From www.bloodjournal.org by guest on June 15, 2017. For personal use only. Blood Spotlight

The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment

Jason Gotlib,1 Julia E. Maxson,2,3 Tracy I. George,4 and Jeffrey W. Tyner2,5

1Division of Hematology, Department of Medicine, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA; 2Knight Cancer Institute, and 3Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR; 4Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM; and 5Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR

Although activation of tyrosine kinase path- the granulocyte-colony stimulating factor therapeutically. Herein, we discuss the po- ways is a shared theme among myelopro- receptor (CSF3R)inCNLandinsome tential impact of these findings for the liferative neoplasms, the pathogenetic basis patients with atypical chronic myeloid leu- classification and treatment of these disor- of chronic neutrophilic leukemia (CNL) has kemia. Inhibition of Janus kinase 2 or SRC ders. (Blood. 2013;122(10):1707-1711) remained elusive. Recently, we identified kinase signaling downstream of mutated high-frequency oncogenic mutations in CSF3R is feasible and should be explored Introduction

In clinical practice, neutrophilia most commonly relates to leukemoid granulocytic dysplasia (eg, hypogranular and hypolobated neutrophils, reactions due to chronic infections, inflammatory diseases, or various abnormal chromatin clumping, pseudo–Pelger-Huet¨ neutrophils).4 The types of malignancies.1 Cytokine-driven neutrophilia accompanying white blood count is >13 3 109/L, with immature granulocytes plasma cell neoplasms is a well-described association.1,2 Chronic >10% of leukocytes and ,20% blasts in the blood and marrow. neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm, Monocytosis and basophilia are not prominent (,2% peripheral with only ;200 patients reported to date, mostly culled from case blood basophils, ,10% peripheral blood monocytes), and the leu- reports and small case series.3 Atypical chronic myeloid leukemia kocyte alkaline phosphatase level may be low, normal, or increased, (aCML) is an uncommon myelodysplastic/myeloproliferative (MDS/ therefore lacking diagnostic utility.4,8,9 A hypercellular bone marrow MPN) neoplasm, with a relative incidence estimated at 1 to 2 cases for is observed with a myeloid hyperplasia and prominent granulocytic every 100 patients with BCR-ABL1-positive chronic myeloid leukemia dysplasia, although multilineage dysplasia may be present. (CML).4,5 The disease course of CNL is variable, but acceleration is typically characterized by refractory neutrophilia, worsening organomegaly, and blastic transformation. In a literature review of 40 patients meeting WHO criteria for true CNL, the median survival was 23.5 Histopathologic and clinical features of CNL months (range, 1-106 months).7 Median time to acute myeloid leukemia and aCML (AML) transformation was 21 months (range, 3-94 months). The most frequent causes of death were intracranial hemorrhage, progres- Absence of both BCR-ABL1 and rearrangement of PDGFRA, sive disease/blastic transformation, and regimen-related toxicity from PDGFRB, or FGFR1 are minimal diagnostic requirements for CNL induction chemotherapy or transplantation.6,7 and aCML.3,4 The clinical and laboratory features of CNL include The largest series of WHO-defined aCML consists of 55 cases hepato/splenomegaly, persistent neutrophilic leukocytosis with min- from an Italian cohort.5 The overall median survival was 25 months imal left shift often characterized by toxic granulation and Dohle¨ compared with survivals ranging from 14 to 30 months gleaned bodies, and elevated leukocyte alkaline phosphatase and vitamin from 3 smaller studies.8-10 In the Italian report, transformation to 1,3,6,7 B12 levels. According to the 2008 World Health Organization acute leukemia occurred in 22 patients (40%), with a median time (WHO) diagnostic criteria for CNL,3 the leukocytosis is >25 3 109/L; from diagnosis of 18 months.5 A multivariate analysis revealed that .80% of leukocytes are segmented neutrophils/band forms; and shorter survival was associated with older age (.65 years), female ,10% are immature granulocytes. Granulocytic dysplasia is not pres- gender, leukocyte count .50 3 109/L, and the presence of immature ent, and there is no monocytosis, eosinophilia, or basophilia. Exam- circulating precursors.5 ination of the bone marrow shows a myeloid hyperplasia with full No standard of care exists for CNL or aCML. Therapy has maturation with ,5% myeloblasts (,1% in the peripheral blood). primarily consisted of hydroxyurea or other oral chemotherapeutics, Megakaryocytes are typically normal, but can include some small as well as interferon-a.1,5-11 These agents can elicit improvement in hypolobated megakaryocytes. Reticulin fibrosis is not significantly blood counts but exhibit no proven disease-modifying benefit. increased. Exclusionary criteria include no evidence of a reactive Although splenic irradiation and splenectomy may provide transient neutrophilia, other MPN, MDS, or overlap MDS/MPN disorder.3 palliation of symptomatic splenomegaly, the latter has been asso- Clinicopathologic characteristics of aCML include splenomeg- ciated with anecdotal worsening of neutrophilic leukocytosis in aly and a neutrophilic leukocytosis with left shift and prominent CNL. The limited experience with induction-type chemotherapy

