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 myelogenous leukemia in blast crisis: retrospective analysis of prognostic factors in 90 patients

 Ninety patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis were reviewed to identify significant prognostic associations. At diagnosis of blast crisis the main clinical, laboratory, and cytogenetic data were recorded and evaluated for prognostic significance. At the time of the analysis 89 patients had died, with a median survival of 11 weeks from diagnosis of blast crisis. Patient characteristics demonstrated in the univariate analysis to have significant association with shorter survival were: thrombocythemia, leukocyte count above 20×10⁹, Karnofsky index <50%, nonlymphoid blast cell morphology, cytogenetic clonal evolution, the presence of a double Philadelphia chromosome or trisomy 8, and no response to therapy. In 17 of 59 patients (29%) evaluable for response to therapy a complete or partial remission was achieved. These responders had a significantly longer median survival (25 weeks) as compared with nonresponders (9 weeks). Response to therapy was significantly better in lymphoid blast crisis and in patients without clonal evolution. In a multivariate analysis containing all significant variables of the univariate analysis two parameters retained their prognostic significance: response to therapy and trisomy 8. In spite of the short overall survival in blast crisis, the determination of prognostic factors may be a useful tool for the clinician planning therapy, especially new therapeutic approaches. Received: 14 November 1995 / Accepted: 20 August 1996     

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。     

Blast crisis of Philadelphia chromosome-positive chronic myelocytic leukemia (CML)

Summary We have studied the clinical courses of 69 patients with blastic crises of Philadelphia chromosome positive CML to identify parameters that were associated with an increased response rate or survival. Cytogenetic analysis at the time of blastic transformation revealed additional chromosome changes in 70% of the patients tested. Bone marrow fibrosis was detected in 58% of evaluable patients. Lymphoblastic transformation was seen in 28% of the patients tested with cell surface marker analysis. The value of 5'-nucleotidase as a marker for distinguishing lymphoid from non-lymphoid blast crisis was confirmed. Of 57 evaluable patients, 23 (40%) responded to therapy (CR/PR longer than 14 days). Median survival was 75 days. Longer survival was related to the following factors: Ph¹-chromosome as the only detectable cytogenetic abnormality; lymphoblastic transformation; no bone marrow fibrosis; high percentage of blasts and promyelocytes in the bone marrow, and response to therapy. No prognostic significance was associated with age, sex, Tdt, LDH, spleen size, duration of the chronic phase of the disease, white blood cell count, Hb, platelet count and percentages of basophils, eosinophils, erythroblasts and blasts and promyelocytes in the peripheral blood. These data confirm the poor prognosis of patients with blastic crisis of CML treated by conventional chemotherapy.     

Allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in second chronic phase attained by imatinib after onset of blast crisis

The prognosis for patients with chronic myeloid leukemia (CML) in blast crisis (BC) remains dismal even with the availability of the BCR-ABL tyrosine kinase inhibitor imatinib, since it only offers short-term benefit in most cases. Allogeneic hematopoietic stem cell transplantation (HSCT) seems to be a viable option for BC-CML patients who attained remission. We treated ten patients with ablative allogeneic HSCT, who achieved second chronic phase (CP) by the use of imatinib after onset of BC. Median patient age was 32 years (range 17–46). Among them, four patients received HSCT from human leukocyte antigen mismatched haplo-identical family donors. After a median follow-up of 24 months (range 8–42), six out of the ten patients were alive in durable complete cytogenetic remission, one patient died in relapse 4 months after transplantation, the others died of severe acute graft-versus-host disease and associated infections. No unusual organ toxicities and engraftment difficulties were observed. Extensive chronic GVHD developed in three of six patients who could be evaluated. Patients transplanted with haplo-identical donors had a high treatment-related modality. Allogeneic HSCT may represent a feasible treatment for patients with CML in second CP attained by imatinib after onset of BC especially when a suitable donor is available.     

