The Natural History of Cyclic Neutropenia: Long-Term Prospective Observations and Current Perspectives.

Abstract 2141

Cyclic neutropenia (CyN) is an autosomal dominant and sporadically occurring hematological disease first described in 1910. Cyclic neutropenia is usually diagnosed in children before age 2 years based of regularly occurring fever, mouth ulcers, and recurrent skin or respiratory infections. In affected families, recognition is generally earlier than for the sporadic cases. Serial neutrophil counts usually show periods of very severe neutropenia (ANC< 0.2 × 10⁹/L) at three week intervals and an intervening peak ANC less than 2.0 × 10⁹/L. A reciprocal monocytosis often occurs during the neutropenic period. Mild anemia is common, particularly in patients with recurrent infections. Cycling of blood neutrophils is more apparent in young children than in adults, who often report severe childhood symptoms ameliorating near puberty or soon thereafter.

Through the Severe Chronic Neutropenia International Registry and Repository- Seattle (SCNIR-Seattle) we have prospectively studied the natural history of 348 patients with a clinical diagnosis of CyN, 181 sporadic cases and 167 patients from 36 families whose pedigrees illustrate autosomal dominant inheritance. Sequencing results for the gene for neutrophil elastase, ELANE, are available for 119 of these patients including at least one member of 18 families. We have prospectively followed all of these patients for up to 25 years.

Patients with typical, 21 day oscillations of blood neutrophils almost always have mutations of ELANE, most frequently mutation in exons 4 or 5. Neutropenic relatives (ANC < 1.5 × 10⁹/L) of an index case of CyN with an ELANE mutation uniformly have the same ELANE mutation, even if they have few symptoms and the neutropenia is not severe. Patients with severe congenital neutropenia and CyN may also have the same or nearly identical mutations; thus the diagnosis of cyclic neutropenia can not be made solely from mutation analysis.

Since 1987 we have treated cyclic neutropenic patients with G-CSF; some patients have been on G-CSF on a daily or alternate-day basis for 25 years. For the population of 209 treated patients enrolled in the SCNIR and treated for a median of 14.8 years, the median daily G-CSF dose is 2.1 mcg/kg/day. We have observed that the dose established during the first year of treatment can be adjusted for body weight and usually maintained indefinitely. Adverse effects are infrequent, particularly with daily or alternate-day treatment, although development of osteopenia remains a concern. A few patients who have transiently interrupted G-CSF; almost all have resumed G-CSF because of recurrence of fever, mouth ulcers, infections or fatigue. We are currently aware of only two CyN patients who have discontinued G-CSF treatment for greater than 2 months without recurrence of symptoms or returning to G-CSF therapy.

In this population, there has been no hematopoietic stem cell transplantation for treatment of CyN and no G-CSF treatment failures. 15 deaths have occurred: 1 from ovarian cancer, 2 related to discontinuation of G-CSF, 2 from cardiac causes, 3 from homicide or accidents, 5 from complicated illnesses with multi-system problems. One closely followed patient never treated with G-CSF developed CML and one patient treated long term with immunosuppressive drugs and G-CSF developed AML. Other than this case, there have been not CyN patients developing AML in more than 5000 years of patient observation. Clostridial sepsis, the frequent cause of death in CyN patients in the pre-G-CSF era, has not been observed in CyN patients on G-CSF.

These long-term observations serve to characterize cyclic neutropenia is a distinctive hematological disorder, very responsive to treatment with G-CSF and without recognized risk of evolution to AML.