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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000014
MYELOID DISEASE: Edited by Martin S. Tallman

The molecular genetics of chronic neutrophilic leukaemia: defining a new era in diagnosis and therapy

Elliott, Michelle A.a,b; Tefferi, Ayalewa

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aDepartment of Internal Medicine, Division of Hematology

bDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

Correspondence to Michelle A. Elliott, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. Tel: +1 507 284 2868; fax: +1 507 266 4972; e-mail:

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Purpose of review: In the current WHO classification of myeloid disorders, chronic neutrophilic leukaemia (CNL) is recognized as a myeloproliferative neoplasm characterized by sustained neutrophilic leukocytosis, hepatosplenomegaly and bone marrow granulocytic hyperplasia without evidence of dysplasia, BCR-ABL1 or rearrangements of PDGFRA, PDGFRB or FGFR1. This diagnosis is contingent upon exclusion of underlying causes of reactive neutrophilia particularly if evidence of myeloid clonality is lacking. The lack of a specific molecular marker has left the diagnosis to be largely one of exclusion. Recently, the molecular landscape shifted with the discovery of specific oncogenic mutations in the colony-stimulating factor 3 receptor gene (CSF3R) in CNL patients. We review the implications for diagnosis, pathogenesis and potential for new therapeutic options.

Recent findings: In 2013, oncogenic mutations in CSF3R were identified in a majority of patients with CNL and demonstrated that their downstream signalling was sensitive to known kinase inhibitors. This discovery was then validated with the demonstration of 100% CSF3R mutational frequency (predominately CSF3RT618I) in strictly WHO-defined CNL. Simultaneously, novel somatic mutations in SETBP1 were found to be enriched in CNL with possible prognostic significance.

Summary: CNL appears to be driven by specific somatic activating CSF3R mutations. These bestow susceptibility to known kinase inhibitors, opening the door to novel specific therapeutic options for CNL. The diagnosis of CNL will no longer be one only of exclusion, and revision of the current WHO diagnostic criteria is expected to include the molecular criterion of CSF3R mutation positivity.

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Chronic neutrophilic leukaemia (CNL) is a rare myeloproliferative neoplasm (MPN) that only attained formal recognition as such within the WHO classification system in 2001 [1]. Key diagnostic criteria include sustained peripheral blood leukocytosis of at least 25 × 109/l (of which >80% are neutrophils) with less than 10% and less than 1% circulating immature granulocytes and myeloblasts [2]. Toxic granulation of the neutrophils may be noted, but there should be no dysplasia or monocytosis, key in the differentiation from atypical chronic myeloid leukaemia (aCML) and chronic myelomonocytic leukaemia (CMML), respectively (Table 1) [2,3]. On biopsy, the bone marrow is hypercellular with granulocytic hyperplasia, normal maturation, no dysplasia and less than 5% myeloblasts [2]. The Philadelphia chromosome and/or the BCR-ABL1 fusion gene are absent, excluding CML. There is no identifiable cause for physiologic neutrophilia (inflammatory, infectious or malignant) or, if present, demonstration of myeloid clonality is required. In particular, plasma cell dyscrasias should be excluded owing to the association with secondary nonclonal neutrophilia [2,4]. There should be no evidence of polycythemia vera, essential thrombocythemia, primary myelofibrosis (PMF), myelodysplastic syndrome (MDS) or MDS/MPN overlap syndromes, such as CMML and aCML.

Table 1
Table 1
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The revised 2008 WHO classification of MPN reflects the discovery of genetic abnormalities in BCR-ABL1 negative MPN, in which the abnormal proliferation is due to clonal rearrangements or mutations of genes that encode protein tyrosine kinases (PTKs) that lead to constitutively activated signal transduction pathways. Some, such as BCR-ABL1 in CML, produce consistent clinical and morphological features that allow the genetic abnormality to be considered a major diagnostic criterion; others such JAK2V617F are not specific for any single MPN, but provide evidence of a clonal rather than a reactive proliferation [5]. Therefore, the updated diagnostic criteria of CNL include molecular exclusion of rearrangements of PDGFRA, PDGFRB or FGFR1[2,5]. Although myeloid clonality in CNL has been established with cytogenetic or molecular anomalies, such as the JAK2V617F mutation, as neither are specific for or of primary pathogenic significance in CNL this diagnosis has remained largely one of exclusion [6,7]. In 2013, the status quo was interrupted with a landmark publication identifying oncogenic mutations in the gene for colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL [8▪▪]. This finding was subsequently validated and clarified with the demonstration of a 100% CSF3R mutational frequency in WHO-defined CNL [9▪▪]. The importance of the discovery of these activating CSF3R mutations is magnified in that their downstream kinase signalling is sensitive to inhibition by currently approved PTKs inhibitors, opening the door to specific therapeutic options for CNL [8▪▪]. This review will focus on these recent discoveries and their implications for CNL diagnosis, management and prognosis.

