXCR4 is expressed on most leukocyte subsets and functions in part to promote hematopoietic stem cell (HSC) and neutrophil homing to and retention in bone marrow. WHIM mutations alter the CXCR4 carboxyl terminus, which enhances and prolongs receptor signaling. As a result, egress of normally produced and functional neutrophils from the bone marrow to the blood is impaired causing neutropenia, a bone marrow pathologic finding referred to as myelokathexis. A similar mechanism may also affect other leukocyte subsets since WHIM patients usually are panleukopenic. Consequently, WHIM patients are predisposed to frequent acute bacterial infections, especially in the sinopulmonary tract, that may cause chronic morbidity, respiratory insufficiency and in some cases premature death. WHIM patients also have marked difficulty clearing infections with Human Papillomavirus (HPV), resulting in persistent cutaneous and anogenital warts that in several reported cases have evolved into cancer. Several deaths have also occurred due to cancer associated with Epstein -Barr virus (EBV) infection. Therapies currently used for WHIMS are non-specific and expensive, and include Granulocyte Colony-Stimulating Factor (G-CSF) (the drug currently approved by the Food and Drug Administration (FDA) to treat severe congenital neutropenia), intravenous immunoglobulin (IVIg), and prophylactic antibiotics. None of these measures has been formally evaluated for efficacy in WHIM syndrome (WHIMS); however, in our clinical experience based on the treatment of 24 WHIM patients seen at the National Institutes of Health (NIH) since 2006, recurrent bacterial infections continue to occur, despite the fact that the absolute neutrophil count (ANC) can be readily maintained above 500 cells/microliter by G-CSF and IgG levels can be restored to the normal range by IVIg. Thus, there continues to be a major unmet medical need for effective therapy in WHIMS despite the availability and application of best therapy for neutropenia and hypogammaglobulinemia in these patients. Plerixafor (Mozobil ) is a specific small molecule antagonist of CXCR4, licensed by the FDA for HSC mobilization for transplantation in cancer, and is therefore a logical candidate for molecularly targeted treatment of WHIMS. The goal of treatment would be to reduce CXCR4 signaling to normal, not to zero, thus, absent any off-target effects, targeted chronic treatment with this agent may be safe. In this regard, 2 recent short term Phase I dose-escalation studies of plerixafor, one from our group, in a total of 9 patients demonstrated that the drug could safely mobilize not only neutrophils, but also all other leukocyte subsets that are decreased in the blood of WHIM patients. A follow-up Phase I study, conducted by our group, in 3 patients given plerixafor 0.02-0.04 mg/kg/d for 6 months demonstrated that these hematopoietic effects were durable. Moreover, the frequency of infection was reduced on plerixafor as compared to retrospective data mined for the three years before starting therapy and prospective data collected for one year after ending therapy, even though 2 of the patients were taking GCSF during the comparison time periods. No new warts occurred during treatment and several existing warts improved or resolved. Although these results are encouraging, the small number of patients studied, limited duration of drug treatment, and retrospective mining of control data leave open to question whether plerixafor is truly efficacious for clinical outcomes in WHIMS. The randomized, double blinded, crossover trial described here is designed to answer this question by establishing the long-term safety and clinical efficacy (primary endpoint: infection severity; multiple secondary endpoints including wart control) of plerixafor as compared to G-CSF in the treatment of WHIMS patients 10-75 years of age. G-CSF as a comparator is required because of its approved use in patients with severe congenital neutropenia (SCN).

Brief outline of study we intend to randomize 20 patients and treat them in a double-blinded manner for 1 year with G-CSF and 1 year with plerixafor using a crossover design to allow direct comparison of infection severity during treatment with both agents, at doses determined by the patient s individual neutrophil response. A schedule of events has been provided in Appendix A. Data will be analyzed as specified in the Statistics section (Section 14) after randomization. Tolerability and patient drug preference will also be assessed.