Chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance: A case report and literature review

Abstract Background Study of the molecular biological characteristics of chronic neutrophilic leukemia complicated with plasma cell disorder (CNL‐PCD) and lymphocytic proliferative disease (CNL‐LPD). Methods The clinical data of a patient with chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance (CNL‐MGUS) in our hospital were reviewed, and the Chinese and/or English literature about CNL‐PCD and CNL‐LPD in PubMed and the Chinese database CNKI in the past 10 years was searched to analyze the molecular biological characteristics of this disease. Results A 73‐year‐old male had persistent leukocytosis for 18 months. The white blood cell count was 46.77 × 109/L and primarily composed of mature neutrophils; hemoglobin: 77 g/L; platelet count: 189 × 109/L. Serum immunofixation electrophoresis showed IgG‐λ monoclonal M protein. A CT scan showed splenomegaly. Next‐generation sequencing (NGS) showed that CSF3R T618I, ASXL1 and RUNX1 mutations were positive. It was diagnosed as CNL‐MGUS. We summarized 10 cases of CNL‐PCD and 1 case of CNL‐LPD who underwent genetic mutation detection reported in the literature. The CSF3R mutational frequency (7/11, 63.6%) was lower than that of isolated CNL. The ASXL1 mutations were all positive (3/3), which may represent a poor prognostic factor. The SETBP1 mutation may promote the progression of CNL‐PCD. We also found JAK2, RUNX1, NRAS, etc. in CNL‐PCD. Conclusions Chronic neutrophilic leukemia may be more inclined to coexist with plasma cell disorder. The CSF3R mutation in CNL‐PCD is still the most common mutated gene compared with isolated CNL. Mutations in SETBP1 and ASXL1 may be poor prognostic factors for CNL‐PCD.

0.38% of clonal plasma cells in the bone marrow, and the results of immunophenotyping were as follows: cKappa-/cLambda+/CD19-/ CD56-/CD117-/CD138+/CD27-/CD38++/CD81+/CD45±. He was diagnosed with CNL-MGUS. After admission, hydroxyurea was used to control the proliferation of leukocytes, febuxostat was used to reduce uric acid, and symptomatic and supportive treatment was administered. However, the patient had a progressive increase in leukocytes, the symptoms of night sweats and fatigue were not obviously improved, and progressive weight loss occurred. On June 13, 2020, he was hospitalized again because of abdominal pain. The abdominal CT showed a low-density shadow of the spleen, suggesting spleen infarction. Repeat NGS showed ASXL1 G635fs (VAF 32.2%), CSF3R T618I (VAF 44.6%), and NRAS G12A (VAF 2.8%). He was treated with low-molecular-weight heparin anticoagulation for more than 1 month. After the symptoms of abdominal pain improved, the patient was treated with ruxolitinib at 15 mg twice daily, in addition to 1 g of hydroxyurea once daily on August 8, 2020. The patient's symptoms of night sweats and fatigue improved, leukocyte proliferation was significantly inhibited, the hemoglobin gradually increased, and no significant changes in bone marrow or immunoglobulin were found after re-examination. A CT of the abdomen showed that the spleen had shrunk compared to before. He is now in stable condition and is under follow-up. Due to the limitations in understanding the disease in the past, some early literature reported that CNL-PCD may be a leukemoid reaction caused by PCD, not real CNL. 12 Myeloma cells and the abnormal immunoglobulins produced by them can stimulate bone marrow stromal cells to produce large amounts of cytokines (such as  and stimulate the proliferation of granulocytes. 13 Nagai detected the concentration of G-CSF in the peripheral blood of a patient with PCD with "CNL." The neutrophil count was proportional to the concentration of G-CSF in serum. 14 Therefore, patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) need to find evidence of myeloid cloning before CNL is diagnosed. We reported a case of elderly CNL-MGUS. Although there are a few reports of CNL with PCD or lymphocytic proliferative disease (LPD) in the literature, most of them are MM or MGUS.