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CNL is a rare disease; although first described in 1920, by the time formal recognition within the WHO classification was attained, only nearly 150 cases had been reported [10–12]. However, upon application of these WHO diagnostic criteria, a critical review of the literature could only confirm 40 cases, suggesting that the true rate of occurrence is lower [6,12–26]. CNL is generally a disease of older adults (median age: 66 years), with a slight majority being male [6].

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Cytogenetics are normal in the majority of patients with CNL [2,6]. In our review, cytogenetic abnormalities were present in 23% of patients studied at diagnosis [6]. Clonal evolution developed during the course of the disease in 25% with normal cytogenetics at baseline. Recurrent abnormalities detected included del (20q), +21, del (11q) and del (12p), all nonrandom yet nonspecific findings in myeloid disorders [27,28].

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The primary role of molecular genetics in the diagnosis of CNL has been in the exclusion of other haematologic neoplasms, as molecularly defined by the WHO. Specifically, diagnosis of CNL is contingent on the molecular exclusion of the BCR-ABL1 (CML) and rearrangements of PDGFRA, PDGFRB or FGFR1 (myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of these genes) [2,5].

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JAK2V617F mutation

The Janus kinase (JAK) tyrosine kinases play important roles in cytokine-induced haematopoietic cell signalling. Cytokine receptors for erythropoietin, thrombopoietin and CSF3 lack phosphorylation activity and upon activation by their respective ligand binding induce phosphorylation of JAKs, which then phosphorylate further downstream targets regulating transcription such as the STAT pathway [29]. The somatic JAK2V617F mutation is the most prevalent mutation in the classic BCR-ABL1 negative MPN (95% in polycythemia vera, 55% in essential thrombocythemia and 65% in PMF), less frequent in unclassified MPNs (20%), CMML (8%) and rare in MDS and AML [30–32]. Thirteen cases of CNL meeting WHO criteria and carrying JAK2V617F have been published [7,33–42]. Curiously, all 10 cases reporting JAK2V617F allele burden were homozygous [7,33–39,41]. The significance of this is unclear, and as yet, there have been no direct comparisons with heterozygous or wild-type cases. The relative frequency of these case reports must be interpreted in the light that the JAK2V617F was often the main reason for reporting and the recent series of 12 WHO defined CNL-carrying CSF3R mutations, all negative for JAK2V617F [9▪▪]. Future studies of molecularly confirmed CNL will clarify the role, if any, of the JAK2V617F in its pathogenesis or if this mutation defines another MPN subtype, mutually exclusive of CSF3R positive CNL, as both operate through the same downstream signalling pathway.

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Colony-stimulating factor 3 receptor mutations

On the basis of the hypothesis that neutrophilic BCR-ABL negative leukaemias are driven by oncogenes that would be sensitive to small-molecule kinase inhibitors, Maxson et al.[8▪▪] undertook deep sequencing with coverage of coding regions of 1862 genes representing potential targets (including kinases, phosphatases, nonkinase growth factor or cytokine receptors) of primary cells from 27 CNL or aCML patients. Strikingly, 59% had mutations in the CSF3R, compared with 1% with AML. CSF3R is the receptor for colony-stimulating factor 3 (CSF3), the primary growth factor of neutrophil production [43]. Functionally distinct cytoplasmic regions in CSF3R are recognized: the membrane proximal region mediates proliferative and survival signals, and the distal cytoplasmic tail is important in transduction of maturation signals and suppression of proliferation [43,44]. Two types of mutations were found; the majority were membrane proximal mutations: CSF3R T618I (n = 12) and CSF3R T615A (n = 2), either in isolation (n = 9) or as a compound mutation with a variety of frameshift or nonsense mutations that truncate the cytoplasmic tail (truncation mutations) [8▪▪]. Eight of nine cases (89%) classified as CNL had CSF3R mutations compared with 44.4% (eight of 18) classified as either aCML or ambiguously as ‘aCML favoured over CNL’. The in-vitro transforming capacity of both the membrane proximal and truncation mutations was shown to be mediated via differing downstream signalling, that is the JAK–STAT and SRC family–TNK2 kinases, respectively, with resultant differential sensitivity to kinase inhibitors. This inhibitory activity of ruxolitinib and dasatinib on colony formation of transduced murine bone marrow cells with mutations signalling through the JAK (membrane proximal mutations) or SRC family–TNK2 (truncation mutations) kinases, respectively, provided a ground breaking observation [8▪▪]. One CNL patient carrying CSF3RT618I, whose primary leukaemia cells exhibited sensitivity to ruxolitinib in vitro, was treated with this drug and demonstrated a dose-dependent clinical response, defined by a reduction in the neutrophil count and normalization of the platelet count, providing ‘proof of concept’ for future clinical investigation [8▪▪].

