Chronic neutrophilic leukemia (CNL) is a rare but serious myeloid malignancy. In a review of reported cases for WHO-defined CNL, CSF3R mutation is found in about 90% cases and confirmed as the molecular basis of CNL. Concurrent mutations are observed in CSF3R-mutated CNL patients, including ASXL1, SETBP1, SRSF2, JAK2, CALR, TET2, NRAS, U2AF1, and CBL. Both ASXL1 and SETBP1 mutations in CNL have been associated with a poor prognosis, whereas, SRSF2 mutation was undetermined. Our patient was a 77-year-old man and had no significant past medical history and symptoms with leukocytosis. Bone marrow (BM) aspirate and biopsy revealed a markedly hypercellular marrow with prominent left-shifted granulopoiesis. Next-generation sequencing (NGS) of DNA from the BM aspirate of a panel of 28 genes, known to be pathogenic in MDS/MPN, detected mutations in CSF3R, SETBP1, and SRSF2, and a diagnosis of CNL was made. The patient did not use a JAK-STAT pathway inhibitor (ruxolitinib) but started on hydroxyurea and alpha-interferon and developed pruritus after 4 months of diagnosis and nasal hemorrhage 1 month later. Then, the patient was diagnosed with CNL with AML transformation and developed intracranial hemorrhage and died. We repeated NGS and found that three additional mutations were detected: ASXL1, PRKDC, MYOM2; variant allele frequency (VAF) of the prior mutations in CSF3R, SETBP1, and SRSF2 increased. The concurrence of CSF3RT618I, ASXL1, SETBP1, and SRSF2 mutation may be a mutationally detrimental combination and contribute to disease progression and AML transformation, as well as the nonspecific treatment of hydroxyurea and alpha-interferon, but the significance and role of PRKDC and MYOM2 mutations were not undetermined.
Hinweise
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Introduction
Chronic neutrophilic leukemia (CNL) is a rare but serious myeloid malignancy. Here, we present a case of CNL and discuss the significance of co-expressed mutations in transformation to acute myeloid leukemia (AML). Our patient was a 77-year-old man and had no significant past medical history and symptoms such as fatigue, weight loss, easy bruising, pruritus, abdominal distention, and night sweats. He was hospitalized with chest pain. There was no splenomegaly and hepatomegaly on physical examination. His complete blood count showed white blood cell (WBC) count 88.90 × 109/L; neutrophil 83.03 × 109/L; red blood cell 3.45 × 109/L; hemoglobin 98 g/L; and platelet 80 × 109/L. Bone marrow (BM) aspirate and biopsy revealed a markedly hypercellular marrow with prominent left-shifted granulopoiesis without dysplasia and blast proliferation. Reticulin fibrosis was not observed. Cytogenetic analysis was normal. Fluorescence in situ hybridization (FISH) results for the JAK2, FGFR1, FIP1L1-PDGFRA, and PDGFRB rearrangement were negative. Polymerase chain reaction results for the BCR-ABL1 fusion, Jak2, MPL, and CALR gene were negative. Next-generation sequencing (NGS) of DNA from the BM aspirate of a panel of 28 genes, known to be pathogenic in MDS/MPN, detected mutations in CSF3R, SETBP1, and SRSF2, and a diagnosis of CNL was made (Tables 1 and 2).
Table 1
The mutation outcomes at diagnosis of CNL. Positive mutations
Gene↩
NM
Exon↩
VAF↩
CSF3R↩
NM_000760:c.1853>T(p.T618I)exon 14↩
44.1%↩
SETBPI↩
NM_015559:c.2608G>(p.G870S)exon4↩
47.1%↩
SRSF2↩
NM_003016:c.284C>A(p.95H)exon 1↩
45.8%↩
Table 2
The mutation outcomes at diagnosis of CNL. Negative mutations
ASXL1↩
BCOR↩
CALR↩
CBL↩
DNMT3A↩
ETV6↩
JAK3↩
MPL↩
NPM1↩
NRAS↩
PHF6↩
PTPN11↩
RUNX1↩
SF3B1↩
STAG2↩
TET2↩
TP53↩
U2AF1↩
ZRSR2↩
↩
↩
↩
↩
↩
The patient did not use a JAK-STAT pathway inhibitor (ruxolitinib) for CSF3RT618I mutation but started on hydroxyurea and alpha-interferon to control the myeloproliferation. After 7 days of treatment, he had stabilization of the peripheral blood count, with WBC 7.77 × 109/L, hemoglobin 76 g/L, and platelet 122 × 109/L. But he had no regular follow-up and developed pruritus after 4 months of diagnosis and nasal hemorrhage 1 month later. Serum LDH was 1335.2 U/L. His WBC count increased to 128.52 × 109/L and hemoglobin and platelets dropped to 68 g/dL and 27 × 109/L, respectively. The peripheral blood smear showed 3% myeloblasts (Fig. 1a) and BM aspirate revealed 23.5% myeloblasts and pathological hematopoiesis (Fig. 1b). A diagnosis of CNL with AML transformation was made. We repeated cytogenetic analysis and NGS. Cytogenetic analysis still was normal. FISH results for the BCR-ABL1, ASS1, and +8 were negative. Using the sequencing panel with 96 genes associated with hematopoietic and lymphoid tissue tumors, three additional mutations were detected: ASXL1, PRKDC, MYOM2; variant allele frequency (VAF) of the prior mutations in CSF3R, SETBP1, and SRSF2 increased (Tables 3 and 4). He was admitted for pruritus and nasal hemorrhage, developed intracranial hemorrhage, and expired.
