Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that present significant challenges in their diagnosis and clinical management 1. Due to their rarity and complexity, these diseases can be difficult to recognize and distinguish from other blood disorders. Additionally, treatment options for CNL and aCML are limited, and the prognosis for affected individuals is generally poor. Most patients with CNL and aCML have a poor prognosis, with a mean overall survival of less than 2 years2,3.

This underscores the need for recognizing these disorders and providing a diagnosis as quickly as possible. 

Here we describe a case of an asymptomatic patient with leukocytosis detected incidentally in laboratory tests as part of the clearance process to undergo plastic surgery. A blood sample was received by the Precipio lab for Omnia work-up which resulted in a diagnosis of a rare case of CSF3R-mutated CMML. By way of Precipio’s Omnia methodology, the pathology team worked closely with the treating physician to dig deeper into this case to reveal a CMML case with rare mutation requiring immediate, aggressive intervention and monitoring.

Case Presentation

A 65 years old female patient presented with leukocytosis, neutrophilia, and anemia after a routine blood work-up for pre-op. She was hypertensive and had a history of hydronephrosis. Weighing 137 lbs, she had lost more than 20 lbs during the past  2 years, and also had a history of hydronephrosis.

Table 1 shows the blood count after repeated measures which revealed persistently elevated leukocytes. The absolute neutrophil count  was 11.9×103/µL, absolute metamyelocytes 168/µL, myelocytes 336/µL, corpromyelocytes 336/µL, and the blasts 336/µL. No splenomegaly or retroperitoneal lymphadenopathy was seen on CT abdomen (without contrast).

Table 1: Blood Work Up
TestNormal RangeResults
WBC (x103/μL)3.71-10.6721.6
RBC (x106/μL)3.87-5.684.35
HGB (g/dL)12-16.7512.4
MCV (μm3)78.4-97.689.9
MCH (pg)26.5-33.528.5
MCHC (g/dL)32.9-35.431.7
PLT (x103/μL)150.5-366.8426
MPV ( μm3)7.42-10.7710.5

Case Work Up &Results:

To rule out bone marrow (BM) dyscrasia, an aspirate was ordered for interpretation, flow cytometry, cytogenetics, clot section, MDS panel, and next-generation sequencing (NGS).

The BM was hypercellular and showed a marked left shifted granulocytic hyperplasia, atypical megakaryocytic hyperplasia, and 2% blasts. BM aspirate smear confirmed the results and showed an increased number of megakaryocytes exhibiting abnormal morphology with an increased proportion of small and hypo-segmented forms. 

The myeloid to erythroid (M: E) ratio was approximately 9:1, which is higher than normal. There was decreased erythroid maturation with mild dyspoiesis. Immature cells consistent with blasts were present and made up 2% of the nucleated cellular elements. The proportion of immature myeloid cells (35%) and basophils (2%) was increased, while the proportion of lymphocytes (7%) and erythroid cells (8%) were reduced. The karyotyping was a normal female. 

The bone marrow features reflected a differential diagnosis, which could include chronic myeloid leukemia, atypical chronic myeloid leukemia, chronic neutrophilic leukemia, and less likely granulocytic hyperplasia. Therefore, additional FISH and molecular studies were conducted to definitively classify the condition.

Results of FISH with a panel of probes specific for detecting recurring chromosome abnormalities in Myeloproliferative Neoplasm (MPN) to include CML were within normal limits. BCR/ABL1 translocation was not detected. The HemeScreen (MPN) panel was negative for JAK2, MPL, and CALR mutations. These results were not consistent with chronic myeloid leukemia, and the possibility of chronic neutrophilic leukemia was raised. To further investigate, a peripheral blood sample was requested for NGS and HemeScreen CSF3R molecular testing.

The HemeScreen CSF3R assay showed a CSF3R exon 14 mutation. NGS revealed a dominant abnormal clone with ASXL1, SRSF2, PTPN11, SETBP1, and CSF3R mutations. The TET2 mutation was detected in a subclone. These genomic abnormalities were most compatible with CMML with CSF3R mutation.

While CSF3R mutation was consistent with CNL, the NGS findings showed additional mutations that also suggest a very rare form of CSF3R-mutated CMML.

Clinical Implications:

CMML is identified by increased numbers of monocytes in the peripheral blood, with an absolute monocyte count of at least 1 x 10^9/L and comprising at least 10% of the total white blood cell count. CMML shares features of myelodysplastic syndromes and myeloproliferative neoplasms, which are characterized by abnormalities in blood cell production and function, and an increased risk of developing acute myeloid leukemia.

As a sole genomic abnormality, CSF3R mutation would be consistent with a diagnosis of Chronic Neutrophilic Leukemia (CNL). In the context of this patient’s peripheral blood picture showing absolute monocytosis, concurrent bone marrow findings, and additional pathogenic mutations detected by NGS (ASXL1, SRSF2, PTPN11, SETBP1, and TET2 genes), this genomic abnormality is consistent with a diagnosis of CSF3R mutated Chronic Myelomonocytic Leukemia. Notably, the CSF3R mutation is rare in CMML, with only ∼40 cases being reported (∼30 cases with CSF3R non-T618I and ∼10 cases with CSF3R T618I, accounting for ∼4% and ∼1% of CMML, respectively). CSF3R T618I with ASXL1 mutations in CMML are associated with adverse outcomes4,5.

This diagnosis has indicated to the treating physician that traditional TKIs would prove ineffective for treatment and thus this patient has been placed on a low dose of hydroxyurea and is being prepared for a bone marrow transplant. 

By utilizing Precipio’s Omnia methodology with a staged and reflex approach to testing based on direct hematopathologist oversight, this enabled more granular insight into the patient’s molecular status. The treating physician was able to diagnose the patient’s condition accurately and determined that they required prompt and intensive treatment, which would be closely monitored for improved outcome.

This presentation is intended for educational purposes only and does not replace independent professional judgment. This document contains proprietary information belonging to Precipio, Inc. No use or disclosure of the information contained herein is permitted without the prior written consent of Precipio Inc.