In follow-up, Pardanani et al.[9▪▪] determined the frequency and specificity of CSF3R mutations in CNL and aCML. Implicated exons 14–17 of CSF3R were sequenced in 54 clinically suspected cases of CNL (n = 35) or aCML (n = 19). Central review confirmed WHO-defined CNL (n = 12), WHO-defined CNL but with a monoclonal gammopathy or lymphoid neoplasm (n = 6) and WHO-defined aCML (n = 9). The remaining clinically suspected cases of CNL (n = 17) and aCML (n = 9) did not meet WHO criteria for their respective diagnosis. Additional cases of CMML (n = 94) and PMF (n = 76) were also screened. This important study identified 14 CSF3R mutations in 13 patients, all of whom belonged to the group with either WHO-defined CNL (n = 12) or unconfirmed CNL (i.e. not meeting WHO criteria; n = 1), but none in the remaining categories. The majority were membrane proximal CSF3R mutations, most frequently CSF3RT618I occurring in 10 (all with WHO-defined CNL); two had CSF3RM696T mutations and one had a CSF3RI598I mutation. There was a 100% CSF3R proximal membrane mutational frequency in WHO-defined CNL. One case coexpressed a truncating CSF3R mutation. The authors concluded that CSF3RT618I is a highly sensitive and specific molecular marker for CNL and should be incorporated into current diagnostic criteria [9▪▪]. None of the cases of WHO-defined CNL but with a monoclonal gammopathy carried a CSF3R mutation, and their median survival differed significantly from those without a monoclonal gammopathy, at 60 and 21 months, respectively [9▪▪]. This observation is consistent with the evidence that monoclonal gammopathy associated CNL represents a plasma cell driven reactive neutrophilia, including spontaneous remissions of ‘CNL’ during treatment of the plasma cell dyscrasia, demonstration of polyclonal neutrophils and the aberrant production of CSF3 by clonal plasma cells [4,45–49]. If evidence of a plasma cell dyscrasia is found during the evaluation of suspected CNL, clonality of the neutrophil lineage was confirmed before making this diagnosis. CSF3R mutational status is a new specific tool for this [2,9▪▪,41].

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Colony-stimulating factor 3 receptor mutations in other myeloid disorders

Nonsense truncation mutations have been reported in nearly 30% of patients with severe congenital neutropenia (SCN) and introduce a stop codon predicted to lead to the loss of the carboxyterminal-negative regulatory domain, resulting in enhanced CSF3-induced proliferative responses in myeloid progenitors [50,51]. Initially suggested to cause SCN, these are now known to be acquired somatic mutations, associated with, but not necessary for, the progression to leukaemia, at which time prevalence increases to 80% [51].

CSF3RT618I was recently reported in blasts of a patient with SCN, after progression to AML. This only involved the leukaemic blasts, was present on the CSR3R allele already carrying a truncation mutation and caused fully autonomous proliferation of myeloid progenitors [52▪▪]. Investigation of CSF3R-T618I in almost 1500 consecutive de-novo AML cases identified only five (prevalence <0.5%). This mutation led to ligand-independent activation of CSF3R through the stabilization of an active dimeric orientation as recently described in the first report of hereditary chronic neutrophilia [53▪,54]. Specifically, the first germline autosomal dominant point mutation (CSF3RT617N) was reported in 12 of 16 members of a three-generation pedigree with chronic neutrophilia associated with splenomegaly, mimicking an MPN [54]. Progression to MDS occurred in one, with an asymptomatic clinical course in the remaining family members with survivals of up to 80 years [54]. This mutation resulted in constitutive activation of CSF3R through the stabilization of an active dimeric orientation with resultant phosphorylation of the JAK–STAT signalling pathway [54]. This mutation had previously been detected rarely as an acquired mutation in acute leukaemia [55]. In this family with hereditary chronic neutrophilia, clinicopathologic features for many affected satisfied the WHO diagnostic criteria for CNL. Germline studies were not performed in the studies initially linking presumed somatic CSF3R mutations to CNL, and it is possible that some familial cases may have been included [8▪▪,9▪▪]. A detailed family history should be pursued during the evaluation of suspected CNL, in view of the possibility of a hereditary process with the prognostic significance this could entail.

