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Targeted Therapy for WHIM Syndrome Shows Promise
NIAID study is the first to examine long-term use of plerixafor in any disease

A team of researchers at NIAID provide encouraging evidence for treating WHIM syndrome, a rare primary immune deficiency disease, with the drug plerixafor. Their study appears in the February 12, 2014, online issue of Blood.

Background

WHIM syndrome is a rare genetic disease of the immune system. Its name is derived from its symptoms: warts, hypogammaglobulinemia, infections, and myelokathexis. Hypogammaglobulinemia is a deficiency in specific infection-fighting antibodies in the blood. Myelokathexis refers to the failure of neutrophils, infection-fighting white blood cells, to move from the bone marrow into the bloodstream, where they can patrol the body. WHIM syndrome patients also have trouble distributing most other types of immune cells to the blood. Such defects in the immune system predispose WHIM syndrome patients to frequent bacterial and viral infections, persistent skin and genital warts, and an increased risk of developing cancer caused by human papillomavirus.

WHIM syndrome patient’s bone marrow sample (left) and blood sample (right).
WHIM syndrome patient’s bone marrow sample (left) and blood sample (right). Pink cells are red blood cells, and blue cells are other blood cells including white blood cells (WBCs). WHIM syndrome is caused by mutations that trap WBCs in the bone marrow. Without circulating WBCs, patients are susceptible to infections and warts. Credit: NIAID Laboratory of Molecular Immunology.

In 2003, researchers at Mt. Sinai School of Medicine discovered that WHIM syndrome is caused by mutations in the CXC chemokine receptor 4 (CXCR4) gene. One of the many functions of CXCR4 is to tether white blood cells to the bone marrow. WHIM mutations result in excessive CXCR4 receptor activity, which further traps the cells.

In 2011, NIAID investigators led by Philip Murphy, M.D., and David McDermott, M.D., first tested the drug plerixafor in WHIM syndrome patients over the course of one week. Plerixafor, which blocks the activity of CXCR4, is approved by the Food and Drug Administration to mobilize blood-forming stem cells from the bone marrow for collection and eventual transplantation after cancer therapy. Because it can mobilize immune cells to the blood in healthy people, it was considered an ideal drug candidate for treating patients with WHIM syndrome. Consistent with this, in their 2011 study, the NIAID researchers observed that plerixafor restored the level of circulating white blood cells in their patients and was well tolerated. A study with similar results was published at the same time by scientists at the University of Washington. However, neither study was long enough to evaluate whether the treatment is safe or effective in preventing infections or treating warts in these patients.

Results of Study

In the latest study, the same NIAID scientists analyzed the safety and effectiveness of plerixafor in treating WHIM syndrome over the course of 6 months, the longest period of time that plerixafor has been evaluated in any disease. They gave three adult WHIM syndrome patients low-dose plerixafor twice daily. The drug increased the numbers of white blood cells in the bloodstream, not only of neutrophils but also lymphocytes and monocytes, within hours of treatment and throughout all 6 months.

During the 6 months of treatment, patients had a lower incidence of infection, with two of the three patients experiencing no infections at all. When patients were given imiquimod in addition to plerixafor to treat warts, new warts did not appear and some warts decreased in size or disappeared, indicating that plerixafor may be better than current standard therapy. No serious side effects from plerixafor were observed, and the drug was better tolerated than the current standard therapy for WHIM syndrome. By focusing on the underlying molecular defect, this study shows that genetic disorders may be treated through a drug-targeted approach.

Significance

Standard therapy for WHIM syndrome using intravenous immunoglobulin, a blood product containing antibodies, or granulocyte colony-stimulating factor (G-CSF), an immune-cell-growth molecule, does not target the CXCR4 defect, is difficult to administer, and is not completely effective. NIAID scientists provide evidence that plerixafor, which blocks CXCR4 activity, may be a more effective targeted therapy.

Long-term use of plerixafor to treat WHIM syndrome or any disease raises safety concerns, because CXCR4 activity is necessary for normal development and immunity. This study is the first clinical trial examining long-term use of plerixafor in any disease, and it shows that low-dose plerixafor, designed to reduce but not eliminate CXCR4 activity, appears safe over the course of 6 months.

Next Steps

The researchers are planning a longer clinical trial to further assess the safety of plerixafor and to directly compare its effectiveness to standard therapy. This trial will involve a larger group of WHIM syndrome patients, including children.

Reference

McDermott DH, Liu Q, Velez D, Lopez L, Anaya-O’Brien S, Ulrick J, Kwatemaa N, Starling J, Fleisher TA, Priel DL, Merideth MA, Giuntoli RL, Evbuomwan MO, Littel P, Marquesen MM, Hilligoss D, DeCastro R, Grimes GJ, Hwang ST, Pittaluga S, Calvo K, Stratton P, Cowen EW, Kuhns DB, Malech HL, and Murphy PM. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood (2014).

Dr. Murphy's lab page

Last Updated February 12, 2014

Last Reviewed February 12, 2014