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.     

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.     

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.     

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.     

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.     

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 neutrophilic leukemia (CNL) with karyotypic abnormalities associated with plasma cell dyscrasia: a case report.

A case of chronic neutrophilic leukemia (CNL), a rare myeloproliferative syndrome associated with monoclonal gammopathy of uncertain significance (MGUS-Type IgGk), is reported. Karyotypic study, carried out on bone marrow, excluded Philadelphia-pos. chronic myeloid leukemia (CML) and showed Y loss (45 XO). Only a few cases of CNL with paraproteinemia have been reported, but no case of associated karyotypic abnormalities and paraproteinemia has so far been described.     

低增生骨髓增生异常综合征的由来和转归

目的探讨低增生骨髓增生异常综合征（ＭＤＳ）的由来和发展。方法对我院１０年中确诊的２５例低增生ＭＤＳ进行了系统分析,对其中１７例患者进行长期追访。结果（１）低增生ＭＤＳ占同期确诊为ＭＤＳ的２１９例患者中１１．４％,确诊时平均年龄为（４４．８±１４．７）岁。（２）ＦＡＢ分型：难治性贫血（ＲＡ）１１例,难治性贫血伴原始细胞增多（ＲＡＥＢ）１４例。（３）低增生ＭＤＳ很可能是ＭＤＳ患者病程中一个阶段,其骨髓增生活跃和低下可以相互转化,这种转化不但可以发生在同一ＦＡＢ亚型内,也可以发生在不同亚型相互转化时。（４）长期随访的１７例患者中有７例转为急性白血病,占４１．２％,６例为急性粒细胞白血病,１例为急性淋巴细胞白血病;７例中３例转为低增生白血病,４例为增生活跃或极度活跃白血病。（５）１７例患者中７例自低增生ＲＡＥＢ转为急性白血病时间为１～７４个月,中数为２７个月。（６）低增生ＭＤＳ的产生与治疗药物无明显相关。结论低增生ＭＤＳ很可能为ＭＤＳ病程中一个阶段而非一种特殊类型。     

Chronic neutrophilic leukemia: a contemporary review

Chronic neutrophilic leukemia (CNL) is recognized as a distinct clinicopathologic entity characterized by sustained mature neutrophilic leukocytosis splenomegaly with bone marrow granulocytic hyperplasia without evidence of dysplasia or striking reticulin fibrosis. This diagnosis is contingent on thorough initial investigation and follow-up to exclude underlying causes of reactive neutrophilia, particularly if evidence of myeloid clonality is lacking. The optimal therapy for CNL remains uncertain. Current management decisions are based on anecdotal reports or extrapolated from therapeutic strategies effective in similar chronic clonal myeloid disorders. Because of the potential for blastic transformation and progressive refractory neutrophilia, allogeneic stem cell transplantation may be appropriate for younger patients. Continued reporting of all cases of CNL and responses to therapeutic strategies must be encouraged.     

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.     

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.     

Manifestations systémiques et auto-immunes des syndromes myélodysplasiques

Myelodysplastic syndromes (MDS) can be associated with systemic or autoimmune diseases. Vasculitides (leucocytoclastic, periarteritis nodosa, micropolyangeitis, Wegener's granulomatosis), relapsing polychondritis, and Sweet's syndrome are the most commonly reported. Refractory anemia with excess of blasts (RAEB), transformed RAEB evolving to an acute leukemia, and chronic myelomonocytic leukemia (CMML) are preferentially associated with these vasculitides or systemic diseases. Corticosteroids are generally effective. Immunosuppressive drugs expose these patients to infectious complications and increase the risk of transformation into acute leukemia. Occurrence of relapsing polychondritis in a patient older than 60 years is associated with a myelodysplastic syndrome in 40% of the cases. Sweet's syndrome is associated in 10% of the cases with acute myeloid leukemia and MDS. Polyarthritis or oligoarthritis with systemic manifestations that include fever, skin rash, and more rarely serositis or haemolytic anemia can occur contemporarily to a MDS. Behçet's disease with intestinal involvement has been reported in patients presenting with trisomy 8 associated MDS. Pathogenic mechanisms underlying the association between MDS and autoimmune or systemic disorders remain to be elucidated.     