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SETBP1 mutations

With the goal of identifying recurrent oncogenic driver mutations for aCML, Piazza et al.[56▪▪] identified somatic heterozygous SETBP1 mutations in 17 with aCML (24.3%), as well as unclassified MDS/MPN (10%), CMML (4%) and CNL (one of four cases), but not in other haematologic malignancies and solid tumour cell lines. SETBP1 encodes SET-binding protein 1, which stabilizes SET, an inhibitor of the tumour suppressor protein phosphatase 2 A (PP2A). SETBP1-mutated cells express higher levels of SETBP1, and have lower PP2A activity with higher proliferative rates, than their wild-type SETBP1 counterparts [56▪▪]. Clinically, the SETBP1-mutated cases had significantly higher leukocytes and a worse prognosis [56▪▪]. Others confirmed SETBP1 mutational frequencies of up to nearly 32% in aCML with lower frequencies in CMML (5–7%), PMF (3%), MDS and secondary AML (2%) with similar clinical correlates [57–60]. Serial samples of such patients indicated that SETBP1 mutations were acquired during leukaemic evolution [61▪]. Four of 12 (33%) cases of WHO-defined CNL were found to carry a SETBP1 mutation. All coexpressed the CSF3RT618I mutation and showed a trend to reduced survival [9▪▪]. If confirmed, SETBP1 mutations may be a prognostic indicator for CNL.

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The clinical course of CNL is heterogeneous. Disease acceleration often manifests as progressive neutrophilia with resistance to previously effective therapy, progressive splenomegaly or worsening thrombocytopenia (not related to therapy), or with cytogenetic clonal evolution. Blast transformation occurs in nearly 20% at a median of 21 months from diagnosis [6]. The median survival of all patients is under 2 years [6,9▪▪]. No specific prognostic markers have been validated for CNL. It is anticipated that in this era of next-generation sequencing, additional oncogenic markers of prognostic significance, such as mutated SETBP1, will be identified [9▪▪].

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Hydroxyurea is the most commonly used drug and is effective in controlling leukocytosis and splenomegaly, at least initially, until there is evidence of disease acceleration or blast transformation [6]. The successful use of alpha-interferon has been reported in four cases only, often with durable responses [12,16,42]. No haematologic complete remission has been reported following standard induction therapy (anthracycline and cytarabine) for the accelerated or blast phase in CNL, and allogeneic hematopoietic stem cell transplantation represents the only known curative treatment. Despite this, relatively few transplants have been reported in the literature, reflecting the rarity of this disease, the older age of many affected and the lack of validated prognostic markers [6,12,17,24,36,62].

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One patient with CNL carrying a JAK-activating CSF3R mutation (CSF3RT618I) had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib [8▪▪]. Treatment with oral ruxolitinib resulted in a marked decrease in neutrophilic leukocytosis and dose escalation led to further reduction and resolution of thrombocytopenia. At the time of writing, no other cases of CNL having received treatment with JAK inhibitors have been reported.

However, this observation and the in-vitro demonstration of inhibitory activity of known kinase inhibitors on CSF3R mutation transduced cells are anticipated to lead to further investigation of specific tyrosine kinases in CNL management [8▪▪].

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CNL is a rare MPN that may be specifically driven by activating mutations of CSR3R, most commonly CSR3RT618I. On the basis of the physiologic function of CSF3R and observations in a familial form with a similarly mutated receptor, constitutive activation of this receptor can account for all the phenotypic manifestations of the chronic phase of this disease. Genomic instability and the acquisition of additional oncogenic mutations with transforming potential, such as SETBP1, likely lead to progressive disease and leukaemic transformation. Further investigation is now being done in order to define the clonal architecture of this until now poorly understood entity. The diagnosis of CNL will no longer be one of exclusion only and revision of the current WHO diagnostic classification is expected to include the molecular criterion of CSF3R mutation positivity. The recent identification of such driving mutations, with downstream signalling pathways sensitive to currently available tyrosine kinase inhibitors, is anticipated to lead to a new therapeutic approach to CNL. However, further research is required as more specific therapies may be required for long-term disease control. Although the individual patient's prognosis with CNL has been difficult to predict, novel molecular markers such as SETBP1 mutations will likely facilitate therapeutic decision making, and further characterization of such mutations is anticipated.

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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chronic; colony-stimulating factor 3 receptor gene mutations; CSF3RT618I; leukaemia; neutrophilic

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