A case of chronic neutrophilic leukemia with trisomy 8

The authors describe a case of chronic neutrophilic leukemia (CNL) showing trisomy of chromosome 8. This anomaly, particularly common in cases of myelodysplastic syndrome (MDS), has never been previously found to be associated with this rare type of leukemia. Thus CNL may occasionally be cytogenetically indistinguishable from cases of MDS.     

Deletion of the long arm of chromosome 20 in a patient with chronic neutrophilic leukemia: Cytogenetic findings in chronic neutrophilic leukemia

We encountered a 67-year-old female with chronic neutrophilic leukemia (CNL). Cytogenetic study showed she had a deletion in the long arm of chromosome 20. This finding indicates that CNL, in this case, is a clonal disorder. Most CNL patients have normal karyotypes, and only four patients with cytogenetic abnormalities, including two cases who received chemotherapy before the cytogenetic abnormality was detected, have been reported. Four of those cases, including our case, had abnormalities in the long arm of chromosome 20. This locus may be associated with the development of CNL. To our knowledge, this is the first case with CNL who showed deletion of the long arm of chromosome 20 before treatment was started. Am. J. Hematol. 54:72–75, 1997 © 1997 Wiley-Liss, Inc.     

Chronic neutrophilic leukemia with marked myelodysplasia terminating in blast crisis

Summary A case of chronic neutrophilic leukemia (CNL) is reported. The patient had a history of bleeding, and showed sustained mature neutrophilic leukocytosis, hepatosplenomegaly, a high leukocyte-alkaline phosphatase score, elevated serum vitamin B₁₂ and uric acid, and the presence of Döhle bodies in the neutrophils. In addition to the above typical features, marked myelodysplastic changes in the erythroid and megakaryocytic series were observed in the bone marrow. Three months after the diagnosis of CNL had been established, the hematological picture evolved into a blast crisis of monocytic type. Such findings give support to the statement of CNL as a distinct entity belonging to the spectrum of the myeloproliferative disorders.     

Chronic Neutrophilic Leukemia with V617F JAK2 Mutation

Chronic neutrophilic leukemia (CNL) is a rare disease grouped under World health organization classification as chronic myeloproliferative disease. It is a diagnosis of exclusion in patients with sustained mature neutrophilia and splenomegaly with no evidence of other myeloproliferative disease or reactive neutrophilia. V617F JAK 2 mutation has been described in classical myeloproliferative diseases, but its association with CNL has been reported in a few cases. Here in, we describe three cases of CNL with presence of V617F JAK 2 mutation. To distinguish CNL from secondary neutrophilia can be difficult. Detection of the V617F JAK 2 mutation in such scenario can provide a useful diagnostic test to establish the neoplastic nature of the neutrophilia.     

Efficacy of imatinib mesylate (STI571) in chronic neutrophilic leukemia with t(15;19): case report

Chronic neutrophilic leukemia (CNL) is a rare hematologic disorder, for which there is no standard therapy. Recently, STI (imatinib mesylate) has been shown to be effective in treating patients with chronic myeloproliferative disorder (CMPD) displaying the translocation of the PDGFbetaR gene. Here, we present a case of a patient with CNL carrying t(15;19)(q13;p13.3) who achieved a cytogenetic remission following treatment with imatinib, 400 mg daily. After failure of alpha interferon and hydroxyurea therapy, a durable and complete clinical and cytogenic remission was induced by imatinib. To our knowledge, this is the first case with CNL who showed complete response with cytogenic remission after treatment of imatinib. The mechanism of response to this molecule is unknown in our case (other oncogenes than c-kit, tyrosine kinase, or PDGFR may be involved). The patient remains in complete remission with an excellent performance status after 7 months of therapy. We demonstrate here that imatinib can induce a clinical and cytogenetic response in a case of CNL associated with a novel translocation other than a 5q33 rearrangement. Further studies including the molecular cloning of the t(15;19)(q13;p13.3) will be important in understanding the pathophysiology of CNL with a heterogeneous clinical course and the exploitation of the basic mechanisms of imatinib treatment.     

