Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia

A combination of mitoxantrone, vincristine, and prednisone was used to treat 19 patients with acute lymphocytic leukemia. Of these, 12 were patients with acute lymphoblastic leukemia (ALL) (9 in first relapse and 5 primarily refractory to standard induction therapy with daunorubicin, vincristine, and prednisone), 2 had a phenotypic ALL relapse after an initial diagnosis of acute myelocytic leukemia and 5 had terminal deoxynucleotidyl transferase positive blastic phase chronic myelogenous leukemia (BCML). Eight patients with ALL (and of these, four with primarily anthracycline resistant disease), and two with BCML achieved complete remission. Five patients died in induction (three ALL from sepsis and two BCML from bleeding), and five had progressive disease. Median duration of response was 5 months, with two primarily refractory ALL patients remaining in continuing complete remission at 28 and 31 months. Treatment was well tolerated, with minimal nausea and vomiting, and oral mucositis. Posttreatment transient hepatic dysfunction was seen in 80% of patients. Mitoxantrone, vincristine, and prednisone are an active combination for the treatment of relapsed or refractory ALL and of terminal deoxynucleotidyl transferase positive BCML. The finding that four of five primarily refractory ALL patients were induced in complete remission supports the contention that mitoxantrone and anthracyclines are not cross-resistant.     

Phase I and II clinical and pharmacological study of 4-demethoxydaunorubicin (idarubicin) in adult patients with acute leukemia

Fifty-two adults treated previously with either acute leukemia (43 patients) or blastic-phase chronic myelogenous leukemia (nine patients) received 4-demethoxydaunorubicin (20 to 45 mg/sq m) i.v. over 2 to 3 days. Three of the ten patients with acute lymphocytic leukemia achieved a complete remission (CR) lasting 5 to 7 weeks. Five of the 28 patients with acute nonlymphocytic leukemia achieved a CR lasting 5 to 80 weeks. All remissions were induced with one course of treatment with a median time to CR of 28 days (range, 22 to 40 days). None of the patients with blastic chronic myelogenous leukemia or secondary leukemia achieved a CR. The drug was well tolerated; mucositis (36%), nausea and vomiting (35%), and hepatic dysfunction (26%) were the most common side effects. Pharmacokinetic observations on five patients demonstrated multiphasic clearance of 4-demethoxydaunorubicin and extensive formation and prolonged retention of 4-demethoxy-13-hydroxydaunorubicin; that metabolite accumulated in plasma on repeated daily dosing. 4-Demethoxydaunorubicin has sufficient antileukemic activity in both acute lymphocytic leukemia and acute nonlymphocytic leukemia to warrant a prospective comparison, in combination regimens, against the conventional anthracyclines, daunorubicin and/or doxorubicin.     

Phase II trial of mitoxantrone in patients with relapsed and refractory acute leukemia

Mitoxantrone, a new anthracenedione, was administered to thirty-nine patients with relapsed and refractory acute leukemia and to 12 patients with blastic crisis of chronic myelogenous leukemia between August 1981 and September 1984. Eleven patients were not evaluable and 40 were analysed. There were 24 males and 16 females with a median age of 37 yrs (range 6-73 yrs). Three of these were less than 15 yrs and 7 more than 60 yrs. The initial dose employed was 1.9 mg/m2/day X 5. Although eventually a starting dose of 12.3 mg/m2/day X 5 was used, about one half of cases were given more than 5 mg/m2/day X 5 by i.v. bolus. Among 25 patients with acute non-lymphocytic leukemia, there were 4 complete and 6 partial remissions. Among 7 patients with acute lymphocytic leukemia there was one complete remission and one partial remission. All patients except one who attained remissions had received prior anthracyclines. One of 8 patients with blastic crisis of chronic myelogenous leukemia had a partial remission. The durations of complete remission were 1, 1, 5+, 13+ and 17 weeks, respectively. Side-effects showed expected bone marrow depression. Mucositis occurred in ten patients. Gastrointestinal symptoms were noted in approximately 50%, but were mostly mild. Mild alopecia occurred occasionally. The trials were too short to allow evaluation of possible cardiac toxicity. These data indicate that mitoxantrone is non-toxic but hematological and a promising single drug for use in treating relapsed and refractory acute leukemia and suggest that further study would be worthwhile in order to identify its role in the first-line therapy of acute leukemia.     