| DISCUSS ION
In addition to our case, we collected 11 cases of PCD or LPD complicated with CNL with evidence of myeloid cloning in PubMed and CNKI (Table 1). From Table 1, we observe no CNL cases complicated with LPD except follicular lymphoma (FL). This phenomenon suggests that CNL may be more inclined to coexist with MGUS or MM instead of coexisting by chance. The common genetic susceptibility loci in MPN and MM, and chronic inflammatory bone marrow microenvironment in MPN that in favor of the proliferation of monoclonal B cells, may be the pathogenesis of concurrence of these two different diseases. [15][16][17] Among the 12 cases we summarized, 11 cases detected CSF3R mutation and 7 cases were positive. We found that CSF3R was the most common mutation among the 12 cases. However, the frequency of CSF3R mutations in CNL-PCD (63.6% 7/11) was lower than that of isolated CNL reported in most of the literature. [18][19][20][21][22][23][24] Whether the existence of both myeloid and lymphoid clones leads to a decrease in the mutation frequency of myeloid CSF3R mutation needs to be further clarified in more cases.  participates in the signal transduction pathway of hematopoiesis and the immune system. Yin reported 4 cases of CNL and found that two of them had only the JAK2 V617F mutation. Although the CSF3R mutation is the main carcinogenic mutation of CNL, a small number of CNL patients may be caused by the JAK2 V617F mutation. 25 Gajendra et al. determined that the JAK2 V617F mutation had no unfavorable effect on the progression and prognosis of CNL. 26 In addition, there is a report that a CNL patient with the JAK2 V617F mutation survived for 96 months. 27 In the 12 cases we reviewed, the prognostic significance of the JAK2 V617F mutation in these patients was not known because the survival time of these two patients was not given.
In the 12 cases we summarized, the positive rate of SETBP1 mutation was 37.5% (3/8), which was close to the median frequency of SETBP1 mutation in isolated CNL. 1,[18][19][20][21][22]28,29  showed that the patient's neoplasm cells were insensitive to the JAK inhibitor fedrotinib. 23 However, a meta-analysis that included 3 reports totaling 56 cases of CNL indicated that the SETBP1 mutation had no unfavorable effect on the prognosis of CNL. 30 As shown in acquired new gene mutations during the follow-up process, 6 and the the treatment process, 4 indicating that CNL-PCD will undergo clonal evolution or blastic evolution. However, whether CNL-PCD is the same as isolated CNL with similarities in clonal evolution or blastic evolution needs to be expanded for further analysis.
Three cases had myeloid mutations detected by NGS, as shown in Table 1. In addition to CSF3R mutations, ASXL1, RUNX1, NRAS, and other mutations were also detected in these cases. Among these patients, the mutation of epigenetic modification ASXL1 was positive (3/3), and case 8 died quickly due to refusal of treatment. 7 Case 10 developed hemopericardium during the course of the disease. 9 The patient we reported had splenic infarction and cachexia before ruxolitinib was added to the treatment. In multivariable analysis, mutated ASXL1 was independently predictive of shortened survival in CNL.
Elliott observed that CNL patients who evolved into chronic myelomonocytic leukemia (CMML) all carried ASXL1 mutations but did not carry SETBP1 mutations. 19 Szuber et al. found that both univariate and multivariate analyses showed that the presence of ASXL1 mutations was significantly related to a reduction in CNL overall survival and incorporated ASXL1 mutations into a prognostic scoring system. 20 From the above-mentioned CNL literature on ASXL1 mutations and three cases we summarized, we speculate that the significance of ASXL1 mutations is similar in isolated CNL and CNL-PCD.
In summary, CNL is a rare disease, and CNL complicated with other diseases is even rarer. What is the relationship between CNL and PCD? Are they close relatives, distant relatives, or two independent diseases? Modern molecular gene detection provides an effective means for accurate diagnosis. With the continuous emergence of future advanced detection technologies such as NGS, as well as the accumulation of research on these cases, more related questions, such as pathogenesis, disease transformation, and prognosis factors, will be revealed.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data used to support the findings of this study are included within the article. And the raw data used to support the findings of this study are available from the corresponding author upon request.