Approach to Nonmalignant Leukopenia and Leukocytosis

Although leukopenia and leukocytosis can raise concern for an underlying hematologic malignancy, many causes are benign. Leukocyte reference ranges span two standard deviations around the population mean, so normal biologic variation alone produces out-of-range results in a predictable minority of people — about 2.5% of healthy persons will have a count above or below the standard range.

Most abnormal leukocyte counts are not malignant. Because reference ranges cover the mean ±2 SD, roughly 2.5% of healthy people fall outside them by chance alone. The initial evaluation is straightforward: personal history and physical examination, family history, a careful review of medications, supplements, and other drug use, complete blood count with differential, and peripheral blood smear.

Lymphopenia and Neutropenia

A decreased absolute lymphocyte count (ALC; lymphopenia, ALC <1000/µL) can be a response to glucocorticoids and other medications or to a variety of bacterial and viral infections. A chronically low ALC accompanied by recurrent infections should prompt evaluation for immunodeficiency, including measurement of immunoglobulin levels.

Don't ignore a persistently low ALC with recurrent infections. Chronic lymphopenia plus recurrent infections is an indication to evaluate for immunodeficiency and to measure immunoglobulin levels.

Neutropenia (absolute neutrophil count [ANC] <1500/µL) can result from impaired marrow production, immune-mediated destruction, or cellular redistribution — especially sequestration in an enlarged spleen from portal hypertension due to cirrhosis or portal vein thrombosis. Its clinical impact depends on the degree of neutropenia, bone marrow reserve, and comorbid conditions; severe neutropenia is defined as an ANC below 500/µL.

Severe neutropenia = ANC <500/µL (0.5 × 10⁹/L). Risk is determined not by the number alone but by the depth of neutropenia, marrow reserve, and comorbid conditions; complications become more common as the ANC falls.

Table 1 lists common nonmalignant causes of abnormal leukocyte counts.

**TABLE 1.** Nonmalignant causes of abnormal leukocyte counts
Neutropenia (ANC <1500/µL)	Lymphopenia (ALC <1000/µL)	Lymphocytosis (ALC >4000/µL)	Neutrophilia (ANC >7700/µL)
Inherited: benign ethnic, cyclic, familial, congenital	Inherited: immunodeficiency disorders	Infections: viral (EBV, CMV, HIV, influenza); bacterial (pertussis, cat scratch disease, Clostridioides difficile); other (tuberculosis, syphilis, babesiosis)	Infections (especially bacterial)
Infections: sepsis, HIV, EBV	Infections: HIV, hepatitis, tuberculosis, typhoid, malaria, measles, fungal (histoplasmosis)	Monoclonal B-cell lymphocytosis	Acute/chronic inflammatory states: inflammatory bowel disease, rheumatologic disorders
Medications: antibiotics (trimethoprim-sulfamethoxazole, dapsone, vancomycin); psychiatric (clozapine, tricyclic antidepressants); immunomodulatory (methotrexate, azathioprine, tacrolimus, mycophenolate, others); thyroid (methimazole, propylthiouracil)	Medications: glucocorticoids, rituximab, immunosuppressants	Drug hypersensitivity reaction	Medications: lithium, glucocorticoids, myeloid growth factors, catecholamines
Nutritional: vitamin B12, folate, copper deficiencies	Systemic disease: autoimmune (SLE, rheumatoid arthritis), sarcoidosis, Cushing syndrome, aplastic anemia	Hyperthyroidism	Asplenia
Autoimmune: primary autoimmune neutropenia; secondary to systemic process (SLE, rheumatoid arthritis)	Other: alcohol, zinc deficiency, protein-losing enteropathy	Asplenia	Cigarette smoking
Aplastic anemia		Cigarette smoking	Obesity
Cellular redistribution (hypersplenism)			Stressors: physical, emotional, intense exercise

ALC = absolute lymphocyte count; ANC = absolute neutrophil count; CMV = cytomegalovirus; EBV = Epstein-Barr virus; SLE = systemic lupus erythematosus.

Benign ethnic neutropenia. Benign ethnic neutropenia (BEN) is a mild, chronically low ANC — typically 1000 to 1500/µL, though it can be lower — that is more common in certain demographics, including persons of African descent (reported in 4.5% of Black and 0.8% of White persons in the United States). Myeloid progenitors are mildly reduced, with a smaller circulating and marrow neutrophil reserve, but myeloid maturation and function are normal. Importantly, BEN does not increase the frequency or severity of infections or cause other significant clinical consequences.

