sign in sign up
<<
Home , Granulocytosis, Leukemia, Leukemoid reaction, Leukocytosis, Myelodysplastic syndrome

(2001) 15, 35–40  2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu REVIEW

Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study MA Elliott1, GW Dewald2, A Tefferi1 and CA Hanson3

1Division of and Internal Medicine, 2Division of Laboratory Genetics, and 3Division of , Mayo Clinic and Mayo Foundation, Rochester, MN, USA

This report describes a single institution’s recent experience ecular rearrangement (c3/a2 junction) that encodes for a 230 with six patients fulfilling the diagnostic criteria of chronic neu- kDa fusion rather than the usual 210 kDa fusion pro- trophilic leukemia. No patient had the Philadelphia chromo- some or the BCR/ABL fusion . None of the common cyto- tein associated with classic CML. genetic abnormalities characteristic of myeloid disorders were We present herein a single institution’s recent experience detected. Two patients demonstrated clonal evolution during with six patients meeting the diagnostic criteria of CNL. the course of the . All responded initially to therapy with hydroxyurea with control of and reduction in . Three patients eventually became refractory to Materials and methods hydroxyurea, manifesting progressive without blastic transformation. Aggressive to control progressive leukocytosis resulted in due to cytopenias in Clinical records from all patients with features consistent with two of these patients. The third patient received less intensive the diagnosis of CNL evaluated at our institution from 1992 chemotherapy and died of progressive disease. One patient to 1998 were reviewed. died after transformation of the disease into undifferentiated Wright–Giemsa-stained slides of peripheral and . Two patients remain alive with stable marrow aspirate smears were reviewed in all six cases. Cyto- disease on hydroxyurea therapy, 12 and 54 months after initial diagnosis. Chronic neutrophilic leukemia is a rare clinicopatho- chemical staining for , myeloperoxidase, chloroacetate logic entity that can be distinguished from chronic myelogen- esterase, and alpha-napthyl butyrate esterase was performed ous leukemia, the recently described neutrophilic-chronic mye- with standard techniques and was available in five of the six logenous leukemia, and . The cases. trephine tissue was obtained in clinical course is heterogeneous, with a definite risk of death all cases, fixed in B5 fixative, decalcified, embedded in paraf- from either blastic transformation or progressive neutrophilic fin, and stained with hematoxylin and eosin for morphologic leukocytosis. Continued study and reporting of these cases must be encouraged. Leukemia (2001) 15, 35–40. assessment. A reticulin stain of the marrow biopsy was avail- Keywords: chronic neutrophilic leukemia; chronic myeloprolifer- able in all cases. Immunoperoxidase staining for kappa, ative disorder; lambda, myeloperoxidase, CD68 (PGM1), CD34, and tryptase was done in all cases by using previously described methods. Special testing, using fluorescent in situ hybridization (FISH) Introduction techniques to analyze interphase nuclei for common cytog- enetic abnormalities characteristic of myeloid disorders, was Chronic neutrophilic leukemia (CNL) is a rare chronic myelo- performed. We limited this study to cases seen from 1992 proliferative disorder that presents as a sustained, mature neu- onward, because the necessary molecular testing for BCR/ABL trophilic leukocytosis with few or no circulating immature was not consistently performed before this time. Thus, appro- , the absence of peripheral blood , priate material for additional confirmatory and exploratory , or , and a normal count. Clini- testing would not have been available. Relevant clinical and cal evaluation fails to disclose an underlying disease process, laboratory data were abstracted from the medical records. D- such as or , capable of causing a leuke- FISH and FISH analysis techniques were used to screen for moid reaction. Splenomegaly, primarily due to neutrophilic BCR/ABL and common myeloid cytogenetic abnormalities, 3 infiltration, is present, and the bone marrow biopsy demon- respectively. strates a granulocytic proliferation without evidence of mor- phologic or striking reticulin fibrosis.1 Cytogenetic