Extreme Leukocytosis in the 21st Century Is Often Iatrogenic
Authors: Hugo Zachary P. , Perry Michael C. , Steensma David P. 
Published: April 2020

Abstract
Background: Most reports of the causes of extreme leukocytosis (i.e., total white blood count (WBC) &gt;50 × 109/L) have included relatively small numbers of cases or data from the era prior to FDA approval of filgrastim (recombinant G-CSF; February 1991), sargramostim (GM-CSF; March 1991), and pegfilgrastim (G-CSF conjugated to polyethylene glycol; January 2002). The contribution of myeloid growth factors to extreme leukocytosis in contemporary medical practice is unclear.
Methods: We evaluated the medical records of all patients with extreme leukocytosis evaluated in the clinical laboratory of the University of Missouri-Columbia (UMC) Medical Center during the years 2000 to 2007. We collected complete blood count data, information on the etiology of the leukocytosis, demographic factors, and clinical complications.
Results: We identified 371 unique patients who had at least one WBC &gt;50 × 109/L during this 8-year period (43.7% females; median age 56 (range 0–92)). Review of the primary cause of the leukocytosis in each case revealed that, while the various subtypes of leukemia (n=165, 44.5% of cases) and leukemoid reactions to general medical disorders (n=155, 41.8%) still represent the most common etiologies of extreme WBC elevation, growth factor-associated leukocytosis (GFL) is common, accounting for 13.7% (n=51) of patients. Among the subset of patients with GFL, the median peak WBC count was 60.8 × 109/L (range, 50–114.7); 51% were female, and the median age was 52 years (range 0–85). The median absolute WBC differential was as follows: neutrophils 40.8 × 109/L, granulocytes 55.7, bands 7.1, lymphocytes 2.4, monocytes 1.3, eosinophils 0, and basophils 0. Most (84%) of the patients receiving growth factors were being treated for cancer, the most common being non-Hodgkin lymphoma (NHL, 19.6%), Hodgkin lymphoma (HL, 11.8%), breast cancer (9.8%), ovarian cancer (5.9%), melanoma (5.9%), and endometrial cancer (5.9%). The non-malignant diagnoses (n = 8) included autoimmune neutropenia, bruton’s agammagloblinemia with pneumonia, leukopenia of undefined etiology, preterm neutropenia/sepsis (n = 4), and neutropenia associated with HIV. 70.6% of patients with GFL were receiving filgrastim, 29.4% pegfilgrastim, and 0% sargramostim. 0% of patients were undergoing conditioning for stem cell transplant. While myeloid growth factors are generally well tolerated, extreme leukocytosis is concerning because it may be associated with serious adverse events such as spontaneous splenic rupture, leukostasis/hyperviscosity, and hemorrhage. Other diagnoses continue to be important contributors to extreme leukocytosis. Of the 165 patients with leukemia, 43% were diagnosed with CLL, 15.8% CML, 15.2% AML, 13.3% ALL, 3.6% CMML, 3.6% BCR/ABL-negative myeloproliferative disorders, and 3.6% NHL. Other diagnoses included plasma cell leukemia, undifferentiated leukemia, and an undefined lymphoproliferative disease with macroglobulinemia variant. The causes of non-clonal leukocytosis (leukemoid reactions) could be divided into four broad categories: infection (n=109, 70.3%), reaction to hemorrhage (n=15, 9.7%), paraneoplastic (n=11, 7.1%), and other miscellaneous causes (20, 12.9%). The most common infections causing extreme leukocytosis include sepsis (59, 54.1%), pneumonia (19, 17.4%), and Clostridium difficile-associated colitis (5, 4.6%). Paraneoplastic causes of leukocytosis were diverse and associated neoplasms included cancer of unknown primary (n = 2), cholangiocarcinoma, extranodal marginal zone B-cell lymphoma, HL, SCLC, NSCLC, lymphoplasmacytic lymphoma, melanoma, peripheral T-cell lymphoma, and squamous cell carcinoma of the penis.
Conclusion: In the current era, extreme leukocytosis is often iatrogenic and associated with filgrastim or pegfilgrastim usage. WBC counts should be routinely monitored in patients receiving pegfilgrastim or filgrastim and the medication discontinued with evolving leukocytosis.