From "benign ethnic neutropenia" to Duffy-null–associated neutrophil count. The low ANC once attributed to race is largely genetic: homozygosity for the ACKR1 (DARC) rs2814778 variant produces the Duffy-null phenotype (Fy[a−b−]), carried by roughly two-thirds of many Black/African-ancestry populations. In one study of healthy Black adults, Duffy-null individuals had a median ANC of about 2800/µL versus 5000/µL in Duffy-positive individuals, and nearly one-quarter had an ANC <2000/µL — values that would be labeled "neutropenia" under standard ranges and could trigger unnecessary workups or chemotherapy dose delays. In 2023, the American Society of Hematology designated "Duffy-null–associated neutrophil count" as the preferred term over "benign ethnic neutropenia" and endorsed genotype-based (race-neutral) ANC reference ranges; the Fy(a−b−) phenotype identifies these individuals far more accurately (~97% sensitive, ~96% specific) than self-identified race (~66%/49%). [2],[3]

Medication-induced neutropenia. Many drugs can cause neutropenia, either by impairing normal granulopoiesis in the bone marrow or through drug-dependent, antibody-mediated immune destruction of circulating neutrophils. These effects typically appear within the first 3 months of drug initiation and are often reversible; medication-induced neutropenia occurs most often in patients older than 50 years. Symptoms can include fever and oral ulcerations or manifestations related to sites of infection, with complications more common at lower ANCs. Treatment centers on stopping the offending agent, and symptoms often resolve within 1 to 3 weeks. Granulocyte colony-stimulating factor (G-CSF) can shorten recovery time and may be used in patients with neutropenia and active infection.

G-CSF in drug-induced agranulocytosis: what the evidence shows. A 2026 review from the Strasbourg registry group found that observational studies and meta-analyses support G-CSF shortening the duration of neutropenia and hospitalization in non-chemotherapy drug-induced agranulocytosis, but a mortality benefit remains uncertain — no randomized trials exist, and treatment algorithms remain empirical. The decision to use G-CSF should weigh the initial neutrophil count, presence of severe infection or sepsis, age, and comorbidities; the cornerstones of management remain immediate withdrawal of the offending drug plus infection control. [5]

Nutritional and autoimmune causes. Cobalamin and folate deficiencies can lower the ANC, often with concomitant macrocytic anemia and, at times, thrombocytopenia. Copper deficiency is a rare cause of neutropenia and anemia that responds to copper supplementation. Autoimmune conditions such as systemic lupus erythematosus can also be associated with isolated neutropenia.

Key points — leukopenia:

Lymphopenia without clinical consequences or an associated illness does not require treatment.
Benign ethnic neutropenia (Duffy-null–associated neutrophil count) causes a chronically low ANC but without significant clinical consequences.
Medication-induced neutropenia occurs most often in patients older than 50 years during the first 3 months of drug treatment; symptoms usually improve within 1 to 3 weeks of stopping the medication.

Neutrophilia, Lymphocytosis, and Monocytosis

Neutrophilia, lymphocytosis, and monocytosis are often reactive, secondary to infection or inflammation. Lymphocytosis accompanies many viral processes; monocytosis accompanies some infections such as tuberculosis.

Acute Epstein-Barr virus infection can present with lymphadenopathy, hepatosplenomegaly, and an elevated ALC, and its atypical lymphocytes may be mistaken for blasts on the peripheral smear.

EBV atypical lymphocytes can mimic blasts. In acute EBV infection, reactive/atypical lymphocytes may be misread as circulating blasts — interpret the smear in clinical context before raising concern for acute leukemia.

Monoclonal B-cell lymphocytosis (MBL) refers to a monoclonal population of B lymphocytes (<5000/µL [5 × 10⁹/L]) that does not meet criteria for chronic lymphocytic leukemia (CLL) or another lymphoproliferative malignancy; it is usually detected incidentally in asymptomatic patients. Approximately 1% to 2% of patients with a clone size greater than 2000/µL evolve to meet criteria for CLL during each year of follow-up; patients with smaller clone sizes have a much lower risk and normal longevity. No intervention is required, but patients should be monitored periodically for signs of progression.

Molecular risk stratification is coming to MBL. Current practice for high-count MBL remains surveillance (periodic CBC and clinical follow-up, no treatment), but a 2024 study of 219 individuals with MBL showed that a combined epigenetic and immunogenetic signature — ELCLV3-21, incorporating IGLV3-21 usage — identified a high-risk subgroup with a progression probability of about 40% at 5 years and 71% at 10 years, and predicted time to first therapy better than the CLL-IPI (c-statistic 0.77 vs 0.67). Molecular profiling may eventually refine the one-size-fits-all "monitor" approach. [4]

Neutrophilia frequently accompanies bacterial infections and can be caused by certain medications, including glucocorticoids. Cigarette smoking is another common cause — mechanism unknown — and the effect often persists for a prolonged period after smoking cessation, sometimes for years. Obesity, especially in women, may also be associated with neutrophilia.

Monocytosis accompanies some infections, such as tuberculosis. Persistent monocytosis (lasting >6 months) without obvious infection, particularly when associated with cytopenias such as anemia or thrombocytopenia, should be referred for evaluation of possible hematopoietic stem cell disorders.