and molecular analyses are negative for the Philadelphia chro- D-FISH for BCR/ABL rearrangement mosome and its molecular counterpart, the BCR/ABL fusion gene. These features distinguish CNL from chronic myelogen- BCR/ABL fusion was studied by using D-FISH, which detects ous leukemia (CML), atypical chronic myeloid leukemia, and double or two BCR/ABL fusion signals in cells with a 3 chronic myelomonocytic leukemia, as defined by the French– t(9;22)(q34q11.2). D-FISH was performed with directly lab- American–British Cooperative Leukemia Group (FAB).2 CNL eled, commercially available BCR and ABL1 probes (Ventana, should also be differentiated from the recently described neu- Tucson, AZ, USA) to show two BCR/ABL fusion signals in cells trophilic-CML (CML-N), in which the Philadelphia chromo- with a t(9;22)(q34q11.2), one on the abnormal some is present but is associated with a novel BCR/ABL mol- 9 and the other on the abnormal chromosome 22. The ABL1 (400 kb) probe set was directly labeled with rhodamine green and included several DNA sequences that hybridize to 9q34 and span the 200-kb breakpoint region of ABL. The BCR (300 Correspondence: MA Elliott, MD, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN kb) probe-set was directly labeled with Texas red and 55905, USA included several DNA sequences that hybridize to 22q11.2 Received 19 July 2000; accepted 18 September 2000 and span breakpoints in both the major and minor BCR. D- Clinical, pathologic and cytogenetic study of CNL MA Elliott et al 36 FISH detects all molecular forms of the Philadelphia chromo- red blood cells showed, at most, mild anisopoikilocytosis. some, including those with breakpoints in the c2/a3 junction. Dacrocytic, or teardrop-shaped, cells were not identified in five of the patients, and only one patient’s blood smear showed a few scattered . were unremark- FISH for common molecular abnormalities associated able, and no hypogranular or large and atypical forms were with myeloid disorders seen. The bone marrow aspirate smears were adequate in all six For each patient, interphase nuclei from bone marrow cells cases and consistently showed marked granulocytic hyper- were studied with DNA probes and FISH to detect anomalies plasia, with more than 80% granulocytic precursors (Figure 2). of 5, 7, 8, 11, and 20. The following commercial DNA probes These smears showed effective granulocytic maturation, the were used in this study: anomalies, probes for majority of granulocytes being at the to seg- 5p12 (D5S23) and 5q31 (EGR1); anomalies, mented stages with no increase in blasts. No dysplastic fea- probes for the centromere (CEP-7) and 7q31 (D7S486); tri- tures such as hypogranulation or pseudo-Pelger–Hue¨t changes somy 8, probes for the centromere (CEP-8), with a centromere were seen, and no Auer rods were identified. Erythroid precur- probe for chromosome 12 (CEP-12) used as a control; translo- sors had normoblastic maturation, and no significant mono- cations involving 11q23, probes for the MLL locus; and 20q− cyte, , or population was seen. Megakary- anomalies, probes for 20q13.2 (breast amplicon). ocytes were quantitatively normal in all cases and had a normal morphologic appearance in four of the six cases. The remaining two cases had, as a minor subpopulation, Results occasional small, monolobated . However, the presence of microforms was not nearly as Clinical and laboratory features at diagnosis prominent as one would expect in CML. Iron stains showed normal to increased storage iron. No ringed sideroblasts were The patients’ age at diagnosis ranged from 54 to 86 years seen in five cases; in one case, rare (,1%) ringed sideroblasts (median 66 years). Four patients presented with of were present. Cytochemical staining with chloroacetate ester- 4.5–9 kg one presented with and one with pruritus. ase and alpha-napthyl butyrate esterase showed no significant None of the patients had , , or infection. The population and no dual-esterase staining pattern. patients all had splenomegaly, palpable at a median of 4.5 cm The bone marrow were uniformly hypercellular, (range 2 to 20 cm) below the left costal margin. All patients with all cases showing an essentially packed marrow. The demonstrated peripheral leukocytosis, with a median white biopsies were consistent with the aspirate findings, showing