British Journal of Haematology
Chronic neutrophilic l eukaemia and plasma cell -related neutrophilic leukaemoid reactions
Journal:For British Peer Journal of Haematology Review Manuscript ID: Draft
Manuscript Type: Ordinary Papers
Date Submitted by the Author: n/a
Complete List of Authors: Bain, Barbara; St Mary's Hospital, Haematology
MGUS, MULTIPLE MYELOMA, CHRONIC LEUKAEMIA, CHRONIC Key Words: NEUTROPHILIC
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1 2 3 Chronic neutrophilic leukaemia and plasma cell related neutrophilic leukaemoid reactions 4 5 1 2 6 Barbara J. Bain and Shahzaib Ahmad 7 1Department of Haematology, Imperial College Healthcare NHS Health Trust and Centre 8 for Haematology, St Mary’s Hospital campus of Imperial College London, St Mary’s 9 2 10 Hospital, Praed Street, London, W2 1NY and Barts and the London School of Medicine 11 and Dentistry, Queen Mary University of London, St Batholomew's Hospital, London 12 EC1A 7BE , UK. 13 14 15 Summary 16 17 Many cases reported as ‘chronic neutrophilic leukaemia’ have had an associated plasma 18 cell neoplasm. RecentFor evidence Peer suggests that Reviewthe great majority of such cases represent a 19 neutrophilic leukaemoid reaction to the underlying multiple myeloma or monoclonal 20 gammopathy of undetermined significance. We have analysed all accessible reported 21 cases to clarify the likely diagnosis and to ascertain whether toxic granulation, Döhle 22 23 bodies and an increased neutrophil alkaline phosphatase score were useful in making a 24 distinction between chronic neutrophilic leukaemia and a neutrophilic leukaemoid 25 reaction. We established that all these changes occur in both conditions. Toxic 26 granulation and Döhle bodies are more consistently present in leukaemoid reactions but 27 28 also occur quite frequently in chronic neutrophilic leukaemia. The neutrophil alkaline 29 phosphatase score is increased in both conditions and is of no value in making a 30 distinction. 31 32 Introduction 33 34 As defined in the 2008 WHO classification (Bain , et al 2008), chronic neutrophilic 35 leukaemia (CNL) is a Ph negative myeloproliferative neoplasm (MPN) characterised by 36 a white cell count (WBC) of at least 25 × 10 9/l with segmented neutrophils and band 37 forms comprising more than 80% of leucocytes, circulating blast cells less than 1%, 38 immature granulocytes (promyelocytes, myelocytes and metamyelocytes) less than 10% 39 9 40 and monocytes less than 1.0 × 10 /l. There is no evidence of another MPN or a 41 myelodysplastic syndrome (MDS), no dysplasia in any lineage and no evidence of a 42 myelodysplastic/myeloproliferative neoplasm (MDS/MPN). There should be no 43 identifiable cause of physiological neutrophilia or, if such is present, there should be 44 45 evidence of clonality. From the early 1900s onwards, more than 200 cases of CNL have 46 been described but many of these would not meet current diagnostic criteria. The first 47 known case meeting current criteria is that described by Tuohy in 1920 as ‘A case of 48 splenomegaly with polymorphonuclear neutrophil hyperleukocytosis’ (Tuohy 1920). 49 However four other early cases had atypical features and appear more likely to have been 50 51 primary myelofibrosis (Emile Weil and Sée 1932, Hirschfeld 1904, Rathery 1902). 52 53 It is important to distinguish CNL from the neutrophilic leukaemoid reaction that can 54 occur with multiple myeloma (plasma cell myeloma) and monoclonal gammopathy of 55 undetermined significance (MGUS), which is attributable to cytokine release by 56 57 neoplastic plasma cells. We were interested in reports of toxic granulation and Döhle 58 59 60 British Journal of Haematology Page 2 of 26
1 2 3 bodies in patients considered to have CNL and we have also observed these phenomena 4 5 in neutrophilic leukaemoid reactions. Since toxic granulation is uncommon in myeloid 6 neoplasms, this caused us to question whether some cases diagnosed as CNL might in 7 fact have had a leukaemoid reaction to a plasma cell neoplasm. An increased neutrophil 8 alkaline phosphatase (NAP) has similarly been described in CNL and in neutrophilic 9 10 leukaemoid reactions. We therefore reviewed published cases of CNL to ascertain 11 whether toxic granulation, Döhle bodies, other cytological abnormalities or an increased 12 NAP were features of cases with a firmly established diagnosis of CNL. We similarly 13 reviewed reported cases of plasma cell associated neutrophilic leukaemoid reaction. We 14 sought to relate any cytological abnormalities in neutrophils to the mutation in CSFR3 , 15 16 which is strongly associated with CNL (Maxson , et al 2013). 