Submitted May 7, 2013; accepted July 19, 2013. Prepublished online as Blood © 2013 by The American Society of Hematology First Edition paper, July 29, 2013; DOI 10.1182/blood-2013-05-500959.

BLOOD, 5 SEPTEMBER 2013 x VOLUME 122, NUMBER 10 1707 From www.bloodjournal.org by guest on June 15, 2017. For personal use only.

1708 GOTLIB et al BLOOD, 5 SEPTEMBER 2013 x VOLUME 122, NUMBER 10

Figure 1. Mutations in CSF3R and SETBP1 are common in CNL and aCML. Percentages of CSF3R, SETBP1, and JAK2 V617F mutations in 29 patients with CNL or aCML are shown. CSF3R mutations arise in 2 classes, nonsense or frameshift mutations that truncate the cytoplasmic tail (truncation mutations) and point mutations in the extracellular domain (membrane proximal mutation), and some cases exhibit both classes of mutations on the same allele (compound mutations). These mutations can occur in isolation or in combination with other mutant genes, with 21% of patients having both CSF3R and SETBP1 mutations. One patient exhibited mutations in both CSF3R (G683R) and JAK2 (V617F); however, the clonality of this double mutation could not be established due to limited material, presenting the possibility of polyclonal populations of tumor cells with distinct mutational profiles. The frequencies of each class of CSF3R mutation alone or in combination with SETBP1 or JAK2 are shown for a combined cohort of CNL and aCML (n 5 29), the CNL cases only (n 5 9), and the aCML cases only (n 5 20). for blastic transformation is generally poor with death related to exhibit different downstream signaling and kinase inhibitor sensi- resistant disease or regimen-related toxicities. Allogeneic trans- tivities. Although CSF3R truncation mutations may exhibit sensitivity plantation may result in favorable long-term outcomes in selected to JAK kinase inhibition in the context of high concentrations of the patients, particularly when undertaken in the chronic phase of CSF3R ligand, downstream signaling operates predominantly through disease.1,5-7,9 SRC kinases and exhibits drug sensitivity to SRC kinase inhibitors such as dasatinib. In contrast, CSF3R membrane proximal mutations strongly activate the JAK/signal transducer and activator of tran- scription pathway and are sensitive to JAK kinase inhibitors such as Cytogenetic/molecular features ruxolitinib. A CNL patient with the CSF3R T618I membrane prox- imal mutation was treated with ruxolitinib and exhibited a marked, Although clonality has been demonstrated in CNL,12,13 the majority 1,6,7 durable decrease in white blood cell and absolute neutrophil counts of patients exhibit normal cytogenetics. The frequency of chro- and resolution of thrombocytopenia (initially reported as a 5-month mosomal changes in aCML is more variable, ranging from 20% to 5,8-10 response, now still responding after 11 months). This case, although 88% in 4 series. In both diseases, trisomy 8 and del (20q) are the anecdotal, provides a strong rationale for the investigation of tyrosine fi most common nonspeci c chromosomal abnormalities observed at kinase inhibitors (TKIs) in CNL and aCML patients. Further inves- diagnosis or at the time of progressive disease. The e19/a2 type tigation in clinical trial settings will be required to determine whether BCR/ABL mRNA transcript (p230) that was initially reported as the JAK kinase inhibition in the setting of CSF3R mutation will lead to molecular basis for some cases of CNL is instead now considered 14 greater decreases in mutation allele burden compared with the re- related to an uncommon neutrophilic variant of CML. Notwith- sponses observed in the setting of JAK2V617F. This will also be standing case reports of JAK2 V617F positivity in selected cases of 11,15,16 informative regarding the extent to which CSF3R mutation is a CNL and aCML, no other recurrent genetic mutations had primary driver of disease. fi been identi ed in these diseases until the recent discoveries of mutant Under normal circumstances, the CSF3R ligand, granulocyte-colony- 15,17 fi SETBP1 and CSF3R. In addition to these newly de ned, high- stimulating factor (G-CSF), promotes growth and survival of myeloid frequency mutations in SETBP1 and CSF3R, other recurrent muta- precursor cells, ultimately leading to differentiation of these myeloid tions in a variety of genes including NRAS, IDH2,andCBL have 17 precursors into neutrophils. In keeping with the prominent role of recently been described in aCML at lower frequencies. G-CSF in the production of neutrophils, deletion of CSF3R leads to neutropenia in mouse models.20 In addition to regulating normal neutrophil homeostasis, G-CSF levels rapidly increase during in- fection, resulting in elevated levels of neutrophils as a component of New genetic findings in CNL and aCML the immune response.21 The normal role of CSF3R in promoting CSF3R mutations neutrophil production is biologically consistent with our observa- tion of CSF3R activating mutations in hematologic malignancies We recently reported that ;50% to 60% of patients with CNL or characterized by high levels of neutrophils. aCML harbor mutations in the receptor for colony-stimulating Mutations in CSF3R have previously been identified in patients factor 3 (CSF3R; GCSFR).15 Among a total of 29 patients, 8 of 9 with severe congenital neutropenia (SCN).22-24 These SCN patients CNL (89%) and 8 of 20 aCML (40%) cases exhibited CSF3R harbor germ-line mutations in neutrophil elastase or other genes mutations. These mutations fall into 2 classes: nonsense or frame- necessary for production of neutrophils. To avoid infections asso- shift mutations that lead to premature truncation of the cytoplasmic ciated with neutropenia, a large percentage of these patients are tail of the receptor (truncation mutations) and point mutations in treated chronically with G-CSF to improve neutrophil production. the extracellular domain of CSF3R (membrane proximal mutations). Approximately one-third of SCN patients eventually acquire truncat- The most common CSF3R mutation in CNL/aCML is the membrane ion mutations in CSF3R (analogous to the truncation mutations we proximal mutation: T618I. CSF3R is known to signal downstream have observed in de novo CNL and aCML), which are associated through both Janus kinase (JAK)18 and SRC tyrosine kinase path- with transformation to myelodysplasia or AML.22,23 Additionally, ways,19 andthe2classesofCSF3R mutations that we observed similar to our observations in CNL/aCML, SCN patients can From www.bloodjournal.org by guest on June 15, 2017. For personal use only.