a count at the time of CNL diagnosis of 67.9 × 109/l marked granulocytic proliferation. No unusual distributional (range 15 to 125 × 109/l). This increase in white blood cells pattern was seen. As compared with other chronic myelopro- was due to neutrophilia (median 62.2 × 109/l, range 14.1 to liferative disorders, no megakaryocyte and no 110.0 × 109/l), almost exclusively at the segmented and band clusters of large atypical megakaryocytes were seen. Fibrosis stage of development. The percentage of white blood cells at was not apparent by hematoxylin and eosin stains, and reticu- or before the metamyelocyte stage was never greater than 2%. lin stain showed 1+ reticulin fibrosis in all six cases (on a scale No absolute or relative monocytosis, eosinophilia, or baso- of 0 to 4). Immunoperoxidase staining for myeloperoxidase, philia was identified. CD68 (PGM1), CD34, and tryptase was noncontributory and Four of the patients were anemic at presentation, with showed no significant monocyte, blast, or mast cell popu- levels ranging from 9.7 to 12.1 g/dl (median 11.6 lation. Kappa and lambda immunostains showed polyclonal g/dl). Two patients had mild at diagnosis, plasma cells in all cases, including the one case with the small with platelet counts of 80 and 117 × 109/l. None of the serum monoclonal protein. patients demonstrated thrombocytosis (median platelet count × 9 × 9 232 10 /l, range 80 to 362 10 /l). The leukocyte alkaline Cytogenetic and molecular features phosphatase score was increased in all patients in whom it was tested (range 167 to 385, normal range 40 to 100). Serum Each of the six patients had normal at the time protein electrophoretic studies were available in five of the six of diagnosis of CNL. None had the patients. One patient had a small IgG kappa monoclonal t(9;22) or the BCR/ABL fusion gene. In addition, D-FISH analy- serum protein at diagnosis. None of the patients had any sig- sis did not detect a c3/a2 BCR/ABL rearrangement in any of nificant co-morbidities, such as infection, malignancy, or sys- the six cases. At the time of initial diagnosis, molecular analy- temic inflammatory disease, capable of causing a reactive sis for BCR abnormalities was also performed with the use of neutrophilia or leukemoid reaction. The clinical features and Southern blotting. FISH was also used to screen interphase laboratory data at diagnosis and during follow-up are nuclei for common anomalies found in myeloid disorders: presented in Table 1. specifically, susceptible loci on 5 (5p12, 5q31), 7 (7q31), 8 ( 8), 11 (11q23), and 20 (20q−) were ana- lyzed. None of the patients demonstrated molecular abnor- Peripheral blood and bone marrow features at malities at these sites. Clonal evolution occurred during the presentation course of the disease in two patients. One of these patients had an abnormal with trisomy 21 (18/20 ) The peripheral blood smear was most remarkable for a promi- 15 months after diagnosis. The other patient had an abnormal nent neutrophilia without a (Figure 1). Although the clone with of the short arm of chromosome 12 cells were primarily at the segmented stage of development, [del(12)(p11.2)] (20/20 metaphases) 23 months after diagnosis occasional band forms were seen. No blast cells or microme- of CNL. Both patients had been treated with hydroxyurea gakaryocytes were seen in any of the cases. Importantly, no for the duration of their disease prior to detection of these dysplastic features were noted in the granulocytic series. The abnormalities.

Leukemia Clinical, pathologic and cytogenetic study of CNL MA Elliott et al 37 Table 1 Clinical and laboratory data in six patients with chronic neutrophilic leukemia

Parameter Cases Median

123456