17 18 Methods For Peer Review 19 We identified and reviewed published cases of chronic neutrophilic leukaemia without an 20 apparent coexisting plasma cell neoplasm. We similarly reviewed reports of patients with 21 22 ‘chronic neutrophilic leukaemia’ or a neutrophilic leukaemoid reaction associated with 23 multiple myeloma or monoclonal gammopathy or undetermined significance (MGUS). 24 Our review included mainly cases published in English but also a small number of cases 25 published in French, Italian or Spanish; we read all available abstracts of cases published 26 27 in other languages (mainly Japanese and Korean). We excluded from the analysis, 28 patients with features of polycythaemia vera, essential thrombocythaemia or primary 9 29 myelofibrosis. We similarly excluded cases with monocytes of 1.0 × 10 /l or more, with 30 other evidence of MDS/MPN, with significant dysplasia, or in whom the ‘CNL’ 31 represented evolution from MDS. In the cases with a confirmed diagnosis of CNL and in 32 33 those with multiple myeloma or MGUS we reviewed written descriptions of neutrophil 34 morphology and published photographs of blood films in order to assess the presence of 35 toxic granulation, Döhle bodies or other cytological abnormalities. We also documented 36 whether NAP was reduced, normal or elevated. 37 38 39 Results 40 At least 53 cases published as ‘chronic neutrophilic leukaemia’ did not meet current 41 diagnostic criteria. We excluded from further consideration a total of eleven cases with 42 features of polycythaemia vera (Billio , et al 2001, Castelli , et al 2015, Exton Smith and 43 44 Chazan 1957, Fujisawa , et al 1992, Harada , et al 1993, Higuchi , et al 1999, Iurlo , et al 45 1990, Lee , et al 2004, Lugassy and Farhi 1989, Shirakura , et al 1979, Tsurumi , et al 46 2002) , nine cases with essential thrombocythaemia (Boggs and Kaplan 1986, Di Donato , 47 et al 1986, Kunishima , et al 1989, Orazi , et al 1989, Zittoun , et al 1994) (case 2), 48 (Noguchi , et al 2001, Ramya , et al 2014, Terré , et al 1999, Zhang , et al 2013) and two 49 50 cases with primary myelofibrosis (Hirayama , et al 1994, Silberstein , et al 1974). We 51 similarly excluded 15 cases with evidence of significant dysplasia or in whom the ‘CNL’ 52 represented evolution from MDS (Cervantes , et al 1988, Cervantes , et al 1990, Mehrotra , 53 et al 1985, Zoumbos , et al 1989) (four cases) , (Dash , et al 1990, Zittoun , et al 1994) (case 54 3), (Carulli , et al 2010, Lee , et al 2001, Merlat , et al 2000, Ota , et al 2000, Pascucci , et al 55 56 1997, Takamatsu , et al 1996, Yamamoto , et al 2002) and also eight patients in whom 57 there was evidence of MDS/MPN, such as monocytosis or significant numbers of 58 59 60 Page 3 of 26 British Journal of Haematology
1 2 3 granulocyte precursors (Kaplan , et al 1992, Nakamine , et al 1988, Zittoun , et al 1994) 4 5 (Case 1) , (Katsuki , et al 2000, Pardanani , et al 2013 (cases 2 and 7), Piliotis , et al 2002, 9 6 Quintero 2004) We did accept one case with a platelet count of 800 × 10 /l as this count 7 was three months after splenectomy (Orazi , et al 1989). We excluded one patient in 8 whom the reported WBC was only 11.3 × 10 9/l (Bohm and Schaefer 2002), one with a 9 WBC of 13.6 × 10 9/l (Zittoun , et al 1994), (case 1), two with counts of 15.5 and 16.2 × 10 9 11 10 /l respectively (Saitoh and Shibata 1996) and three in whom the neutrophils were 65% 12 (Yasui , et al 2003), 68% (Bohm and Schaefer 2002) and 74% (Bohm and Schaefer 2002) 13 but we did include several patients in whom CNL appeared to be the most likely 14 diagnosis but the reported WBC did not quite reach the 25 × 10 9/l or the neutrophils were 15 16 not quite the >80% required by the WHO classification; this approach is justified by the 17 variability of the WBC and percentage of neutrophils over time. A single patient was 18 excluded as there wasFor rearrangement Peer of PDGFRA Review (Jain , et al 2013). After exclusion of a 19 total of 53 cases, there remained for review a total of 146 patients with CNL without an 20 apparent plasma cell neoplasm (Table 1). Fifteen patients had cytologically normal 21 22 neutrophils. Toxic granulation was observed in 22 patients; in 11 of these cases Döhle 23 bodies were also present, in one with accompanying vacuolation, and in two there was 24 also neutrophil hypersegmentation. In one recent report of nine patients, one patient had 25 documented toxic granulation and Döhle bodies and it was stated that these were 26 27 common morphological features in patients with a CSFR3 mutation (Maxson , et al 2013). 28 Ring neutrophils were noted in four patients in a single publication (Kanoh , et al 1986) 29 and one patient had neutrophil hypersegmentation without other abnormal features 30 (Sugino , et al 2009). In nine cases there was some reference to morphology but 31 insufficient for a judgement to be made as to what changes were actually present. In 95 32 33 patients there was neither a description of the morphological features of neutrophils nor 34 an interpretable image. 