Further evidence for the molecular heterogeneity of chronic myeloid leukemia

Summary Cytogenetic and molecular techniques were performed on samples obtained from 29 patients with chronic myelocytic leukemia (CML); 27 were in the chronic phase and two were in blast crisis. A further five cases were also analyzed, two with atypical CML (aCML), one with chronic neutrophilic leukemia (CNL), and two with juvenile CML (JCML). Most of the cases with typical CML were Philadelphia chromosome (Ph) positive and had a rearrangement within the major breakpoint cluster region (M-bcr). One of these cases was shown to be Ph positive but showed no rearrangement within the M-bcr. Two cases with clinical features typical of CML were Ph negative. One of these showed a rearrangement within the M-bcr, but no rearrangement was demonstrated in the other. Both patients in blast crisis were Ph positive and M-bcr positive. One showed a second Ph. Patients with aCML were Ph negative and had no M-bcr rearrangement. A polymorphism within the M-bcr was found withBglII in one case. No Ph chromosome or M-bcr rearrangement was found in CNL or JCML. These data support the molecular heterogeneity reported in CML.     

Evolution to acute myeloblastic leukemia from chronic neutrophilic leukemia with dysplastic features in granulocytic lineage

We experienced the case of an 82-year-old man with chronic neutrophilic leukemia (CNL) with dysplastic features in the granulocytic lineage which subsequently progressed to acute myeloblastic leukemia (AML) with myelofibrosis. The patient had hepatosplenomegaly, but there was no evident cause of neutrophilic leukocytosis. The cytogenetic study showed that he had a normal karyotype. Concentrations of the serum granulocyte colony-stimulating factor (G-CSF) were not detectable. Two years after the diagnosis of CNL, blastic transformation to AML occurred with myelofibrosis and significant morphological abnormalities in neutrophils. The blasts were positive for myeloperoxidase, CD33, CD34, and HLA-DR, and the presence of dysplasia within the granulocytic lineage suggested that he had an abnormality at the level of the granulocyte-committed progenitors. Heterogeneous origins of CNL might lead to various clinicopathological features in each case.     

Chimeric del20q in a case of chronic neutrophilic leukemia

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder in which recurrent abnormalities of chromosome 20 have been reported. We report the case of a 76-year-old woman with CNL with partial deletion of the long arm of chromosome 20 in a subset of bone marrow metaphases, suggesting coexistence of a clonal stem cell disorder and normal hematopoiesis. Review of the literature suggests that such mosaicism is common in CNL, possibly accounting for the favorable prognosis observed in many patients with this disorder.     

Chronic neutrophilic leukemia

Summary Chronic neutrophilic leukemia (CNL) is a very rare entity, which has to be included among the chronic myeloid leukemias. Once an underlying cause of neutrophilia is excluded, the diagnosis of CNL is based on exclusion of chronic granulocytic and other types of chronic myeloid leukemias. The classification proposed by Sheperd et al. has proven to be helpful, but it must be completed by cytogenetic analysis and the search for bcr rearrangement by molecular biology methods, in order to confirm the absence of Philadelphia chromosome and of bcr-abl hybrid gene. We report here four cases of CNL, with confirmed absence of bcr rearrangement in two cases. Two patients died, 12 and 8 years after diagnosis, the second one following transformation into myelofibrosis with myeloid metaplasia. The other two died of acute myelogenous leukemia, the first one, 25 years after diagnosis of CNL, following a 3-year phase of acceleration. The last patient presented combined features of CNL and refractory anemia with excess of blasts, and was characterized by both progressive leukocytosis and severe thrombocytopenia; acute transformation into acute myelogenous leukemia occurred 6 months after diagnosis and death 1 month later. Among the 30 cases reported so far, plus the four presented here, combined myelodysplastic features were observed in five cases and transformation into acute myelogenous leukemia in six. Chronic neutrophilic leukemias should be reported regularity, in view of the uncertain and low frequency of this hematological disease.     

The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes

A somatic mutation in the JH2 autoinhibitory domain of the Janus kinase 2 (JAK2) tyrosine kinase was recently described in polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia. The prevalence of this mutation in either "atypical" myeloproliferative disorders (MPDs) or the myelodysplastic syndromes (MDSs) is unknown. Bone marrow-derived genomic DNA from 245 patients--119 with chronic myelomonocytic leukemia (CMML), 101 with MDS, 11 with hypereosinophilic syndrome (HES), 8 with systemic mastocytosis (SM), and 6 with chronic neutrophilic leukemia (CNL)--was screened for the JAK2 V617F mutation. A mutant allele was detected in 11 patients: 3 with CMML (3%), 5 with MDS (5%), 2 with SM, and 1 with CNL. Interestingly, one of the patients with SM and the patient with CNL with JAK2 V617F had a history of lymphoma, and this patient with SM also had associated myelofibrosis and CMML. The current observation strengthens the specific association between JAK2 V617F and classic MPD, but also suggests an infrequent occurrence in other myeloid disorders.     