Age (years) 66 66 55 74 54 86 66 , at diagnosis (cm) 4 4 8 5 2 20 4.5 Spleen, maximum (cm) 10 11 20 14 17 20 15.5 Hemoglobin (g/dl) 11.1 9.7 12.1 14.5 14.6 10.5 11.6 WBC (×109/l) 71 125 103.3 15 36.4 64.7 67.9 % 94 88 85 94 89.9 89 89.5 % immaturea 045023.5 % blasts 0 0 0 0 0 0.5 % 3 0 2 3 2 3.5 % eos/baso 0/0 0/0 1/0 0/0 0/0 0.5/0.5 Neutrophils (× 109/l) 66.7 110.0 87.8 14.1 32.7 57.6 62.2 Platelets (× 109/l) 252 212 117 80 268 362 232 BM cellularity 100 100 100 95 95 100 100 % grans in BM 82 96 94 81 90 86 88 Reticulin fibrosisb 1+ 1+ 1+ 1+ 1+ 1+ 1+ LAP score (nl 40–100) 365 385 274 167 LDH (nl 112–257 U/l) 431 964 225 201 151 669 46 XX 46 XX 46 XY 46 XY 46 XY 46 XY Clonal evolution None None +21 None −12p None Therapy First line HU HU HU HU HU HU Second Ara-C 6-TG/A IFN-α Third 6-TG/A 2-CDA Fourth IDR/A Int. A Maximal WBC 71 155.8 297 52.7 187.1 64.7 113.4 % neutrophils 94 93 83.5 90 77.5 89 % blasts 0 0 0 1 1 0.5 Survival (mo) 54+ 18 16.5 33+ 32 23 27.5 Status at last F/U Alive Dead Dead Alive Dead Dead Terminal course ∀ ANC ∀ ANC ∀ ANC BT Cause of death Rx PD Rx BT a% immature, % , , and . bReticulin fibrosis scale of 0 to 4+. A or Ara-C, cytarabine; ∀ ANC, rising neutrophilia refractory to therapy; BM, bone marrow; BT, blastic transformation; 2-CDA, 2-chlorodeoxy- adenosine; eos/baso, /; F/U, follow-up; % grans in BM, % granulocytic precursors in bone marrow aspirate; HU, hydroxyurea; IDR, idarubicin; IFN-α, interferon-alpha; Int, intermediate-dose; LAP, leukocyte ; LDH, lactate dehydro- genase; PD, progressive disease; Rx, therapy-related cytopenia; 6-TG, thioguanine; WBC, white blood cells.

Figure 1 Wright–Giemsa-stained slide of peripheral blood demon- × Figure 2 Wright–Giemsa-stained slide of a bone marrow biopsy strating neutrophilia without left shift (original magnification 1000). specimen showing marked granulocytic proliferation with slight reticulin fibrosis. No megakaryocyte clustering is present (original magification ×400).

Leukemia Clinical, pathologic and cytogenetic study of CNL MA Elliott et al 38 Clinical course characterized patients with CNL and allows a more detailed description and understanding of this disease. No underlying disease process as a cause of reactive leuko- CNL is characterized by a sustained, mature neutrophilia cytosis became apparent during a median follow-up of 27.5 with few or no circulating immature granulocytes, splenomeg- months (range 18 to 54 months). Progressive neutrophilia and aly, and bone marrow hypercellularity with marked granulo- progressive splenomegaly were found in all patients during cytic hyperplasia and mild reticulin fibrosis. No myelodys- follow-up, despite the use of cytoreductive therapy when indi- plasia or characteristics of the more common chronic cated. No significant changes in the peripheral blood or bone myeloproliferative disorders were present in the six patients marrow morphologic features were noted as compared with from this study. It is also essential to note that cytogenetic and the original presenting blood and bone marrow material. The molecular analyses were negative for the Philadelphia chro- one patient in whom a small monoclonal protein was ident- mosome and its molecular counterpart, the BCR/ABL fusion ified at diagnosis showed no evidence of a progressive plasma gene. The characteristics seen in cases of chronic neutrophilic cell proliferative disorder. The monoclonal protein remained leukemia can overlap with, and thus must be distinguished stable during prolonged follow-up (54 months), and bone from, other chronic processes, both benign and malignant, marrow biopsy immunostaining for kappa and lambda light that have a neutrophilic component. These would include chains failed to identify a clonal plasma cell population. The reactive leukocytosis, leukemoid reaction, chronic myelogen- median maximal spleen size palpable below the left costal ous leukemia, other chronic myeloproliferative disorders, and margin was 15.5 cm (range 10 to 20 cm), and the median myelodysplastic syndromes, including chronic myelomono- maximal count was 113.4 × 109/l (range 52.7 cytic leukemia. Looking for the presence or absence of parti- to 297 × 109/l). cular morphologic features is crucial when one considers the All patients responded initially to therapy with hydroxyurea, differential diagnosis of CNL. All six of our cases showed with satisfactory control of leukocytosis and reduction in exclusive neutrophilia without granulocytic immaturity or evi- splenomegaly, when therapy to control these manifestations dence of proliferation of any other myeloid lineage. Subtle was required. Three patients eventually became refractory to features of myelodysplasia must be sought in order to exclude hydroxyurea, manifesting progressive neutrophilia without an unusual presentation of myelodysplasia. Dysgranulopoiesis blast transformation at 6, 12, and 13 months, with maximal and