35 The NAP was elevated in 82 cases of CNL, normal in six and low in two. In 56 36 cases this information was not available. 37 Because of the paucity of information, it was difficult to relate cytology and NAP 38 39 to specific genetic abnormalities associated with CNL. Of the eight patients with a 40 CSF3R mutation reported by Maxson et al. (Maxson , et al 2013), five of whom also has a 41 SETBP1 mutation (Gotlib , et al 2013), one was reported as having toxic granulation and 42 Döhle bodies and it was stated that these were common morphological features in 43 44 patients with a CSFR3 mutation; NAP was not reported. Information on cytology and 45 NAP was not available for the 10 patients reported by Pardanani et al ., who met the 46 WHO criteria for CNL and who has a CSF3R mutation, in two cases accompanied by a 47 SETBP1 mutation (Pardanani , et al 2013). Information was similarly not available for a 48 total of 10 further patients with a CSFR3 mutation, often accompanied by a SETBP1 or 49 50 ASXL1 mutation (Cui , et al 2014, Lasho , et al 2014, Menezes , et al 2013). Of 14 reported 51 cases with JAK2 V617F, toxic granulation was present in two, in one case associated with 52 Döhle bodies, one case showed hypersegmented neutrophils and five were cytologically 53 normal; there was no useful information available in six cases (Gajendra , et al 2014, 54 Imashuku , et al 2012, Kako , et al 2007, Lea , et al 2006, Maxson , et al 2013, Mc Lornan , 55 56 et al 2005, Ortiz Cruz , et al 2012, Steensma , et al 2005, Sugino , et al 2009, Thiele 2009, 57 58 59 60 British Journal of Haematology Page 4 of 26
1 2 3 Uemura , et al 2009, Wang , et al 2014). Six of the 14 patients had a high NAP and in 4 5 eight information on NAP was not available. 6 There were a total of 49 patients with ‘CNL’ or neutrophilic leukaemoid reaction 7 associated with multiple myeloma or MGUS (Table 2). Since MGUS is not rare in the 8 age range in which CNL usually occurs, we cannot exclude that some patients did 9 10 actually have both CNL and a plasma cell neoplasm. This is so for a patient who 11 developed CSF3R mutated CNL two years after detection of MGUS (Blombery , et al 12 2014) and for a patient in whom there was both smouldering myeloma and a homozygous 13 JAK2 V617F mutation (Nedeljkovic , et al 2014). The co existence of two unrelated 14 conditions also seems likely in a patient in whom the neutrophilia diminished as the 15 16 myeloma became manifest (Rovira , et al 1990). Evolution of ‘CNL’ into acute myeloid 17 leukaemia (AML) might be taken as evidence of the neoplastic nature of the apparent 18 CNL; however in threeFor patients Peer in whom this Reviewoccurred there had been prior treatment 19 with leukaemogenic drugs such as busulphan and melphalan (Tursz , et al 1974) (patient 20 4) , (Dincol , et al 2002, Lewis , et al 1986) so these cases were not excluded from the 21 22 analysis. Case 4 reported by Zoumbos et al (Zoumbos , et al 1989) is of interest as this 23 patient presented with ‘CNL’ and subsequently developed both kappa light chain 24 myeloma and acute myeloid leukaemia; however the patient had trilineage 25 myelodysplasia and so, with current diagnostic criteria, the initial presentation was as 26 27 MDS/MPN rather than CNL . Having excluded the three patients in whom coexistence of 28 two unrelated conditions was definite or likely, there remained 46 patients for analysis. 29 Morphology of the neutrophils was described or illustrated in 28 cases and was not 30 available in 18. Toxic granulation (Figure 1) was common, being reported in 25 of 27 31 described cases; it was often associated with the presence of Döhle bodies (11 cases), 32 33 vacuoles (1 patient) or both (1 patient). A further patient had Döhle bodies without toxic 34 granulation. Neutrophils appeared normal in two patients. NAP was available in 31 35 patients; it was increased in 28, normal in two and very low in one. 36 The associated plasma cell neoplasm was multiple myeloma in 27 cases, MGUS 37 in 18 cases and plasmacytoma in one case. Kappa light chains were expressed in 15 38 39 patients, lambda in 22 and both light chain types in one patient; in eight patients this 40 information was not available. 41 Comparison of data from the two groups of patients shows that toxic granulation 42 and Döhle bodies are observed not infrequently in CNL but are more consistently 43 44 associated with a neutrophilic leukaemoid reaction (Table 3). A high NAP is equally 45 common in the two groups of disorders (Table 4). 46 47 Discussion 48 The lack of any specific cytogenetic abnormality has complicated the accurate diagnosis 49 50 of CNL; until recently, information on molecular genetic abnormalities was also sparse so 51 that there was often no evidence of clonality in cases in which this diagnosis was made. 52 This situation has altered with the recent description of a strong association between a 53 mutation in CSFR3 , encoding the receptor for granulocyte colony stimulating factor (G 54 CSF) (Maxson , et al 2013) and a diagnosis of CNL and the subsequent reporting of a co 55 56 existing mutation of SETBP1 or ASXL1 in a significant proportion of patients (Cui , et al 57 2014, Lasho , et al 2014, Menezes , et al 2013). Maxon et al . detected a CSFR3 mutation 58 59 60 Page 5 of 26 British Journal of Haematology
