Plerixafor Versus G-CSF in the Treatment of People With WHIM Syndrome
Condition: Myelokathexis; Infections; Neutropenia; Warts; Hypogammaglobulinemia
MeSH terms: Neutropenia; Agammaglobulinemia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Plerixafor; G-CSF
Intervention type(s): Drug; Drug
Intervention description(s): Twice daily low dose injection for 14 months.; Twice daily low dose injection for 14 months.
Other intervention name(s): Mozobil; Neupogen
Intervention MeSH terms: Plerixafor
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Immunodeficiency; Neutropenia; Mozobil; Myelokathexis; Warts