dyserythropoiesis should not be present; cytochemical leukocyte counts of 156, 187, and 297 × 109/l, respectively. stains for ringed sideroblasts, marrow monocytes, and dual Any response to subsequent therapy with various agents, esterase-positive cells must be negative in a bone marrow including low-dose cytarabine, 6-thioguanine, 2-chlorodeoxy- specimen for a myelodysplastic process to be excluded. More adenosine, and interferon-alpha, was short-lived. Systemic importantly in considering CNL, other chronic myeloprolifer- induction-type chemotherapy, con- ative disorders must be excluded. From a morphologic basis, sisting of an idarubicin/cytarabine combination or intermedi- the absence of dacrocytes, basophilia, and immature granulo- ate-dose cytarabine, was used in an attempt to control refrac- cytes was a striking feature in the peripheral blood from our tory leukocytosis in two of these patients. This resulted in patients. In contrast to the bone marrow findings in agnogenic death in both cases because of severe prolonged cytopenias myeloid metaplasia, vera, and essential throm- following induction therapy, at 18 and 32 months after the bocythemia, the bone marrow from patients with CNL consist- initial diagnosis of CNL. The third patient died from compli- ently showed no large, atypical megakaryocytes and megakar- cations of progressive disease at 16.5 months, despite the con- yocytic clustering and no significant reticulin fibrosis. Indeed, tinued use of less intensive outpatient chemotherapy with 6- only two of the cases showed any megakaryocytic abnormali- thioguanine and subcutaneous cytarabine. The final docu- ties, at most having an occasional monolobated megakaryo- mented leukocyte count was 297 × 109/l, and the cells con- cyte present. sisted largely of mature neutrophils without blastic trans- It may also sometimes be difficult to confidently distinguish formation. Another patient’s disease transformed into CNL from reactive leukocytosis or a leukemoid reaction. The undifferentiated acute myeloid leukemia (FAB-M0) 21 months peripheral blood in CNL shows mature neutrophilia, while after the diagnosis of CNL; this patient’s disease had pre- that of a leukemoid reaction can be left shifted. Left-shifted viously been well controlled on a stable daily dose of associated with eosinophilia or basophilia hydroxyurea. The patient declined aggressive induction characterizes CML and helps to distinguish it from CNL. Most chemotherapy in favor of supportive measures and survived of the cases from this study showed a packed bone marrow 8 weeks after the diagnosis of acute leukemia. Two patients, biopsy together with a slight increase in reticulin fibrosis; age 75 and 70 years, remain alive with stable disease on these were typically the only morphologic findings that differ- hydroxyurea, 12 and 54 months, respectively, from initial entiated CNL from a benign, reactive process. Practically, it diagnosis of CNL (Table 1). may be impossible to make a diagnosis of CNL solely on mor- phologic grounds if the marrow is not packed and if the degree of reticulin fibrosis is not convincing. Thus, correlation Discussion with clinical history and presentation, together with a ‘tincture of time’, is often needed before one can make a diagnosis of Although CNL is commonly included as part of the chronic this malignant disorder with certainty. Some previously myeloproliferative disorders, fewer than 100 cases have been reported cases of supposed CNL were diagnosed in associ- reported since its original description in 1920, with most ation with other disease processes, such as , being case reports.4 Moreover, it is likely that not all of the agnogenic myeloid metaplasia, myelodysplastic syndromes, reported cases represented true CNL. Molecular studies for the , and .13–16 These BCR/ABL rearrangement, which must be negative before this may not represent true cases of CNL, as the presence of diagnosis can be made, have been performed only in cases another clonal hematologic malignancy would certainly con- described since 1992, accounting for fewer than 10 reported found this diagnosis. In such cases it is difficult to know cases.5–12 This study is the largest reported series of well- whether the ‘CNL’ picture is a reactive leukocytosis rather