1 2 3 in eight of nine patients with CNL and in eight of 20 patients with a diagnosis of atypical 4 5 chronic myeloid leukaemia (aCML) (Maxson , et al 2013). In a subsequent series of 6 patients reported by Pardanani et al . in whom the diagnosis was reviewed before the 7 molecular results were known, CSFR3 mutation was found in all 12 patients with 8 confirmed CNL (without MGUS); this series included three patients in whom the 9 10 diagnosis of CNL was accepted but the WHO criteria were not quite met (one with 11% 11 immature granulocytes, one with 10% monocytes and one with 78% rather than >80% 12 neutrophils) (Pardanani , et al 2013). Pardanani et al . found no CSFR3 mutation in 9 13 patients designated aCML in whom exons 14‒17 were screened and mutation was 14 similarly absent in 94 patients with chronic myelomonocytic leukaemia (CMML) and in 15 16 76 with primary myelofibrosis in whom only exon 14 was analysed (Pardanani , et al 17 2013). In this series, an additional mutation in SETBP1 was found in four of 12 cases of 18 CSFR3 mutated CNLFor (Pardanani Peer, et al 2013) .Review CSFR3 mutation was absent in 5 patients 19 with a plasma cell neoplasm who were considered to meet the WHO criteria for CNL 20 (Pardanani , et al 2013). In a third series of patients with CNL, a CSFR3 mutation was 21 22 found in six of 14 patients with CNL, two of 58 with aCML and two of 146 with chronic 23 myelomonocytic leukaemia (Meggendorfer , et al 2014) . Other mutations found in 24 patients with CNL in this third series were ASXL1 (8/14 cases), TET2 (4/4 cases), SRSF2 25 (3/14) and SETBP1 (2/14 cases), with only SETBP1 mutation coexisting with CSFR3 26 27 mutation; only mutation of CSFR3 was significantly more common in CNL than in 28 aCML and CMML. In addition to these recently characterised molecular genetic 29 abnormalities, at least 14 cases of CNL with a JAK2 V617F mutation have been reported 30 (Gajendra , et al 2014, Imashuku , et al 2012, Kako , et al 2007, Lea , et al 2006, Lee , et al 31 2012, Mc Lornan , et al 2005, Ortiz Cruz , et al 2012, Pardanani , et al 2013, Steensma , et 32 33 al 2005, Sugino , et al 2009, Uemura , et al 2009) Gajendra 2014 (3 cases) ). In addition, 34 JAK2 V617F was found in a further patient with a clinical diagnosis of CNL but with a 35 WBC of only 16.7 × 10 9/l (85% neutrophils) (Pardanani , et al 2013). 36 37 Our assessment of the significance of toxic granulation and Döhle bodies was made 38 39 difficulty by the very inexact diagnostic criteria that have been applied since the disease 40 was first described in 1920. We can only reiterate the comment of Reilly (Reilly 2002) 41 that “The literature … is frequently confusing and often incomplete”. In addition, many 42 reports make no mention of neutrophil cytology so that the number of cases that could be 43 44 assessed was considerably fewer than the total reported. Despite this, we have 45 demonstrated that toxic granulation can occur in both CNL and in neutrophilic 46 leukaemoid reactions but is much more consistently present in the latter. We were unable 47 make an adequate assessment of neutrophil cytology in relation to CSFR3 or other 48 mutations as recent papers focusing on molecular abnormalities have included few 49 50 morphological details. We observed an increased NAP in both CNL and plasma cell 51 associated neutrophilia with a similar frequency being observed in the two groups of 52 patients. 53 54 Truncating mutations of CSF3R can lead to both constitutive overexpression of the 55 56 receptor and also to ligand hypersensitivity while proximal membrane mutations render 57 cells ligand independent (Maxson , et al 2013). We postulate that truncating and possibly 58 59 60 British Journal of Haematology Page 6 of 26