Chronic monocytic leukemia terminating in blastic transformation

Summary Chronic monocytic leukemia (CMoL) is a rare disorder, closely related to malignant histiocytosis, but a separate entity. The clinical course of the patient described in this case report was characterized by persistent monocytosis without response to cytotoxic therapy, and a large number of infections. On two occasions a clone of cells containing an extra chromosome 20 was observed. The disease terminated in a phase with rapidly increasing numbers of immature monocytoid cells, corresponding to blastic transformation.     

Analysis of altered proteins related to blast crisis in chronic myeloid leukemia by proteomic study

Introduction: Chromic myeloid leukemia (CML) blast crisis (BC) and imatinib (IM) resistance is a significant barrier to the effective treatment of the disease. Methods: Expression profiles of differential proteins were identified, and new biomarkers or pathways related to BC in CML were screened through proteomic analysis. Total proteins from primary bone marrow cells of CML patients in chronic phase (CP) and BC were separated via two‐dimensional (2D) polyacrylamide gel electrophoresis and then analyzed by imagemaster 5.0 software to detect differential protein spots which were already identified by mass spectrometry. Based on the variation of the whole expression profile, some key proteins were picked out for Western blot to confirm the accuracy of proteomics data. Moreover, related signal pathways involving those proteins were investigated. Results: The result indicated that thirteen protein points between CML‐CP and CML‐BC were successfully determined. Results from Western blot of RhoA, hnRNPK, ANXA1, PSMB4, and LTA4H were similar to those from 2D polyacrylamide gel electrophoresis. Most of those proteins were involved in the proteosome pathway and the small G‐protein pathway. Conclusion: A group of proteins associated with BC can be obtained and the result of this study might provide clues for further research.     

Cytogenetic heterogeneity in blast crisis (BC) of chronic myelogenous leukemia (CML)

Summary New cytogenetic findings are reported in a patient who entered into an accelerated blastic phase of chronic myelogenous leukemia (CML). The cytogenetic findings of this case can be described as 46, xy, t (5; 7) (q31; q11), t (9; 22) (q34; q11), Ph'. The prognostic implications in such patients with rare and unusual cytogenetic findings are discussed.     

Idarubicin and intermediate-dose cytarabine for myeloid blast crisis of chronic myelogenous leukemia – results of a phase-II trial

 Sixteen patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in myeloid blast crisis were treated with cytarabine (AraC) 600 mg/m² two times daily for 5 days and idarubicin 12 mg/m² for 3 days. Patients achieving a second chronic phase received interferon (IFN) alpha 2b 5 mio units/day daily and AraC 20 mg/day subcutaneously 14 days every month. Study end points were remission rate and survival. Four patients (25%) entered a second chronic phase and had a median survival of 31.1 weeks (range 16.1–111 weeks). Nine patients (56%) experienced blast crisis again and had a median survival of 12.9 weeks (range 5.1–59.3 weeks). Three patients (18.8%) died of septic complications during marrow aplasia. The median overall survival was 16.1 weeks (range 2.6–111 weeks) with no significant difference between responders and nonresponding patients. We conclude that AraC/idarubicin is as effective as other intensive regimens in inducing second chronic phase in patients with myeloid blast crisis of CML. Remission duration and survival are comparable to previous results. Further studies to improve survival are required. Received: May 7, 1998 / Accepted: August 7, 1998     

Chronic myeloid leukemia with minor-bcr breakpoint developed hybrid type of blast crisis

Although a breakpoint in the minor breakpoint cluster region (m-bcr) of the BCR gene is observed in about two-thirds of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, this type of genomic rearrangement occurs very rarely in chronic myeloid leukemia (CML). We describe here the eighth case of m-bcr CML, and delineate unique clinical characteristics found in common to the 7 cases reported previously. Monocytosis with a low neutrophil/monocyte ratio resembling chronic myelomonocytic leukemia was the most striking feature of m-bcr CML. Splenomegaly and basophilia were not conspicuous in chronic phase. A high percentage of immature granulocytes and low neutrophil alkaline phosphatase score were the findings in common with classical CML. Lymphoid and myeloid blast changes have been observed at and shortly after presentation so far. We found a hybrid type of blast crisis in the course of m-bcr CML.Thus, m-bcr CML may be a definite subtype of CML, exhibiting distinct clinical characteristics. The presence of fusion product of m-bcr mRNA in an earlier myeloid cell may involve monocytic lineage in addition to myeloproliferative defects. Am. J. Hematol. 57:320–325, 1998. © 1998 Wiley-Liss, Inc.     