Leukemia Clinical, pathologic and cytogenetic study of CNL MA Elliott et al 39 than a discrete disease. Indeed, Standen et al.,17 using restric- ony formation also demonstrated these abnormalities. By tion fragment length polymorphisms and the pattern of X inac- contrast, cytogenetic analysis of – and tivation of the X-linked probe M27 β, demonstrated poly- macrophage colony-forming units, formed by exposure to clonal leukocytes in a reported case of concurrent CNL and interleukin-3 and granulocyte–macrophage colony-stimulat- multiple myeloma, suggesting that the neutrophilia in this ing factor, and burst-forming unit-erythroid induced by patient was reactive. Resolution of the leukocytosis following showed a normal karyotype, as did the patient’s treatment of the myeloma with and phytohemagglutinin-stimulated T cells and Epstein–Barr - further supported this hypothesis.17 transformed B . Thus, it appears that the neoplas- Thus, the clonal nature of CNL has been the subject of tic process, at least in this case, originated in progenitors cap- controversy. Unlike CML, no characteristic clonal chromo- able only of differentiating into granulocytes, and that some somal or molecular marker has been identified. Similar to of these progenitors acquired the ability to form colonies other chronic myeloproliferative disorders, eg, polycythemia spontaneously, thus providing further evidence in support of vera and essential , distinguishing a clonal a distinct granulocyte-specific myeloproliferative disorder.7 hematologic disorder from a reactive process may be difficult, In the present series, all patients demonstrated a normal particularly early in the course of the disease. A sustained, karyotype at diagnosis. To exclude the possibility of molecular progressive neutrophilia, splenomegaly, a packed bone mar- rearrangements that may be missed by the conventional cyto- row with marked granulocytic proliferation, absence of an genetic techniques, FISH analysis was performed to screen for underlying disorder, and evolution to a terminal course, due some of the more common abnormalities characteristic of either to blastic transformation or a refractory leukocytosis, as chronic myeloid disorders. This analysis did not reveal any seen in the cases presented here, argue against a reactive pro- masked or variant chromosome abnormalities. The recently cess and are consistent with CNL representing a clonal, myel- described entity of CML-N, having an associated novel oproliferative disorder. BCR/ABL fusion with c3/a2 junction, may be confused with The clonal nature of CNL has been confirmed in individual CNL.20 However, CML-N should be considered as a variant cases by several investigators on the basis of cytogenetic of CML, separate from CNL. CML-N has to date been abnormalities, progenitor cell assays, and X-inactivation pat- described only in association with the Philadelphia chromo- terns.6,7,9 Most well-documented cases of CNL have normal some, which, by definition, precludes classification as CNL. cytogenetics. Among cases with cytogenetic abnormalities, Molecular analysis in this series did not detect the c3/a2 chromosome anomalies are heterogeneous, and no consistent BCR/ABL rearrangement in any of the six cases and thus we abnormality has been associated with CNL. Most likely, the excluded the possibility of a molecular rearrangement in the primary genetic event that to CNL is submicroscopic and absence of a cytogenetically recognizable t(9;22). This under- is not detectable by conventional cytogenetic studies. If that scores the importance of performing cytogenetic and molecu- is so, the chromosome abnormalities reported so far may be lar studies in the chronic myeloproliferative disorders. During related to cytogenetic evolution and represent secondary the disease course, secondary chromosomal abnormalities abnormalities in the pathogenesis of CNL. Reported isolated were detected in two cases. Whether these represented spon- abnormalities have included , with taneous clonal evolution due to disease progression or deletion of the long arm of chromosome 20 (20q−), isolated induced by chronic cytotoxic therapy remains 20q−, deletion of part of the long arm of chromosome 11 with unknown. breakpoints at 11q14, trisomy 21, and complex .7,9– Optimal therapy of CNL remains to be defined. In the ear- 11,18 