1 2 3 other mutations of CSF3R can lead to toxic granulation and Döhle bodies in CNL 4 5 whereas in neutrophilic leukaemoid reactions associated with plasma cell neoplasms 6 similar cytological changes result from the synthesis of G CSF by neoplastic plasma cells, 7 which has been repeatedly demonstrated (Kohmura , et al 2004, Kusaba , et al 2004, 8 Nagai , et al 1996, Rodríguez Medina , et al 2013, Saitoh and Shibata 1996, Sebasky , et al 9 10 2008, Usuda , et al 1997). 11 12 We have confirmed the already reported preferential association of a neutrophilic 13 leukaemoid reaction with lambda expressing neoplastic plasma cells (Reilly 2002, 14 Standen , et al 1990). Nevertheless only 59% of strictly defined cases were lambda 15 16 associated. 17 18 The discovery of theFor CSFR3 andPeer other mutations Review in CNL is likely to make a major 19 contribution to the diagnosis of CNL and it seems possible that this will lead to a 20 redefinition of the WHO diagnostic criteria. Consideration of the extent to which the 21 22 WHO criteria might be altered if a CSFR3 or other relevant mutation is demonstrated 23 awaits the availability of further data. It seems prudent to require evidence of clonality of 24 myeloid cells before making a diagnosis of CNL in a patient with MGUS or multiple 25 myeloma since the majority of cases in which this diagnosis is suspected represent a 26 27 leukaemoid reaction. Conversely, demonstration of polyclonal neutrophils (Standen , et al 28 1993) or increased plasma G CSF provides strong supporting evidence for a diagnosis of 29 a leukaemoid reaction. The presence of toxic granulation and Döhle bodies is more likely 30 in a leukaemoid reaction than in CNL but the NAP does not aid in the distinction and is 31 now of little diagnostic value. 32 33 34 Acknowledgements 35 The two authors together performed the research, carried out the analysis and wrote the 36 paper. 37 38 39 40 Legend for figure 41 Peripheral blood film from an unpublished case of neutrophilic leukaemoid reaction 42 associated with multiple myeloma showing neutrophilia, toxic granulation, increased 43 44 background staining and rouleaux formation. 45 46 47 References 48 Bain, B.J., Brunning, R.D., W., V.J. & Thiele, J. (2008) In Swerdlow, S.H., Campo, E., 49 50 Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J. & Vardiman J.W. (Eds) 51 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, 52 Lyon, France, pp. 38‒39. 53 Billio, A., Venturi, R., Morello, E., Rosanelli, C., Pescosta, N. & Coser, P. (2001) 54 Chronic neutrophilic leukemia evolving from polycythemia vera with multiple 55 56 chromosome rearrangements: a case report . Haematologica, 86, 1225‒1226. 57 58 59 60 Page 7 of 26 British Journal of Haematology
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1 2 3 4 5 Table 1 6 Summary of cases of chronic neutrophilic leukaemia in which cytological features of 7 neutrophils were described or illustrated. 8 9 Age and WBC (× Description of NAP References 10 9 11 gender 10 /l), neutrophils 12 neutrophils 13 58/F 65, 99% Normal granules NA (Tuohy 1920) 14 , et al 15 72/M 60, 96% Not described High (Tanzer 16 1964) 17 76/F 15‒45, >85% ‘Shift to the left’ High (Gingold , et al 18 For Peer Review 1964) 19 66/F 50, 95% Not described High (Jackson and 20 21 Clark 1965) 22 58/M 69.4, 98% Döhle bodies present High (Rubin 1966) 23 over 2½ years; no TG 24 apparent in photograph 25 26 74/M 27, 80% Not described High (Shindo , et al 27 1977) 28 60/M 89, 78%; Döhle bodies and High (You and 29 (case 1) later 188, prominent TG Weisbrot 1979) 30 85% 31 32 81/M 39.7, 94% Döhle bodies and High (You and 33 (case 2) prominent TG Weisbrot 1979) 34 74/M 166.5, 91% Döhle bodies High (Aoki , et al 35 1979)* 36 37 49/M 132, 96% Not described High (Bareford and 38 Jacobs 1980) 39 49/M NA TG in photograph High (Yam 1982) 40 67/M 71.5, 96% Normal High (Dotten , et al 41 42 1982) 43 50/M 25.2, 76% Normal High (Feremans , et 44 al 1983) 45 66/M 66, 87% Not described High (Sponza , et al 46 47 1985) 48 75/F NA 2% ring shaped nuclei High (Kanoh , et al 49 (case 1) 1986) 50 53/M NA 3.5% ring shaped nuclei High (Kanoh , et al 51 (case 2) 1986) 52 53 70/M NA 3% ring shaped nuclei High (Kanoh , et al 54 (case 3) 1986) 55 26/F NA 10% ring shaped nuclei High (Kanoh , et al 56 (case 4) 1986) 57 58 72/F 129, 81% Not described High (Hossfeld , et al 59 60 British Journal of Haematology Page 14 of 26