Severe Bleeding Tendency Caused by Leukemic Infiltration and Destruction of Vascular Walls in Chronic Neutrophilic Leukemia

Bleeding is reportedly one of the major causes of death in patients with chronic neutrophilic leukemia (CNL), but thrombocytopenia, abnormal platelet functions, or coagulopathy has been confirmed to be the cause of the bleeding tendency in only a small proportion of the patients. We report the case of a 49-year-old woman with CNL who experienced episodes of cutaneous and recurrent multiple cerebral hemorrhages without severe thrombocytopenia, detectable abnormal platelet functions, or coagulating dysfunction. Histological examination of specimens obtained at autopsy showed extensive infiltration and destruction of vascular walls by leukemic cells, which could explain her severe bleeding tendency. This study is the first to clearly show that the infiltration and destruction of vascular walls by leukemic cells can cause fatal bleeding episodes without warning from laboratory findings. Further studies are needed to elucidate the mechanism of the infiltration and destruction of blood vessels by CNL cells and to develop effective measures to control the growth and infiltration of CNL cells.     

Chronic neutrophilic leukemia with an associated V617F JAK2 tyrosine kinase mutation

Chronic neutrophilic leukemia (CNL) is a rare disease and can cause considerable diagnostic difficulty. Although the V617F JAK2 mutation has been described by several groups to be associated with classical myeloproliferative disorders (MPD), this same mutation has been detected with a low incidence in atypical MPD, such as CNL. Here we report the presence of the V617F mutation in a CNL patient, who is unusual for having survived for more than 96 months, with little disease progression. It remains to be established what role this mutation, which gives cells a proliferative advantage, might play in the pathogenesis and prognosis of rare atypical MPD.     

Changes in the megakaryocyte-platelet system in chronic neutrophilic leukemia]

Platelet functions and morphological changes of megakaryocytes were investigated in three cases with chronic neutrophilic leukemia (CNL). The bleeding time was prolonged, the ADP, collagen, epinephrine-induced aggregation of platelets decreased in one case. The adhesiveness, epinephrine-induced aggregation and adenine nucleotide content of platelets decreased in one other case. Megakaryocyte size in CNL was larger than in CML and this difference of the megakaryocyte sizes was related to DNA content distribution of the megakaryocytes. Atypical megakaryocytes were apparently found in one case. The present study suggests that CNL is a stem cell disorder.     

A case of chronic neutrophilic leukemia with original chromosomal abnormalities

We report a new case of the unusual myeloproliferative syndrome chronic neutrophilic leukemia (CNL) that met all the criteria generally required for the diagnosis of this entity. The patient presented abnormalities in platelet function not previously reported that may explain the bleeding tendency observed in these patients. The study of neutrophil function suggested also defective mobility and intracellular bactericidal activity. The chromosomal study revealed original abnormalities consisting of multiple chromosomal ruptures and figures. The disease was controlled with busulfan. After 20 months, the patient died of sepsis. An autopsy was performed confirming the diagnosis and ruling out the existence of a cause of a leukemoid reaction, such as cancer or granulomatous disease.     

Chronic neutrophilic leukemia and chronic myelomonocytic leukemia: WHO defined

The World Health Organization (WHO) classification of myeloid disorders has provided updated parameters for the consistent diagnosis of two previously less than optimally defined chronic myeloid disorders, CNL and CMML. The classification of these disorders, which had been controversial, is now better defined and provides more clinically and biologically relevant disease definitions to enable uniform diagnosis and a framework to evaluate natural history and therapeutic interventions. CNL is now recognized as a distinct entity among the chronic myeloproliferative disorders and CMML is included within the new category of 'myelodysplastic/myeloproliferative diseases' (MDS/MPD). Predominant neutrophilia defines CNL whereas CMML is defined by predominant and monocytosis. In each case these defining features must be distinguished from reactive causes for the same in the absence of clear evidence of myeloid clonality (CNL and CMML) or dysplasia (CMML). The exclusion of underlying bcr/abl-driven oncogenesis is an essential component in the diagnosis of these chronic leukemic processes. The optimal therapy for both CNL and CMML remains uncertain. Current management decisions are based on small studies or extrapolated from therapeutic strategies that are effective in similar chronic, clonal myeloid disorders. Given the potential for evolution to acute leukemia or progressive refractory leucocytosis or cytopenias, allogeneic stem cell transplantation might be appropriate for younger patients. Continued reporting and investigation of specific therapeutic strategies and responses must be encouraged.     