Persistent monocytosis deserves referral. Monocytosis lasting more than 6 months without an obvious infectious explanation — particularly when accompanied by anemia or thrombocytopenia — should prompt referral for evaluation of a possible hematopoietic stem cell disorder.

Key points — leukocytosis:

Cigarette smoking is a common cause of chronic neutrophilia; the mechanism is unknown, and neutrophilia may persist for a year or more following smoking cessation.
Monoclonal B-cell lymphocytosis occurs in generally asymptomatic patients who lack other criteria for a diagnosis of chronic lymphocytic leukemia; monitor periodically, no intervention needed.

References

MKSAP 19 — Hematology American College of Physicians (2022). "Approach to Nonmalignant Leukopenia and Leukocytosis," pp. 1–3.
Absolute neutrophil count by Duffy status among healthy Black and African American adults Merz LE, Story CM, Osei MA, et al. Blood Adv 2023;7(3):317–320.
Terms and Definitions for ANC by Duffy Status American Society of Hematology (2023). ASH Diversity, Equity & Inclusion resource document.
Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature Abdelbaky SB, Giacopelli B, Rabe KG, et al. Blood 2024;143(17):1752–1757.
Factors Influencing the Use of G-CSF in Drug-Induced Agranulocytosis Andrès E, Terrade JE, Jannot X, Lorenzo-Villalba N. Hematol Rep 2026;18(1):14.

Approach to Nonmalignant Leukopenia and Leukocytosis

Added 5 August 2026

Related Moji cards

Because leukocyte reference ranges span the mean ± ____ SD, roughly ____% of healthy people fall outside the standard range by chance alone.

Leukocyte reference ranges span two standard deviations around the population mean, so normal biologic variation alone produces out-of-range results in a predictable minority — about 2.5% of healthy persons will have a count above or below the standard range. Most abnormal leukocyte counts are not malignant.

MKSAP 19 B.4 Ch.1

Neutropenia is defined as an ANC below ____/µL, and severe neutropenia is defined as an ANC below ____/µL.

Neutropenia is defined as an absolute neutrophil count (ANC) below 1500/µL, and severe neutropenia as an ANC below 500/µL. Clinical risk is determined not by the count alone but by the depth of neutropenia, bone marrow reserve, and comorbid conditions; complications become more common as the ANC falls.

MKSAP 19 B.4 Ch.1

Lymphopenia is defined as an ALC below ____/µL; a chronically low ALC with recurrent infections should prompt evaluation for ____ and measurement of immunoglobulin levels.

Lymphopenia (absolute lymphocyte count <1000/µL) can be a response to glucocorticoids and other medications or to a variety of bacterial and viral infections. A chronically low ALC accompanied by recurrent infections should prompt evaluation for immunodeficiency, including measurement of immunoglobulin levels. Lymphopenia without clinical consequences or an associated illness does not require treatment.

MKSAP 19 B.4 Ch.1

Nutritional causes of neutropenia include deficiencies of vitamin B12, folate, and ____; neutropenia can also result from cellular redistribution with sequestration in an enlarged spleen due to ____.

Neutropenia can result from impaired marrow production, immune-mediated destruction, or cellular redistribution — especially sequestration in an enlarged spleen from portal hypertension due to cirrhosis or portal vein thrombosis. Nutritional causes include vitamin B12, folate, and copper deficiencies (cobalamin and folate often with macrocytic anemia; copper deficiency is rare but responds to supplementation).

MKSAP 19 B.4 Ch.1

Classic drugs that cause neutropenia include the antibiotic ____, the antipsychotic ____, and the antithyroid agents methimazole and propylthiouracil.

Common medications causing neutropenia include antibiotics (trimethoprim-sulfamethoxazole, dapsone, vancomycin), psychiatric agents (clozapine, tricyclic antidepressants), immunomodulators (methotrexate, azathioprine, tacrolimus, mycophenolate), and thyroid drugs (methimazole, propylthiouracil). Mechanisms include impaired granulopoiesis and drug-dependent antibody-mediated destruction of neutrophils.

MKSAP 19 B.4 Ch.1

Drug-induced neutropenia typically appears within the first ____ months of drug initiation, occurs most often in patients older than ____ years, and symptoms usually improve within 1 to 3 weeks of stopping the offending agent.

Medication-induced neutropenia occurs most often in patients older than 50 years and typically appears within the first 3 months of drug initiation. It is often reversible: treatment centers on stopping the offending agent, and symptoms usually resolve within 1 to 3 weeks. G-CSF can shorten recovery time and may be used in patients with neutropenia and active infection.