1 2 3 4 (case 1) 1987) 5 71/F 101, 89% Not described Normal then (Hossfeld , et al 6 (case 2) high 1987) 7 56/F 33.7, 79% Not described in abstract High (Nakase , et al 8 1987)* 9 10 63/M 30.4‒51, TG High (Lim , et al 11 75‒85% 1987)† 12 40/F 10‒36, 91% Not described High (Tang , et al 13 1987) 14 15 45/F 35, 86% Not described High (Sundar , et al 16 1988) 17 71/M 49.6, NA Not described in abstract High (Tohyama , et 18 For Peer Review al 1988) 19 , et al 20 77/F 45.9, 92% Not described High (Lorente 21 1988) 22 71/M 51.6, 94% Döhle bodies and High (Orazi , et al 23 prominent TG 1989) 24 , et al 25 67/M 105, 88% Not described in abstract High (Okada 26 1989)* 27 81/F 31.9, 96% TG and Döhle bodies High (Oogushi , et al 28 1989) 29 78/M NA ‘Mature neutrophils’ High (Wang , et al 30 31 1990)* 32 77/M 62‒73, ‘A few toxic High (Ho and Wang 33 89‒95% granulations’ 1991) 34 79/F 40.1, 83% Not described High (Churdchu , et 35 36 al 1991) 37 48/M 38, 87% Not described High (Storek 1992) 38 65/M 37.5, 8 4% TG, Döhle bodies High (Ohtsuki , et al 39 1992) 40 , et al 41 65/F 93, 89% Not described High (Kaplan 42 (case 1) 1992) 43 61/M 110, 96% Not described High (Kaplan , et al 44 (case 2) 1992) 45 , et al 46 65/M 48.4, 83% Not described High (Kaplan 47 (case 3) 1992) 48 80/F 73, 81% Not described High (Kaplan , et al 49 (case 6) 1992) 50 76/M 146, 83% TG, vacuoles and Döhle High (Jeon , et al 51 52 bodies 1992)* 53 68/F 36.8, 86% Not described NA (Meyer , et al 54 (case 1) 1993) 55 70/F 31.9, 94% Not described High (Meyer , et al 56 57 (case 2) 1993) 58 59 60 Page 15 of 26 British Journal of Haematology
1 2 3 4 60/F 100, 98.5% ‘No dysplasia’ High (Kwong and 5 Cheng 1993) 6 74/M 20‒40, 80% Not described High (Castanet , et al 7 1993) 8 70/M 41, 82% Mainly normal, no TG or High (Takemori , et 9 10 Döhle bodies al 1994) 11 65/M 19.7‒31.4, Not described High (Zittoun , et al 12 (case 1) 92% 1994) 13 14 15/F 40.2, 88% Not described High (Hasle , et al 15 (case 1) 1996) 16 25/M 45.7, 89% Not described NA (Hasle , et al 17 18 (case 2) For Peer Review 1996) 19 75/M 84.6, 92% TG High (Cho , et al 20 1996)‡ 21 NA 50.2, 90% Not described High (Saitoh and 22 23 (case 3) Shibata 1996) 24 NA 46.5, 91% Not described High (Saitoh and 25 (case 4) Shibata 1996) 26 NA 48.8, 91% Not described High (Saitoh and 27 (case 5) Shibata 1996) 28 29 67/F 36.7, 81% Photograph shows High (Matano , et al 30 possible TG 1997) 31 68/M 156, 86% Not described High (Perez Simon , 32 et al 1997) 33 34 63/M 84, 9 2% ‘Left shift’ High (Yanagisawa , 35 et al 1998), 36 (Kojima , et al 37 1999) 38 , et al 39 44/M 12‒24.7, 84% Not described High (Kojima 40 1999) 41 76/F 49.7, 97% Normal High (Frank , et al 42 2000) 43 , et al 44 74/F 85 Not described but appear Normal (Willard 45 normal in photograph 2001) 46 68/M 58, 78% TG and Döhle bodies NA (Umashankar , 47 et al 2001) 48 56/M 40.8, 90% Not described NA (Hara , et al 49 50 2001) 51 65/F 116, 94% Not described High (Kobayashi , et 52 (case 1) al 2002) 53 61/M 74.5, 80.8% Not described High (Kobayashi , et 54 55 (case 2) al 2002) 56 68/M 34.7, 86.5 Not described High (Kobayashi , et 57 (case 3) al 2002) 58 59 60 British Journal of Haematology Page 16 of 26
1 2 3 4 40/F 22. 6, 84% Not described High (Bohm and 5 (case 1) Schaefer 2002) 6 69/M 49.2, 88% Not described Very low (Bohm and 7 (case 4) Schaefer 2002) 8 77/F 89, 95% Not described Normal (Bohm and 9 10 (case 5) Schaefer 2002) 11 64/M 41.7, 84% Not described Normal (Bohm and 12 (case 6) Schaefer 2002) 13 81/F 35, 95% Not described High (Bohm and 14 15 (case 8) Schaefer 2002) 16 37/F 36.3, 92% Not described High (Bohm and 17 (case 9) Schaefer 2002) 18 72/F 38, 90%For Not Peer described Review Low (Bohm and 19 20 (case 10) Schaefer 2002) 21 64/M 109, 87% Not described High (Bohm and 22 (case 11) Schaefer 2002) 23 52/F 30, 82% Not described High (Bohm and 24 (case 12) Schaefer 2002) 25 26 72/M 22.8, 82% Not described Normal (Bohm and 27 (case 13) Schaefer 2002) 28 63/F 24.6, 78% Not described Normal (Bohm and 29 (case 14) Schaefer 2002) 30 31 42/F NA Not described NA (Reilly 2002) 32 58/F 36.5, 92% Not described NA (Hasegawa , et 33 al 2003) 34 54/F 36.6, 89.7% ‘Mild dysplastic features’ High (Yoshida , et al 35 36 (not specified) 2004) 37 48/M 45 TG High (Choi , et al 38 2004) 39 54/M 32, 85% Normal High (Krishnan , et al 40 41 2004) 42 80/M 28, 90% Some TG High (Sai , et al 43 2004) 44 66/F 71, 94% Not described High (Elliott , et al 45 (case 1) 2001, Elliott , et 46 47 al 2005) 48 66/F 125.7, 88% Not described High (Elliott , et al 49 (case 2) 2001, Elliott , et 50 al 2005) 51 52 55/M 103.3, 85% Not described High (Elliott , et al 53 (case 3) 2001, Elliott , et 54 al 2005) 55 74/M 50, 94% Not described NA (Elliott , et al 56 , et 57 (case 4) 2001, Elliott 58 al 2005) 59 60 Page 17 of 26 British Journal of Haematology