Frequent association of idiopathic myelofibrosis with plasma cell dyscrasias

Summary In a retrospective analysis of 199 cases of myeloproliferative diseases a concomitant plasma cell dyscrasia was found in three out of 46 patients with idiopathic myelofibrosis. Chronic myeloid leukemia, polycythemia vera or unclassifiable myeloproliferative disorders were in no case associated with monoclonal gammopathy. One patient with idiopathic myelofibrosis had primarily coexistent IgG- paraproteinemia and increasing osteolytic lesions; histologic evidence of multiple myeloma, however, was insufficient. In the second patient the interval between diagnosis of idiopathic myelofibrosis and IgG- paraproteinemia was 11 years. After a stable period of 9 years' duration the paraprotein level rapidly increased, associated with depression of normal background immunoglobulins and progressive bone marrow failure. The exact nature of this patient's malignant plasma cell dyscrasia remained uncertain. In the third case benign monoclonal gammopathy of the IgM- type was diagnosed 13 years after idiopathic myelofibrosis. A review of the literature confirms a remarkably high incidence of monoclonal gammopathies in idiopathic myelofibrosis. Benign monoclonal gammopathy seems to occur in at least 8% of the patients while only a few cases of concomitant multiple myeloma have been reported. It may be speculated that plasma cell dyscrasias in idiopathic myelofibrosis reflect involvement of the lymphoid lineage in the neoplastic stem cell disorder.Abbreviations CML chronic myeloid leukemia - IMF idiopathic myelofibrosis - LAP leucocyte alkaline phosphatase - LP lymphoplasmacytoid - MG monoclonal gammopathy - MM multiple myeloma - PV polycythemia vera - WBC white blood cell This paper is dedicated to Professor Dr. Karl Lennert on the occasion of his 65th birthday     

慢性中性粒细胞白血病5例临床分析

目的：探讨慢性中性粒细胞白血病（CNL）的诊断，治疗和预后。方法：对5例CNL患者的临床表现，实验室特点，治疗方法和预后进行分析。结果：5例CNL患者中，4例脾脏肿大；所有患者血液中中性粒细胞持续增多，骨髓粒系增生并以成熟中性粒细胞为主，中性粒细胞碱性磷酸酶（NAP）积分增高，Ph染色体或bcr/abl融合基因阴性；使用马利兰及羟基脲治疗后患者症状有所改善，脾脏缩小及血液中白细胞数下降；1例患者诊断后7年发生急性变。结论：CNL是一种少见类型的慢性白血病，其特点与慢性髓细胞白血病不同；马利兰及羟基脲对其有一定疗效；预后具有异质性。     

Chronic granulocytic leukemia, neutrophilic type, with paraproteinemia (IgA type K).

A patient with chronic granulocytic leukemia, neutrophilic type, was followed for 28 months. A paraproteinemia, IgA type K, and Bence Jones proteinuria (K) appeared without prior chemotherapy with alkylating agents.     

Thalidomide-associated hepatitis: a case report

We report a case of hepatitis in a 58-year-old woman being treated with thalidomide for end-stage plasma cell leukemia. The patient had a medical history including chronic stable hepatitis C infection. At diagnosis there was a severe anemia, thrombocytopenia, hypercalcemia, IgG paraproteinemia, peripheral blood myeloma cells, and a marrow plasmacytosis with lytic bony lesion. The disease was refractory to standard chemotherapy, and she was treated with oral thalidomide. Within 1 week she became jaundiced and developed a marked transaminitis. This promptly resolved upon cessation of thalidomide alone. Thalidomide has recently enjoyed renewed interest as a treatment in many disorders, including plasma cell leukemia. To our knowledge, this is the first reported case of thalidomide-associated hepatotoxicity. Although the mechanism of its actions on the liver are uncertain, it is possible that thalidomide acts as a direct hepatotoxin or as an immuno-modulator, altering the activity of chronic viral hepatitis. We present this case to increase awareness of a new potential side effect of thalidomide as its clinical indications expand.     

Polymyositis associated with chronic myelogenous leukemia

Summary A 53-year-old man with chronic myelogenous leukemia developed progressive proximal muscle weakness with electromyographic and histologic features consistent with polymyositis. Although the association of polymyositis with solid tumors is well recognized, an association with hematologic malignancies has not been firmly established. A survey of the world medical literature reveals one previously reported case of polymyositis and one of dermatomyositis associated with chronic myelogenous leukemia. We conclude that polymyositis does occur in association with chronic myelogenous leukemia. Recognition of this association is important, since treatment of polymyositis can be successful.