Background:

- WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is a rare disease. It can cause cancers, infections, and warts. Researchers want to see if a drug called plerixafor can treat WHIMS.

Objective:

- To compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for preventing infections in people with WHIMS.

Eligibility:

- People ages 10-75 with WHIMS who have a CXCR4 gene mutation.

Design:

• Participants will be screened with a medical history, physical exam, and blood and urine tests. They may have heart and spleen tests and body scans. They may have samples of skin or warts taken. Researchers may take photographs of warts.
• Participants will start twice daily self-injections of G-CSF. Their doctors will decide the dosage.
• Initial Period (4-12 weeks)
• Participants will:
• continue the injections and their usual antibiotics and/or immunoglobulin
• have blood drawn
• keep a daily health diary
• Participants will visit the clinic for 2 days without injections.
• Adjustment Period 1 (8 weeks):
• Participants will:
• continue twice daily injections from home
• continue the daily health diary
• have blood tests every 2 weeks.
• Treatment Year 1:
• Participants will
• receive either plerixafor or G-CSF injections twice daily
• continue the health diary
• have blood tests every 2 months
• visit the clinic about every 4 months
• At the end of year 1, participants will visit the clinic for an evaluation. They will switch to the other study drug. They will have an 8-week adjustment and 1-year treatment period.
• At the end of year 2, participants will visit the clinic to complete their injections and go back to their previous G-CSF regimen. Participants will continue their daily health diary and have blood tests for 5-6 months.

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.

• INCLUSION CRITERIA:

Subjects are eligible to enter the study if they meet all of the following criteria:

1. Age greater than or equal to 10 and less than or equal to 75 years.

2. Heterozygous mutation in the C-tail of CXCR4 in addition to a clinical diagnosis of WHIMS.

3. Documented neutropenia with a baseline ANC below 1500 cells/microL of blood.

4. History of severe and/or recurrent infections.

5. Willingness to interrupt G-CSF medication, 2 days prior to study drug injection.

6. Must have a local medical provider for medical management.

7. Must be willing to provide blood, plasma, serum, and DNA samples for storage.

8. All study subjects must agree not to become pregnant or impregnate a female. Women of childbearing potential must agree to take appropriate steps to avoid becoming pregnant for the duration of the study. Participants in whom pregnancy is biologically possible must use at least 2 study approved methods of contraception, one of which must be a barrier method, and must continue contraception until 5 months after stopping the study drug:

   • Male or female condoms with a spermicide,
   • Diaphragm or cervical cap with spermicide,
   • Intrauterine device,
   • Contraceptive pills or patch, Norplant, Depo-Provera or other FDA-approved contraceptive,
   • Male partner with vasectomy and documented aspermatogenic sterility.

9. Willingness to comply with the study medications, visits, and procedures, as deemed necessary by the principal investigator (PI).

EXCLUSION CRITERIA:

If any of the following exclusion criteria are met, a subject will not be enrolled in this study:

1. Neutropenia due to maturation defects in the myeloid lineage or a type of neutropenia, which in the investigator s opinion, is unlikely to improve from the medication administered in this study.
2. Pregnant or breast-feeding women.
3. Known hypersensitivity to plerixafor, G-CSF, or any components of the products.
4. Predisposition to or history of life-threatening cardiac arrhythmia.
5. Requiring dialysis or having markedly impaired renal function with a Creatinine Clearance (CrCl) <15 mL/min.
6. Condition that in the investigator s opinion places a subject at undue risk by participating in the study.

up to 14 months on each study drug

Definitions were identical to those as listed on clinicaltrials.gov. Adverse events were obtained from repeated in-person participant evaluation approximately every 4 months and laboratory testing approximately every 2 months during each drug treatment.

1. Highly variable disease phenotypic expression made crossover design optimal but a placebo arm was not included due to infection risk of severe neutropenia
2. Prophylactic supplemental immunoglobulin and antibiotics were allowed
3. Tolerance of G-CSF was insured prior to randomization but plerixafor was never used before randomization in 17/19 patients,
4. Non-inferiority analysis of primary endpoint was not planned because there were no defined equivalence margins