1 2 3 , et al 4 54/M 36.4, 89.5% Not described High (Elliott 5 (case 5) 2001, Elliott , et 6 al 2005) 7 86/M 64.7, 89% Not described NA (Elliott , et al 8 (case 6) 2001, Elliott , et 9 10 al 2005) 11 71/M 26.9, 81% Not described NA (Elliott , et al 12 (case 7) 2005) 13 47/M 22.6, 87% Not described NA (Elliott , et al 14 15 (case 8) 2005) 16 85/M 41.5, 83% Not described NA (Elliott , et al 17 (case 9) 2005) 18 77/M 47.1, 82%For Not Peer described Review NA (Elliott , et al 19 (case 10) 2005) 20 21 78/M 29.4, 76% Not described NA (Elliott , et al 22 (case 11) 2005) 23 72/M 58.7, 82% Not described NA (Elliott , et al 24 (case 12) 2005) 25 26 61/M 54, 88% ‘Segmented neutrophils’ NA (Mc Lornan , et 27 al 2005) 28 NA NA Not described NA (Steensma , et 29 al 2005) 30 31 68/M 55.3, 88.5% Not described NA (Izumi , et al 32 2005) 33 56/F 39.1, 86% ‘Mature neutrophilia’ NA (Lea , et al 34 2006) 35 , et al 36 44/M 33.6, 91% Not described High (Bhave 37 2006) 38 46/M 23.8, 89% Not described but NA (Kako , et al 39 photograph of BM does 2007) 40 not show TG 41 42 74/M 79.3, 89% Not described but High (Gan , et al 43 photograph of BM does 2007) 44 not show TG 45 83/F 29, 92.8% Not described Normal (Shigekiyo , et 46 47 al 2008) 48 81/M 30.7, 75% Not described NA (Neureiter , et 49 al 2008) 50 68/F 42, 88% TG, photograph shows High (Amato , et al 51 52 Döhle bodies 2008) 53 23/M 19.8, 85% TG and Döhle bodies High (Goto , et al 54 2009) 55 70/F 37.4, 88% Hypersegmented High (Sugino , et al 56 neutrophils 2009) 57 58 86/F 32.4, 85% ‘No dysplastic features’ High (Uemura , et al 59 60 British Journal of Haematology Page 18 of 26
1 2 3 4 2009) 5 70/M 49, NA TG NA (Thiele 2009) 6 59/M 137, 96% TG, some NA (Ziai , et al 7 hypersegmentation 2010) 8 64/M 124, 102% Photograph does not NA (Ortiz Cruz , et 9 10 (sic) show TG al 2012) 11 80/M 31.9, 91.9% Not described High (Imashuku , et 12 al 2012) 13 61/M 52.1, 79% Photograph does not High (Chen , et al 14 15 show TG 2013) 16 73/F 178.6, 96% TG and Döhle bodies NA (Maxson , et al 17 (case 10) 2013) 18 Eight For Not Peer described but ReviewTG NA × 8 (Maxson , et al 19 20 further and Döhle bodies stated 2013) 21 cases to be ‘common 22 morphologic features 23 among CNL … patients 24 carrying CSF3R 25 26 mutations’ 27 Ten Not described NA × 10 (Pardanani , et 28 cases al 2013) 29 66/M 66. 91.5 No dysplasia NA (Menezes , et al 30 31 2013) 32 39/F 124.8, NA Not described NA (Taylor , et al 33 2013) 34 66/F 180, NA Not described NA (Lasho , et al 35 36 2014) 37 64/M 34, >90% TG, hypersegmentation High (Ranjan , et al 38 2014) 39 53/F 34, 93% Normal High (Gajendra , et al 40 (case 1) 2014) 41 42 59/M 29, 88% Normal High (Gajendra , et al 43 (case 2) 2014) 44 61/M 42, 88% Normal High (Gajendra , et al 45 2014) 46 47 45/M 70, 90% TG High (Rane , et al 48 2014) 49 Eight Not described × 8 NA × 8 (Cui , et al 50 cases 2014) 51 , et al 52 41/F 61.7, 85% TG and Döhle bodies NA (Wang 53 2014) 54 33/M 71.8. 81% No TG NA Kaur 2015 55 56 57 58 59 60 Page 19 of 26 British Journal of Haematology
1 2 3 Abbreviations: BM, bone marrow; CNL, chronic neutrophilic leukaemia; F, female; M, 4 5 male; NA, not available; NAP, neutrophil alkaline phosphatase; TG, toxic granules; 6 WBC, white blood cell count 7 8 * Abstract only read, article in Japanese 9 10 † Abstract and tables only read, article in Korean 11 ‡ Article in Korean, only part available in English 12 § Abstract only read, article in Korean 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 20 of 26
1 2 3 4 5 6 7 8 9 10 11 Table 2 12 13 Chronic neutrophilic leukaemia or neutrophilic leukaemoid reaction associated with a plasma 14 cell neoplasm 15 16 Age WBC (× Description of NAP Nature of References 17 and 10 9/l), neutrophils plasma cell 18 gender neutrophilsFor Peer Reviewneoplasm 19 20 74/M 46.6, 85% TG and Döhle High IgA lambda (Tursz , et al 1974) 21 (Patient neutrophils bodies MM 22 3) (monocytes 23 2.7 × 10 9/l, 24 6%) 25 60/F 28, 95% TG NA IgG lambda Tursz 1974 26 (Patient MM* 27 4) 28 29 68/F 30, 90% TG High IgG lambda (Carcassonne , et 30 neutrophils MM al 1977) 31 32 70/M 19, 88% TG and High IgA kappa MM (Vorobiof , et al 33 Pelger Huët 1978) 34 anomaly 35 57/F 40 Not described High IgG kappa MM Nakahara 1978, 36 cited by Watanabe 37 38 and di Guglielmo 39 60/M 35.9, 90% Not described High IgA lambda (Naparstek , et al 40 MGUS 1980) 41 64/F 35, 80%; 5% Normal Normal IgG lambda (Franchi , et al 42 granulocyte MM 15 years 1984) 43 precursors after ‘CNL’ 44 71/M 77.6, 89% TG and Döhle High IgG lambda (Watanabe , et al 45 bodies and IgA kappa 1984) 46 47 MGUS 48 65/F 57, 87% TG High IgG lambda (Mehrotra , et al 49 MGUS 1985) 50 67/F 25.3, 91% TG and Döhle High IgA lambda (Lewis , et al 51 (case 1) bodies MGUS, later 1986) 52 MM 53 72/F 36.3, 91% Not described High Ig A lambda (Lewis , et al 54 (case 2) MM † 1986) 55 56 57 68/M 35, 94% TG High IgA kappa (Di Guglielmo , et 58 59 60 Page 21 of 26 British Journal of Haematology