Early relapse of JAK2 V617F-positive chronic neutrophilic leukemia with central nervous system infiltration after unrelated bone marrow transplantation

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by a proliferation mainly of mature neutrophils. The prognosis is generally poor and an optimal therapeutic strategy remains to be determined. Allogeneic hematopoietic stem cell transplantation (HSCT) is expected to be the only curative therapy so far. We report a 46-year-old male with progressive CNL who underwent bone marrow transplantation from an HLA-matched unrelated donor. After engraftment was achieved on day 35, relapse of CNL was confirmed on day 50. The progression of CNL was very rapid afterward and infiltration to the central nervous system was observed. The Janus Kinase 2 (JAK2) V617F homozygous mutation was detected from the peripheral blood or bone marrow samples throughout the clinical course. From comparison with reports of successful HSCT for CNL in the literature, it was inferred that HSCT should be performed in a stable status before progression. Furthermore, JAK2 V617F-positive CNL may contain an aggressive disease entity in contrast to previous reports. Accumulation of experiences is required to establish a definite role of HSCT in the treatment of CNL and a prognostic significance of JAK2 mutation in CNL.     

急性红白血病55例染色体特征和预后分析

目的探讨急性红白血病（M6）染色体特征和预后因素。方法回顾性分析55例患者染色体核型特征,采用病例对照方法,分为原发组和骨髓增生异常综合征（MDS）转化组;染色体核型异常组和正常组,并分析各组异基因造血干细胞移植（all-HSCT）治疗和（或）化疗疗效及生存预后因素。结果45例经染色体检查,18例正常,染色体异常检出率为60．0％（27／45）,其中复杂异常17例,简单异常10例,10例可见亚二倍体或超二倍体明显增多,18．5％（5／27）5号染色体受累,25．9％（7／27）7号或8号染色体受累。55例患者完全缓解（CR）率63．6％;MDS转化组CR率（42．8％）显著低于原发组（85．2％）,P〈0．05;染色体核型异常组CR率（37．0％）显著低于正常组（83．3％）,P〈0．01。生存预后因素：随访中位时间30（3—79）个月,染色体核型异常组和MDS转化M6患者生存期（OS）和无病生存期（DFS）,移植治疗者较化疗者显著延长（P〈0．01）。16例患者行all-HSCT治疗,其中9例为染色体核型异常MDS转化M6患者,4例为未缓解患者;移植后11例DFS 28个月,2年生存率68．7％（11／16）。结论染色体核型异常和（或）MDS转化M6患者常规化疗疗效差、生存期短,预后差,all-HSCT治疗显著延长生存期,改善预后,染色体核型异常和（或）MDS转化M6患者,宜早期all-HSCT治疗。     

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.     

骨髓增生异常综合征患者T细胞受体基因重排的检测价值

目的 为了解骨髓增生异常综合征（ＭＤＳ）患者Ｔ细胞受体（ＴＣＲ）基因重排情况。方法 应用聚合酶链反应检测３６例ＭＤＳ患者ＴＣＲＶγＩ－Ｊγ基因重排。结果 ８例（２２．２％）ＭＤＳ患者检测出克隆性ＴＣＲＶγＩ－Ｊγ基因重排;难治性贫血伴有原始细胞增多（ＲＡＥＢ）,慢性粒－单细胞白血病（ＣＭＭＬ）和转化中的ＲＡＥＢ（ＲＡＥＢ－Ｔ）组ＴＣＲＶγＩ－Ｊγ基因重排阳性ＭＤＳ转化为急性白血病时间显著短于重排阴     