BLOOD, 5 SEPTEMBER 2013 x VOLUME 122, NUMBER 10 GENETICS OF CHRONIC NEUTROPHILIC LEUKEMIA AND ATYPICAL CML 1709

Figure 2. Provisional diagnostic algorithm for neutrophilia and genetically informed treatment options. †FISH probes for myeloid-associated cytogenetic abnormalities can be used to complement standard karyotype analysis to establish the presence of a clonal myeloid disorder. Cytogenetic/FISH or molecular evaluation of rearranged PDGFRA/B, and FGFR1 should also be considered if eosinophilia is present. ‡Testing for JAK2 V617F, infrequently identified in CNL or atypical CML, should also be considered. The list of relevant mutations, including molecular abnormalities in complementary signaling pathways to CSF3R and SETBP1, may expand over time. *For patients who are CSF3R-mutation negative, use of a JAK inhibitor (particularly if JAK2 V617F positive) or SRC kinase inhibitor could be considered since mutations in the same or related signaling pathways may be present.

acquire compound CSF3R mutations. A recent paper described CSF3R truncation mutations result in a loss of a portion of the a case of a SCN patient who acquired a CSF3R truncation mutation cytoplasmic domain of the receptor, suggesting possible molecular followed by a T618I point mutation (reported as T595I using the mechanisms for receptor activation. Truncated CSF3R may lack the traditional CSF3R numbering system that does not include the signal di-leucine internalization motif, resulting in an increase in cell sur- peptide).24 face expression of the receptor.25 These truncated receptors may also From www.bloodjournal.org by guest on June 15, 2017. For personal use only.