Kwong and Cheng6 reported a case with clinical and liest reported cases, splenic irradiation and were hematologic features consistent with CNL, with normal cyto- used to reduce tumor bulk and relieve abdominal discomfort.1 genetics and absence of the BCR rearrangement. The clonal Splenectomy has resulted in worsening of the degree of neu- nature of the myeloid proliferation was demonstrated by the trophilic leukocytosis.1,11 Treatment of CNL to date has con- methylation pattern of the X-linked hypoxanthine phos- sisted largely of therapy with agents such as oral hydroxyurea, phoribosyl transferase (HPRT) gene. Froberg et al 9 localized , and 6-thioguanine.1,6,11 These agents have demon- the abnormal clone, as recognized by a chromosomal strated efficacy in controlling leukocytosis and splenomegaly deletion, to the granulocytic population in a patient with CNL. and in inducing a prolonged stable phase. The successful use By cytogenetic analysis, this patient’s peripheral blood and of interferon-alpha has also been reported, with similar thera- bone marrow had an 11q14 deletion. FISH was performed peutic effects on leukocytosis and splenomegaly.8 None on peripheral blood smears using a chromosome 11-specific of these treatment modalities has demonstrated curative probe, and was localized to only the granulo- potential. cyte population. Like that of other chronic myeloproliferative disorders, the The origin of the neoplastic clone in CNL has long been clinical course of CNL is heterogeneous. Some patients exhibit considered to be from granulocyte-committed progenitors,19 a prolonged stable phase with minimal or no intervention, but and this was recently demonstrated by Yanagisawa et al 7 in there is a definite risk of death from either leukemic transform- an elegant study using colony-forming progenitor cell assays ation or progressive, refractory neutrophilic leukocytosis, as combined with cytogenetic analysis. They reported a patient further demonstrated by this report.1,8,10,12 Thus, the use of with CNL who had complex chromosomal abnormalities aggressive therapeutic strategies for patients who can tolerate without evidence of t(9;22) translocation or the BCR/ABL such an approach appears warranted. A palliative approach rearrangement. The patient’s peripheral blood and bone mar- may be reasonable in older patients with a poor performance row mononuclear cells were isolated and in culture were status or significant co-morbidities, but for patients without found to spontaneously form colonies consisting of large num- these features alternative strategies should be considered, such bers of mature granulocytes. Cytogenetic analysis of these as allogeneic bone marrow or peripheral transplan- spontaneously formed colonies revealed chromosomal abnor- tation. Allogeneic bone marrow transplantation has been malities identical to those in the patient’s bone marrow. Gran- reported in one case of CNL which met the diagnostic criteria ulocyte colony-stimulating factor-enhanced granulocyte col- for this disorder.11 The patient underwent a sibling donor bone

Leukemia Clinical, pathologic and cytogenetic study of CNL MA Elliott et al 40 marrow transplant, disparate for one B locus and one DR Dewald GW. A special fluorescent in situ hybridization technique locus. Conditioning consisted of total body irradiation, cyclo- to study peripheral blood and assess the effectiveness of interferon phosphamide, and anti-thymocyte globulin. The patient therapy in chronic myeloid leukemia. Blood 1998; 92: 2315– 2321. remains alive and disease-free more than 6 years after the pro- 4 Touhy EL. A case of splenomegaly with polymorphonuclear neu- cedure. It must be noted that this patient was only 15 years of trophil hyperleukocytosis. Am J Med Sci 1920; 160: 18–25. age at the time of diagnosis, considerably younger than most 5 Storek J. Chronic neutrophilic leukemia: case report documenting reported cases of CNL, which tends to occur in older patients.1 the absence of bcr- rearrangement. Am J Hematol 1992; 41: In the series presented here, four patients were older than 66 304. years and the youngest was 54 years of age at the time of 6 Kwong YL, Cheng G. Clonal nature of chronic neutrophilic leuke- mia. Blood 1993; 82: 1035–1036. initial diagnosis. 