CAG方案治疗中高危骨髓增生异常综合征和急性髓系白血病的疗效观察

目的:观察阿糖胞苷、阿克拉霉素和粒细胞集落刺激因子联合方案(CAG方案)治疗中、高危骨髓增生异常综合征(MDS)和老年初治、难治、复发和继发于MDS的急性髓系白血病(AML)的临床疗效及不良反应。方法:应用CAG方案治疗MDS9例和AML23例,完成1个疗程后评估疗效,治疗失败患者则退出观察,有效者继续接受1个疗程治疗。结果:9例MDS临床均有效,其中完全缓解4例(44.4%)。部分缓解3例(33.3%),血液学进步伴骨髓缓解1例(11.1%),骨髓缓解1例(11.1%)。AML临床总有效13例(56.5%),其中完全缓解9例(39.1%),部分缓解4例(17.4%)。大部分患者出现了可以耐受的轻微不良反应,主要表现为骨髓抑制。结论:CAG治疗中、高危MDS和预后差的AML安全有效,长期疗效需进一步观察。     

Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML

Somatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We resequenced SF3B1, U2AF35, and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia. We found missense mutations in 2 juvenile myelomonocytic leukemia cases and in 1 child with systemic mastocytosis with MDS. In 1 juvenile myelomonocytic leukemia patient, the SRSF2 mutation that initially coexisted with an oncogenic NRAS mutation was absent at relapse, whereas the NRAS mutation persisted and a second, concomitant NRAS mutation later emerged. The patient with systemic mastocytosis and MDS carried both mutated U2AF35 and KIT in a single clone as confirmed by clonal sequencing. In the adult MDS patients sequenced for control purposes, we detected previously reported mutations in 7/30 and a novel SRSF2 deletion (c.284_307del) in 3 of 30 patients. These findings implicate that spliceosome mutations are rare in pediatric MDS and juvenile myelomonocytic leukemia and are unlikely to operate as driver mutations.     

Transformation of chronic myelomonocytic leukemia to acute lymphoblastic leukemia: Case report and review of the literature of lymphoblastic transformation of myelodysplastic syndrome

If chronic myelomonocytic leukemia (CMML) transforms into an acute leukemic phase, the blast crisis is invariably myeloid. Occasionally, the other subtypes of myelodysplastic syndrome (MDS) (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation) have been noted to transform into acute lymphoblastic leukemia (ALL). We now report a case of CMML that transformed into ALL and we review the literature of 13 other cases of MDS with ALL transformation. Such cases provide suggestive clinical evidence that MDS can involve a pluripotent stem cell. © 1955 Wiley-Liss, Inc.     

Chronic neutrophilic leukemia clinicopathological investigation on Japanese cases: with the questionnaire

The clinical picture and disease features of chronic neutrophilic leukemia (CNL), a rare hematological disorder, were investigated among 38 patients collected from Japanese reports. According to the diagnostic criteria, review of Japanese literature was carried out, using the questionnaire to the reporters of CNL cases. The rate of return for the questionnaire was 23/29 (79.3%). Of the 38 CNL patients, 26 were men and 12 were women. Their mean age at diagnosis was 65.2 years. The mean value of initial laboratory data were as follows; leukocyte count 54,000/mm3 with 86.9% mature neutrophils, hemoglobin 10.6g/dl, platelet count 22.0 X 10(4)/mm3, NCC from the bone marrow 44.9 X 10(4)/mm3, and NAP score 400.5. The CFU-C value was decreased in 17 of 24 cases examined. Two among the thirteen cases showed an increase of CSF activity in serum, and none was detected in urine of four cases. The clinical course in 33 cases were evaluated, and the median survival after the diagnosis was 21 months. Three cases terminated blastic crisis. Two had features similar to polycythemia during their course. The association with monoclonal gammopathy or multiple myeloma was found in 8 cases (21.8%), and this appears to be among the presenting clinical characteristics. Hemorrhagic diathesis was often fatal and was the most frequent cause of death (13 out of 28 cases died). Postmortem examination showed occasional systemic infiltration with neutrophils or leukemic cells in most organs including liver and spleen.