Possible effect of medroxyprogesterone acetate (MPA) in lymphoid blast crisis of chronic myelogenous leukemia

Summary A patient with a lymphoid blast crisis of a chronic myelogenous leukemia (CML) was treated with vindesine, vincristine and prednisone. Blasts disappeared from the peripheral blood but persisted at a level of 60% in the bone marrow. After 5 weeks of continuous therapy, the patient became thrombopenic, and 2 weeks later blasts rose to 31%. After 7 weeks, 1 g MPA was given daily p.o. and weekly vincristine treatment was resumed. Blasts disappeared again from the peripheral blood, thrombocytes rose to a maximum of 274 g/l, and a remission with less than 5% blasts was demonstrated in the bone marrow. In another relapse after withdrawal of MPA, estrogen and progesterone receptors (PR) were found in the leukemic cells. Thus, a remission was seen during treatment with vincristine, prednisone, and MPA after a deterioration with vincristine and prednisone alone in a PR-positive leukemia, and an effect of MPA in this lymphoid blast crisis of a CML has to be discussed.This work was presented at the Annual Congress of the German and the Austrian Society of Hematology and Oncology, Essen, 10–13 October 1993     

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.     

T-lymphoid blast crisis in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is considered to be a pleuripotential stem cell disorder with the capacity to differentiate into myeloid, erythroid, megakaryocytic, and lymphoid cell lines. Consequently, blast crisis (BC) involving each of the above lineages has been well described. Among lymphoblastic crises, differentiation frequently occurs along B-cell lineage. We report four patients of CML who terminated in T-cell extramedullary BC in lymph nodes after a variable duration of chronic phase. The T-lineage was established by characteristic cytochemical staining and reactivity with a panel of anti-T-cell monoclonal antibodies. All four cases were Philadelphia (Ph) chromosome positive and demonstrated the Ph chromosome and associated anomalies (extra Ph, +19) in the lymph nodes. Our data adds to the growing evidence that CML is a disorder of the common stem cell from which T, B, and myeloid precursors originate.     

Recent progress in acute leukemia and myelodysplasia

The advances and progress in the understanding and management of acute leukemia and myelodysplasia continue to occur at an exponential rate. While this has led to more therapy options, clinicians and researchers are now facing more challenges in terms of clinical decision-making and more unanswered questions. This paper has outlined some conundrums in acute leukemia and myelodysplasia, and the efforts that are underway to address these.     

Myeloid/natural killer cell precursor blast crisis of chronic myelogenous leukemia with two Philadelphia (Ph-1) chromosomes

We report on a 30-year-old patient with blast crisis of a chronic myelogenous leukemia (CML) that shows immunophenotypic features similar to those of the myeloid/natural killer (NK) cell precursor leukemia previously described. Expression of CD13/CD33/CD65 as well as MPO+/LF- blasts was classified as a myelogenous blast crisis of a CML. In addition, the blasts were positive for CD7/CD56. Other lymphoid markers were not expressed. Cytogenetic and molecular cytogenetic examinations showed two Philadelphia (Ph-1) chromosomes and a trisomy 8. Similar to expression of the myeloid/NK cell precursor phenotype in acute myelogenous leukemia (AML), it is possible to exhibit this phenotype in Ph-1-positive CML. Only one case report of myeloid/NK precursor phenotype blast crisis of CML was found in the literature. Therefore, it is not clear whether this phenotype is a distinct biologic and clinical disease entity of CML, as is the case in the respective AML phenotype.     