MKSAP 19 B.4 Ch.1

Benign ethnic neutropenia is now termed Duffy-null–associated neutrophil count: it results from homozygosity for the ____ (DARC) rs2814778 variant producing the Fy(a−b−) phenotype, and ASH 2023 endorsed ____-based (race-neutral) ANC reference ranges.

The low ANC once attributed to race is largely genetic: homozygosity for the ACKR1 (DARC) rs2814778 variant produces the Duffy-null phenotype Fy(a−b−), carried by roughly two-thirds of many Black/African-ancestry populations. In 2023, the American Society of Hematology designated "Duffy-null–associated neutrophil count" as the preferred term over "benign ethnic neutropenia" and endorsed genotype-based (race-neutral) ANC reference ranges. The condition causes a chronically low ANC (typically 1000–1500/µL) but does not increase infection frequency or severity and requires no treatment.

MKSAP 19 B.4 Ch.1; ASH Duffy-null terminology 2023

Duffy-null healthy Black adults have a median ANC of about ____/µL versus 5000/µL in Duffy-positive individuals, and nearly one-quarter have an ANC below ____/µL that would be labeled neutropenia under standard ranges.

In one study of healthy Black adults, Duffy-null individuals had a median ANC of about 2800/µL versus 5000/µL in Duffy-positive individuals, and nearly one-quarter had an ANC <2000/µL — values that would be labeled "neutropenia" under standard ranges and could trigger unnecessary workups or chemotherapy dose delays. The Fy(a−b−) phenotype identifies these individuals far more accurately (~97% sensitive, ~96% specific) than self-identified race (~66%/49%).

MKSAP 19 B.4 Ch.1; Merz et al, Blood Adv 2023; ASH Duffy-null terminology 2023

Monoclonal B-cell lymphocytosis is a monoclonal B-cell population below ____/µL that does not meet criteria for ____; about 1–2% per year of patients with clone sizes above 2000/µL progress, and management is periodic monitoring without intervention.

Monoclonal B-cell lymphocytosis (MBL) refers to a monoclonal population of B lymphocytes (<5000/µL) that does not meet criteria for chronic lymphocytic leukemia (CLL) or another lymphoproliferative malignancy; it is usually detected incidentally in asymptomatic patients. Approximately 1% to 2% of patients with a clone size greater than 2000/µL evolve to meet CLL criteria each year; smaller clones carry a much lower risk and normal longevity. No intervention is required, but patients should be monitored periodically for signs of progression.

MKSAP 19 B.4 Ch.1

In a 2024 MBL study, the epigenetic and immunogenetic signature ____ identified a high-risk subgroup with a progression probability of about ____% at 5 years and 71% at 10 years, outperforming the CLL-IPI for time to first therapy.

Current practice for high-count MBL remains surveillance (periodic CBC and clinical follow-up, no treatment). A 2024 study of 219 individuals with MBL showed that a combined epigenetic and immunogenetic signature — ELCLV3-21, incorporating IGLV3-21 usage — identified a high-risk subgroup with a progression probability of about 40% at 5 years and 71% at 10 years, and predicted time to first therapy better than the CLL-IPI (c-statistic 0.77 vs 0.67).

MKSAP 19 B.4 Ch.1; MBL risk signature, Blood 2024

Common causes of neutrophilia include bacterial infections, ____ use, and cigarette smoking; smoking-associated neutrophilia may persist for ____ after cessation.

Neutrophilia frequently accompanies bacterial infections and acute/chronic inflammatory states, and can be caused by medications including glucocorticoids, lithium, myeloid growth factors, and catecholamines. Other causes include asplenia, obesity (especially in women), physical/emotional stressors, and cigarette smoking — mechanism unknown — with the effect often persisting for years after smoking cessation.

MKSAP 19 B.4 Ch.1

In acute EBV infection, reactive/____ lymphocytes on the peripheral smear may be mistaken for circulating ____; the smear should be interpreted in clinical context before raising concern for acute leukemia.

Acute Epstein-Barr virus infection can present with lymphadenopathy, hepatosplenomegaly, and an elevated ALC; its reactive/atypical lymphocytes may be mistaken for blasts on the peripheral smear. Interpret the smear in clinical context before raising concern for acute leukemia. Lymphocytosis accompanies many viral processes (EBV, CMV, HIV, influenza) and some bacterial infections (pertussis, cat scratch disease, C. difficile).

MKSAP 19 B.4 Ch.1

Monocytosis accompanies infections such as ____; monocytosis persisting more than ____ months without an obvious infectious explanation, particularly with cytopenias, should prompt referral to evaluate for a possible hematopoietic stem cell disorder.

Monocytosis is often reactive and accompanies some infections such as tuberculosis. Persistent monocytosis lasting more than 6 months without an obvious infectious explanation — particularly when associated with cytopenias such as anemia or thrombocytopenia — should be referred for evaluation of possible hematopoietic stem cell disorders.

MKSAP 19 B.4 Ch.1

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