1 2 3 MGUS al 1986) 4 5 57/M 55.4, 90% Not described Very low Kappa MM (Zoumbos , et al 6 five years after 1987) 7 presentation 8 9 31/F 23.9, 82% Not described High Kappa Bence (Rovira , et al 10 Jones MM 7 1990) 11 years after 12 presentation 13 with ‘CNL’, 14 ‡ 15 WBC then fell 16 NA NA TG and Döhle NA in IgG lambda (Dieguez , et al 17 bodies abstract MM 1992) 18 For Peer Review 19 76/M 22.3, 85% Not described High IgG kappa (Masini , et al 20 MGUS 1992) 21 76/F 72.3, 91% TG and Döhle High IgG lambda (Standen , et al 22 23 (case 1) bodies MM 1990) 24 65/F 32, 86% TG and High Plasmacytoma (Standen, et al 25 (case 2) occasional with an IgG 1990) 26 Döhle body lambda 27 paraprotein, 28 later MM 29 73/F 25, 83% Numerous High IgA lambda (Troussard, et al 30 Döhle bodies MM 1992) 31 32 33 58/F 23, 80% Not described High IgG kappa MM (Troussard, et al 34 1992) 35 36 61/F 66, 90% TG, High IgA lambda (Florensa , et al 37 vacuolation, MGUS 1993) 38 Döhle bodies 39 60/F 62.4, 85% TG and Döhle High Kappa (Cehreli , et al 40 41 bodies Bence‒Jones 1994) 42 MM 43 57/F 33.4, 95% TG (fibrillar High IgA lambda (Mori , et al 1995) 44 inclusions on MM 45 EM) 46 30/M 42.2, 91% TG High IgG kappa (Ito , et al 1996) 47 MGUS 48 73/M 28.08, 85% Not described High IgG kappa (Nagai , et al 49 50 MGUS 1996) 51 52 56/M 99, 98% Not described High IgA lambda (Usuda , et al 53 MM 1997) 54 68/F 50.9, 94% TG and High IgG lambda (Kim , et al 1998) 55 vacuoles MM 56 57 71/M 38, 86% TG and Döhle High IgG kappa (DinÇol , et al 58 59 60 British Journal of Haematology Page 22 of 26
1 2 3 bodies MM § 2002) 4 , et al 5 68/M 29.9, 82% TG High Lambda (Kusaba 6 Bence‒Jones 2004) 7 MM 8 94/M 31.3, 90.5% No TG Normal IgG kappa MM (Kohmura, et al 9 2004) 10 74/M 25.6, 71% TG High Lambda (Fukuno , et al 11 Bence‒Jones 2006) 12 MM 13 , et al 14 64/F 93, 93% TG NA IgG kappa MM (Kim 2007) 15 16 40/F 21, 76% TG High IgM lambda (Gnerre , et al 17 MM 2007) 18 56/M 29, NA For TG andPeer Döhle NA Review IgG kappa MM (Sebasky , et al 19 bodies 2008) 20 66/F 40‒60, NA Occasional TG NA IgA lambda (Thiele 2009) 21 MM (13% 22 23 plasma cells) 24 60/F 44.11, 79% Not described High IgA kappa (Hartley , et al 25 MGUS 2010) 26 64/F 25.4, 70% Not described High IgA MGUS (Cabrera Aguilar 27 2012 ) 28 77/F 45, 90% Not described High IgA kappa MM (Quiroz , et al 29 2010, Rodríguez 30 Medina , et al 31 32 2013) 33 64/M 28.7, 90% Not described NA MGUS (Pardanani , et al 34 2013) 35 71/F 48.4, 82% Not described NA MGUS (Pardanani , et al 36 2013) 37 52/M 27.8, 90% Not described NA MGUS (Pardanani , et al 38 2013) 39 , et al 40 68/F 138, 95% Not described NA MGUS (Pardanani 41 2013) 42 83/M 114.3, 84% Not described NA MGUS (Pardanani , et al 43 2013) 44 57/F 114, 92% TG NA IgG kappa (Blombery , et al 45 MGUS with a 2014) 46 normal blood 47 count 2 years 48 prior to 49 50 developing 51 CNL with 52 CSF3R 53 mutation ‡ 54 81/M 26.8, NA No TG or NA IgG kappa (Nedeljkovic , et al 55 dysplasia smouldering 2014 ) 56 MM, 57 homozygous 58 59 60 Page 23 of 26 British Journal of Haematology
1 2 3 JAK2 V617F ‡ 4 , et al 5 63/F 65.5, 91% TG and Döhle NA Lambda Bence (Taiwo 6 bodies Jones MM 2014) 7 46/M 65.3, 93% Not described NA in MGUS (Cui , et al 2014) 8 (Case 9) in English English 9 52/F 26.53, 75% Not described NA in MGUS (Cui , et al 2014) 10 (Case in English English 11 10) 12 52/M 22.5, 84% ¶ TG and Döhle NA IgG lambda (Milojkovic, et al 13 14 bodies MM 2015) 15 16 Abbreviations: CNL, chronic neutrophilic leukaemia; EM, electron microscopy; F, female; Ig, 17 immunoglobulin; M, male; MGUS, monoclonal gammopathy of undetermined significance; NA, 18 not available; MM, multipleFor myeloma. Peer Review 19 * Three years later developed acute myeloid leukaemia but had received cyclophosphamide and 20 melphalan 21 † ‘Blastic transformation’ but patient had received melphalan and busulphan over the previous 22 four years 23 ‡ Excluded from analysis as interpreted as two independent neoplasms 24 § 25 ‘Blastic transformation’1.5 years after presentation having had 6 cycles of melphalan ¶ 26 On hydroxycarbamide 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 24 of 26
1 2 3 Table 3 4 5 Comparison of cytological features in chronic neutrophilic leukaemia and neutrophilic 6 leukaemoid reaction in patients for whom data were available 7 8 Chronic neutrophilic Leukaemoid reaction 9 10 leukaemia (n = 51) (n = 28) 11 Toxic granulation and 11 11 12 Döhle bodies 13 Toxic granulation without 11 14 14 15 Döhle bodies 16 Döhle bodies without toxic 0 1 17 granulation 18 Other or not clearlyFor Peer14 Review 0 19 specified 20 21 Cytologically normal 15 2 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 25 of 26 British Journal of Haematology
1 2 3 4 5 6 Table 4 7 Comparison of neutrophil alkaline phosphatase in chronic neutrophilic leukaemia and 8 neutrophilic leukaemoid reaction in patients for whom data were available 9 10 11 Chronic neutrophilic Leukaemoid reaction (n = 12 leukaemia (n= 90) 31) 13 High 82 28 14 15 Normal 6 2 16 Low 2 1 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 British Journal of Haematology Page 26 of 26
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Figure 1 33 67x50mm (300 x 300 DPI) 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60