Megakaryocytic blast crisis as first presentation of chronic myeloid leukemia

We describe an extremely rare case of megakaryocytic blast crisis as first presentation of chronic myeloid leukemia. The patient had a very high platelet count and developed an ischemic stroke with seizures. She was treated with hydroxyurea, platelet apheresis, ARA-C, and idarubicin in order to obtain a prompt reduction of thrombocytosis and then with imatinib 600 mg/die PO. The therapy induced a complete hematological remission with a resolution of neurological signs within 4 weeks.     

Association of non-alcoholic steatohepatitis (NASH) with chronic neutrophilic leukemia

A 54-yr-old female having chronic neutrophilic leukemia (CNL) associated with severe liver injury is presented. Physical examination on admission showed severe jaundice, hepatosplenomegaly, massive ascites, and pretibial edema. Complete blood count showed a hemoglobin level of 9.1 g/dL, platelet count of 25.8 x 10(4)/microL, and white blood cell count of 36.6 x 10(3)/microL with 89.7% neutrophils. Blood chemistry showed hyperbilirubinemia (21.9 mg/dL) with normal transaminase levels. There was no abnormality in serum cholesterol, triglyceride, or glucose levels. Neutrophil alkaline phosphatase activity was significantly elevated. Bone marrow aspiration showed myeloid hyperplasia with normal karyotype. Rearrangement of the bcr/abl was not detected by either polymerase chain reaction or fluorescence in situ hybridization. Human androgen receptor gene assay (HUMARA) of the bone marrow cells showed clonal proliferation of neutrophils. The patient was diagnosed as having CNL. To evaluate the pathogenesis of the liver injury, a needle biopsy was performed, which showed steatohepatitis with infiltration of neutrophils. As the patient had no history of alcohol abuse, a diagnosis of non-alcoholic steatohepatitis (NASH) was made. Assuming that the infiltration of abnormal neutrophils into the liver contributed to the development of NASH, she was treated with cytoreductive chemotherapy (cytosine arabinoside: 100 mg/d, 1-3 doses/wk). With decreases in white blood cell counts, serum bilirubin levels decreased gradually to 1.5 mg/mL. A postchemotherapy liver biopsy specimen showed marked improvement of the fatty degenerative change. To our knowledge, this is the first report describing the development of NASH in a myeloproliferative disorder. We believe that the infiltration of leukemic cells contributed to the development of NASH in this patient.     

Neutrophil function and cytokine-specific signaling in chronic neutrophilic leukemia

We diagnosed an 86-year-old woman with chronic neutrophilic leukemia (CNL) because she showed sustained leukocytosis dominated by mature neutrophils, hepatosplenomegaly, high neutrophilic alkaline phosphatase score, absence of the Ph chromosome, low serum level of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and no evidence of leukemoid reaction. We found that the extent of stimulation of her neutrophil functions by G-CSF and GM-CSF was greatly reduced compared to healthy donars neutrophils. We showed that CNL neutrophils have intact expression of granulocyte colony-stimulating factor receptor (G-CSFR) and granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR). This suggests that failure of enhancement by G-CSF and GM-CSF in CNL neutrophil functions might be due to disturbances in the intracellular domains of G-CSFR and GM-CSFR, regardless of external cytokine stimulation. However, the patient's neutrophils did not show any mutations in the G-CSFR and GM-CSFR intracellular critical regions. We also showed that stat3 and mitogen-activated protein kinase activation by G-CSF or GM-CSF in the patient's neutrophils were significantly lower than those in healthy donor neutrophils. These results suggest that deficiency of CNL neutrophil function might be due to insufficiency of some inflammatory cytokine-specific signaling. Hence, we are the first to show that CNL neutrophils have partially insufficiency in some cytokine-specific signaling. Further studies are needed to elucidate the signal transduction pathways relating to functional defects in CNL neutrophils.