Fig. 1
a Peripheral blood (Giemsa, ×200). b Bone marrow aspirate (Giemsa, ×400)
Table 3
The mutation outcomes at AML transformation. Positive mutations
Gene↩
NM↩
Exon↩
VAF↩
ASXL1↩
NM_015338:c.2338C>T(p.Q780*)exon12↩
46.1%↩
CSF3R↩
NM_000760:c.1853C>T(p.T618I)exon14↩
49.6%↩
SETBP1↩
NM_015559:c.2608G>A(p.G870S)exon4↩
48.6%↩
SRSF2↩
NM_003016:c.284C>A(p.P95H)exon1↩
49.7%↩
PRKDC↩
NM_006904:c.9921+1G>T exon70↩
4%↩
MYOM2↩
NM_003970:c.3901T>C(p.Y1301H)exon33↩
51%↩
Table 4
The mutation outcomes at AML transformation. Negative mutations
ABCB1
ABL1
ANKRD26
APC
ARID1A
ARID1B
ARID2
ATG2B
ATM
ATRX
B2M
BCL10
BCL2
BCL6
BCOR
BCORL1
BIRC3
BLM
BPGM
BRAF
BRCA1
BRCA2
BRIP1
BTG1
BTK
CALR
CARD11
CBL
CBLC
CBLC
CCND1
CCND3
CD28
CD58
CD79A
CD79B
CDKN1A
CDKN2A
CDKN2B
CEBPA
CHD8
CIITA
CREBBP
CRLF2
CSF1R
CTCF
CUX1
CXCR4
DDX41
DIS3
DKC1
DNM2
DNMT3A
EED
EGFR
EGLN1
ELANE
EP300
EPHA7
EPOR
ETV6
EZH2
FAM46C
FAS
FAT1
FBXO11
FBXW7
FLT3
FOXO1
GATA1
GATA2
GFI1
GNA13
GNAI2
GNAS
GNB1
GSKIP
HAXI
HRAS
ID3
IDH1
IDH2
IKZF1
IKZF2
IKZF3
IL7R
IRF4
IRF8
ITPKB
JAK1
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In a review of reported cases for WHO-defined CNL, CSF3R mutation is found in about 90% cases [1] and confirmed as the molecular basis of CNL. Concurrent mutations are observed in patients with CSF3R-mutated CNL, including ASXL1, SETBP1, SRSF2, JAK2, CALR, TET2, NRAS, U2AF1, and CBL [2‐7]. Elliott et al. found that presence of ASXL1 mutation and thrombocytopenia in CSF3R-mutated CNL were independently predictive of shortened survival on multivariable analysis [2]. Two patients with SETBP1-mutated and ASXL1-unmutated developed AML transformation, whereas two other patients with ASXL1-mutated and SETBP1-unmutated evolved into chronic myelomonocytic leukemia (CMML) in their study. Both ASXL1 mutation and SETBP1 mutation in CNL have been associated with a poor prognosis. SRSF2 mutation has been frequently reported in myelodysplastic syndromes (MDS) and CMML patients which is related to shorter OS and may be considered as an adverse prognostic risk factor in MDS, but not in CMML [8], however, which was undetermined in CNL. In our case, ASXL1 mutation (along with thrombocytopenia) was detected with PRKDC and MYOM2 mutations without the sequencing panel at preliminary diagnosis at low levels, and VAF of CSF3RT618I, SETBP1, and SRSF2 increased at progression to AML transformation. It suggested that concurrence of CSF3RT618I, ASXL1, SETBP1, and SRSF2 mutation may be a mutationally detrimental combination and contribute to disease progression and AML transformation, as well as the nonspecific treatment of hydroxyurea and alpha-interferon, but the significance and role of PRKDC and MYOM2 mutations were not undetermined.
In conclusion, we report here that concurrence of CSF3RT618I, ASXL1, SETBP1, and SRSF2 mutations may co-contribute to AML transformation, but their interactions with PRKDC and MYOM2 mutations in the pathogenesis of CNL as well as their prognostic implications remain to be determined.
Declarations
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.
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Conflict of interest
The authors declare no competing interests.
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