1710 GOTLIB et al BLOOD, 5 SEPTEMBER 2013 x VOLUME 122, NUMBER 10 lack the binding site for suppressor of cytokine signaling 3, which for these diseases and suggests a close relationship between these reduces trafficking of CSF3R to the lysosome. The functional con- neutrophilic leukemias. These findings may also lend more speci- sequence of these truncations is altered and increased receptor activ- ficity to the WHO diagnostic criteria for CNL and aCML, which are ity conferring ligand hypersensitivity. In contrast, the membrane variably applied in routine clinical practice. In patients for whom the proximal mutations exhibit receptor activation in the complete absence cause of neutrophilia is not easily discernible, the incorporation of of ligand,15,24 suggesting distinct mechanisms of activation of these CSF3R mutation testing can be a useful point-of-care diagnostic to classes of CSF3R mutations. These distinct mechanisms may contrib- evaluate for the presence of a clonal myeloid disorder, as well as the ute to the differential downstream signaling and drug sensitivity of potential for genetically informed therapy (Figure 2). truncation vs membrane proximal mutations. In fact, 4 of 5 patients The basis for phenotypic differences between CSF3R mutation- with truncation mutations also had the T618I point mutation, indi- positive CNL and aCML may relate to multiple factors. These likely cating that acquisition of both classes of mutations may be advan- include patient genetic background, characteristics of the distinct tageous for tumor pathogenesis. CSF3R mutation (eg, hematopoietic cell of origin, allele burden, activation of distinct signaling cascades), and the accompanying SETBP1 mutations clonal architecture of these neoplasms (eg, mutations of SETBP1, Recurrent mutations in SETBP1 were recently identified in 25% of JAK2 V617F, or other genes). CNL may be the archetype of aCML patients.17 Set binding protein (SETBP1) interacts with SET, an MPN whose pathogenesis is predominantly characterized by a negative regulator of the tumor suppressor protein phosphatase 2A mutations of CSF3R, whereas aCML may be more genetically (PP2A).26 SETBP1 protects SET from protease cleavage, thus heterogeneous. increasing the amount of SET available to repress the activity of Given the poor prognosis of these disorders, the potential appli- PP2A.27 In AML, SETBP1 overexpression is significantly associ- cability of JAK or SRC kinase inhibitors is an important bench-to- ated with reduced survival, indicating that SETBP1 may be relevant bedside implication of the discovery of activating CSF3R mutations. to leukemia oncogenesis.27 SETBP1 is mutated at lower frequencies These drugs are expected to be more effective in the chronic phase of in unclassified MDS/MPN (10%) and CMML (4%), but no SETBP1 disease before increasing genetic complexity associated with disease mutations are found in AML, acute lymphoblastic leukemia, chronic transformation supervenes, and therapeutic inhibition of CSF3R- lymphocytic leukemia, or solid tumors.17 SETBP1 mutations in related signaling may be less relevant. Future experience with these aCML were associated with higher white blood cell counts at diagnosis agents will inform whether complete hematologic remissions and in- and poorer survival.17 Similarly, overall survival was significantly depth molecular responses are realized, similar to experience with worse for CMML patients with SETBP1 mutations.28,29 TKIs in CML and PDGFRA/B-rearranged myeloid neoplasms as- In aCML, the majority of SETBP1 mutations are located in a 14 sociated with eosinophilia. Ultimately, comparison