白血病细胞端粒酶活性的研究

目的：研究白血病细胞端粒酶活性表达及其意义。方法：采用PCR-ELISA半定量方法测定端粒酶活性。结果：68.6％(59／86)急性白血病(AL)患者和80％(12／15)慢性粒细胞白血病急性变(CML-BP)患者表达高端粒酶活性；而慢性粒细胞白血病慢性期(CML-CP)患者，无一例表达高端粒酶活性。急性淋巴细胞白血病患者端粒酶活性高于急性髓性白血病患者，CML-BP端粒酶活性高于CML-CP，而CML-CP端粒酶活性则低于正常对照组。AL端粒酶活性水平与患者的性别、年龄无关，也与治疗后缓解率无关。结论：激活或上调端粒酶活性在大多数AL发生和慢性粒细胞白血病急性变过程中起着重要作用；端粒酶活性测定可鉴别CML-BP与CML-CP；端粒酶可能是一潜在的治疗白血病的新靶点。     

Chemotherapy of Acute Myelocytic Leukemia of Adults: I: A Study of Influences of Chemotherapy on Survival Time

No remarkable progress had been made in the chemotherapy ofacute leukemia before 1948 when Farber et al. reported a caseof complete remission from acute leukemia of children with aminopterine,a purine antagonist. The survival time for cases of adult acute myelocytic leukemiareveals that the survival time was 2.0–2.2 months in theyears when supportive therapy alone was provided, but it isa fact that the survival time has been extended due to the growingmarked availability of sophisticated antileukemic agents. Iconducted a study on the remission rate, duration of remissionand survival time with particular reference to their relationswith various factors of chemotherapy.     

慢性粒细胞白血病急变期与急性白血病细胞形态学特征差异分析

目的：探讨慢性粒细胞白血病急变期与急性白血病细胞形态学特征差异.方法：对11例急变期的慢性粒细胞白血病及52例初发急性白血病的骨髓及外周血细胞形态学差异进行分析.结果：11例慢性粒细胞白血病急变期患者,2例为急淋变,9例为急粒变.52例初发白血病,急性淋巴细胞白血病15例,急性非淋巴细胞白血病37例.慢性粒细胞白血病急粒变患者外周血嗜酸和或嗜碱细胞高于正常值,血小板多大于50×109/L,骨髓增生极度活跃,各期细胞均可见,原始及早幼粒细胞明显增高,伴有嗜酸和或嗜碱粒细胞增多,NAP积分可正常,这与急性粒细胞白血病有所差异.慢性粒细胞白血病急淋变患者外周血涂片可见早幼粒细胞及嗜酸、嗜碱粒细胞增多,这与急性淋巴细胞白血病不同.此外,尚需结合临床病史及细胞遗传学检查予以鉴别.结论：慢性粒细胞白血病患者急变期外周血及骨髓多有嗜酸及嗜碱粒细胞增多,早幼粒细胞增多,同时结合NAP,临床病史及细胞遗传学检查可与急性白血病相鉴别.     

Intensive treatment of acute leukemia in adults 70 years of age and older

The results of treatment for acute leukemia since 1973 in 87 patients aged 70 years or more are summarized. The overall complete remission rate was 27/78 (35%) in acute myelogenous leukemia and 5/9 (56%) in acute lymphocytic leukemia or acute undifferentiated leukemia for cytosine arabinoside combined with either anthracyclines (rubidazone or Adriamycin [doxorubicin]) or m-AMSA (amsacrine). The remission duration was short with a median of 33 weeks, and the median overall survival was only 6 weeks. Those patients without identifiable infection, liver enlargement, and a serum glutamic oxaloacetic transaminase less than or equal to 40 U/ml constituted a more favorable subgroup. Although the complete remission rate improved further research is needed to develop effective maintenance strategies.     

Trends in survival after diagnosis with hematologic malignancy in adolescence or young adulthood in the United States, 1981‐2005

BACKGROUND:

There are few population‐based studies of long‐term survival of adolescents and young adults with hematologic malignancies; most pertain to patients diagnosed in the 1990s or earlier. Period analysis was used to obtain up‐to‐date information on survival expectations of adolescents and young adults diagnosed with hematologic malignancies through the early 21st century.

METHODS:

Period analysis was used to calculate 5‐ and 10‐year relative survival for adolescents and young adults diagnosed with Hodgkin lymphoma (HL), non‐Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), and chronic myelocytic leukemia (CML) for 5 5‐year periods from 1981‐1985 to 2001‐2005, using data from the Surveillance, Epidemiology, and End Results database.