7 Yanagisawa K, Ohminami H, Sato M, Takada K, Hasegawa H, Yasukawa M, Fujita S. Neoplastic involvement of granulocytic lin- eage, not granulocytic-monocytic, monocytic, or erythrocytic lin- Conclusion eage, in a patient with chronic neutrophilic leukemia. Am J Hema- tol 1998; 57: 221–224. 8 Meyer S, Feremans W, Cantiniaux B, Capel P, Huygen K, Dicato CNL is an uncommon chronic myeloproliferative disorder of M. Successful alpha-2b-interferon therapy for chronic neutrophilic the granulocytic lineage which must be distinguished from leukemia. Am J Hematol 1993; 43: 307–309. other chronic processes that have a neutrophilic component, 9 Froberg MK, Brunning RD, Dorion P, Litz CE, Torlakovic E. Dem- such as reactive leukocytosis, leukemoid reaction, CML, CML- onstration of clonality in neutrophils using FISH in a case of N, other chronic myeloproliferative disorders, and myelo- chronic neutrophilic leukemia. Leukemia 1998; 12: 623–626. 10 Matano S, Nakamura S, Kobayashi K, Yoshida T, Matsuda T, Sugi- dysplastic syndromes, including chronic myelomonocytic leu- moto T. Deletion of the long arm of chromosome 20 in a patient kemia. The optimal therapy for CNL remains to be deter- with chronic neutrophilic leukemia: cytogenetic findings in mined. Given the rarity of this disorder, it is unlikely that chronic neutrophilic leukemia. Am J Hematol 1997; 54: 72–75. randomized, controlled trials will be feasible. Therefore, man- 11 Hasle H, Olesen G, Kerndrup G, Philip P, Jacobsen N. Chronic agement decisions will have to be based on anecdotal reports leukaemia in adolescence and young adulthood. Br J or extrapolated from therapeutic strategies effective in similar Haematol 1996; 94: 628–630. 12 Kojima K, Yasukawa M, Hara M, Nawa Y, Kimura Y, Narumi H, chronic clonal myeloid disorders. Continued reporting of Fujita S. Familial occurrence of chronic neutrophilic leukaemia. cases of CNL and responses to therapeutic strategies must be Br J Haematol 1999; 105: 428–430. encouraged. Other than anecdotal experience with allogeneic 13 Lugassy G, Farhi R. Chronic neutrophilic leukemia associated with bone marrow transplantation, no therapy has demonstrated polycythemia vera. Am J Hematol 1989; 31: 300–301. curative potential in CNL. Given the potential for blastic trans- 14 Zittoun R, Rea D, Ngoc LH, Ramond S. Chronic neutrophilic leu- formation and progressive refractory neutrophilia, an aggress- kemia. A study of four cases. Ann Hematol 1994; 68: 55–60. 15 Zoumbos NC, Symeonidis A, Kourakli-Symeonidis A. Chronic ive approach may be appropriate for younger patients who neutrophilic leukemia with dysplastic features. A new variant of meet the criteria for this diagnosis. Continued study of these the myelodysplastic syndromes. Acta Haematol 1989; 82: 156– patients is warranted to better determine the and 160. the most appropriate therapy of this disease. 16 Standen GR, Jasani B, Wagstaff M, Wardrop CA. Chronic neutro- philic leukemia and multiple myeloma. An association with lambda light chain expression. Cancer 1990; 66: 162–166. 17 Standen GR, Steers FJ, Jones L. Clonality of chronic neutrophilic References leukaemia associated with myeloma: analysis using the X-linked probe M27 beta. J Clin Pathol 1993; 46: 297–298. 1 You W, Weisbrot IM. Chronic neutrophilic leukemia. Report of 18 Orazi A, Cattoretti G, Sozzi G. A case of chronic neutrophilic two cases and review of the literature. Am J Clin Pathol 1979; 72: leukemia with trisomy 8. Acta Haematol 1989; 81: 148–151. 233–242. 19 Di Donato C, Croci G, Lazzari S, Scarduelli L, Vignoli R, Buia 2 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gral- M, Tramaloni C, Maccari S, Plancher AC. Chronic neutrophilic nick H, Sultan C, Cox C. The chronic myeloid leukaemias: guide- leukemia: description of a new case with karyotypic abnormali- lines for distinguishing chronic granulocytic, atypical chronic ties. Am J Clin Pathol 1986; 85: 369–371. myeloid, and chronic myelomonocytic leukaemia. Proposals by 20 Pane F, Frigeri F, Sindona M, Luciano L, Ferrara F, Cimino R, the French–American–British Cooperative Leukaemia Group. Br J Meloni G, Saglio G, Salvatore F, Rotoli B. Neutrophilic-chronic Haematol 1994; 87: 746–754. myeloid leukemia: a distinct disease with a specific molecular 3 Buno I, Wyatt WA, Zinsmeister AR, Dietz-Band J, Silver RT, marker. Blood 1996; 88: 2410–2414.

Leukemia