of TKI-treated amino acid stretch that is also mutated in Schinzel-Giedion syn- patients to historical controls will help determine whether these drome, a rare genetic disease characterized by congenital malfor- therapies impact disease endpoints such as leukemia-free progres- mations, mental retardation, and a high prevalence of epithelial sion and overall survival. tumors.30 When phosphorylated, this mutational hotspot is bound by the E3 ubiquitin ligase subunit b-TrCP1, leading to ubiquitination of SETBP1 and subsequent degradation.17 The SETBP1 mutants disrupt this consensus b-TrCP motif, leading to increased SETBP1 and SET expression, which lowers PP2A activity and increases proliferation Acknowledgments of cells.17 This increased cellular proliferation may be relevant to the pathobiology of aCML. We apologize to investigators whose work was not included and referenced in this review due to space restrictions. J.G. is supported by the Charles and Ann Johnson Foundation. CSF3R SETBP1 J.E.M. is supported in part by the Training Program in Molecular and mutational overlap Hematology 5T32HL007781-20. J.W.T. is supported by grants from The Leukemia and Lymphoma Society, the V Foundation CSF3R and SETBP1 mutations are not mutually exclusive in CNL/ for Cancer Research, the Gabrielle’s Angel Foundation for Cancer aCML. In follow-up sequencing of an expanded cohort of 29 patients Research, the William Lawrence and Blanche Hughes Fund, and the from the New England Journal of Medicine report,15 21% have ex- National Cancer Institute (4 R00CA151457-03). hibited both CSF3R and SETBP1 mutations, with 31% of samples having CSF3R mutations only and 7% with SETBP1 mutations only (Figure 1). These combinatorial mutations suggest a requirement for different therapeutic approaches tailored to the molecular profile of individual patients. Although these recent studies have increased Authorship our understanding of the genetic drivers of CNL and aCML, this knowledge is lacking in ;30% of patients. Functional genomic Contribution: J.G., J.E.M., T.I.G., and J.W.T. contributed to the studies will permit a more comprehensive understanding of the writing of the manuscript. molecular complexity of these diseases. Conflict-of-interest disclosure: J.G. and J.W.T. receive funding for administration of clinical trials from Incyte, manufacturer of ruxolitinib, and J.G. additionally serves on an Incyte advisory board. Summary The remaining authors declare no competing financial interests. Correspondence: Jason Gotlib, Department of Medicine (Hema- The discovery of high-frequency CSF3R mutations in CNL, and to tology), Stanford Cancer Institute, 875 Blake Wilbur Dr, Room a lesser extent in aCML, identifies a new major diagnostic criterion 2324, Stanford, CA 94305-5821; e-mail: [email protected]. From www.bloodjournal.org by guest on June 15, 2017. For personal use only.

BLOOD, 5 SEPTEMBER 2013 x VOLUME 122, NUMBER 10 GENETICS OF CHRONIC NEUTROPHILIC LEUKEMIA AND ATYPICAL CML 1711

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2013 122: 1707-1711 doi:10.1182/blood-2013-05-500959 originally published online July 29, 2013

The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment

Jason Gotlib, Julia E. Maxson, Tracy I. George and Jeffrey W. Tyner

Updated information and services can be found at: http://www.bloodjournal.org/content/122/10/1707.full.html Articles on similar topics can be found in the following Blood collections Blood Spotlight (64 articles) Free Research Articles (4527 articles) Myeloid Neoplasia (1686 articles)

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