RESULTS:

Survival strongly improved for each of the 5 hematologic malignancies. Increases in 10‐year relative survival between 1981‐1985 and 2001‐2005 were as follows: HL, from 80.4% to 93.4%; NHL, from 55.6% to 76.2%; ALL, from 30.5% to 52.1%; AML, from 15.2% to 45.1%; CML, from 0 to 74.5% (P < .001 in all cases). However, although survival improved steadily throughout the period examined for the lymphomas and CML, survival was stable during the late 1990s and early 21st century for the acute leukemias.

CONCLUSIONS:

Survival expectations for adolescents and young adults with hematologic malignancies have strongly improved since the 1980s. However, with the exception of HL, survival rates have not reached the levels observed for children diagnosed with these malignancies, and survival expectations for patients with acute leukemia have stabilized at relatively low levels. Cancer 2009. © 2009 American Cancer Society.     

Autologous stem cell transplantation for adult acute leukemia

Autologous stem cell transplantation using marrow or peripheral blood is routinely used to consolidate patients with acute myelocytic leukemia in complete remission. The situation is less clear for adult acute lymphocytic leukemia in which results achieved with all strategies are disappointing.In acute myelocytic leukemia, autografts should be done in patients with good and standard risk factors. Patients with high-risk acute myelocytic leukemia defined by poor cytogenetics or failure to achieve remission with the first induction course, should proceed to allogeneic stem cell transplantation with the best available human leukocyte antigen-identical donor (family or unrelated), and the nature of the conditioning regimen (myelo-ablative or non-myelo-ablative) should be decided in relation to age, and the patient's clinical condition. Results of autografting in acute myelocytic leukemia rely strongly on the quality of the graft. Higher doses of infused stem cells translate into lower relapse rates. Marrow purging with cyclophosphamide derivatives also diminishes the relapse incidence. Autologous stem cell transplantations using peripheral blood are presently preferred to marrow as the source of stem cells, but an aggressive prior in vivo purge (high-dose consolidation course(s) before cytaphereses) is then mandatory. In good-risk acute myelocytic leukemia, autografting is superior to high-dose ARA-C; in standard-risk acute myelocytic leukemia, both are supposedly equivalent. There is no prospective randomized study testing the two approaches in the good-standard-risk population. We presently test the combination of marrow and blood both purged by mafosfamide.In adult acute lymphocytic leukemia, good-risk patients get the best benefit from autografting over conventional chemotherapy. Maintenance chemotherapy after transplant is likely to bring benefit.Research in progress aims at facilitating access of the largest number of patients to autografting and at introducing posttransplant immunomodulation maneuvers such as tumor vaccination.     

急性髓系白血病合并慢性淋巴细胞白血病一例报道及文献复习

 目的 探讨急性髓系白血病（AML）合并慢性淋巴细胞白血病（CLL）的临床特点、病因、诊断、治疗及预后。方法 临床诊断1例AML合并CLL,并就相关文献进行复习。结果 患者经MA方案（米托蒽醌10 mg／d第1 ~ 3天,阿糖胞苷150 mg／d第1,3,5,7天,200 mg第2,4,6天）化疗后取得完全缓解,但CD19阳性的淋巴细胞（表达CD20,CD23,SIgM,部分表达CD5,CD22,CD25）仍然存在,于9个月后AML复发未能再次缓解而死亡。结论 AML合并CLL为一种具有特殊生物学特征的罕见疾病,免疫分型和细胞遗传学技术在疾病的诊断和认识中发挥重要作用,治疗应以AML为主。     

5-azacytidine in refractory acute leukemia

11 patients (aged 23--75 years) with refractory acute leukemia were treated at the Maine Medical Center with 5-Azacytidine, 150 mg/m2/day, by continuous infusion for 5 days every 2 weeks. Prior therapy included anthracycline/cytosine arabinoside protocols. Of the 8 patients with refractory de novo acute myelogenous leukemia, 6 achieved remission at an overall response rate of 75% (3 complete remission and 3 partial remission). An average of 1.67 courses was necessary to achieve a response. Remissions were not seen in blastic chronic myelogenous leukemia nor in acute leukemia secondary to cytotoxic drugs. Toxicity included myelosuppression, moderate nausea and vomiting, abnormal liver function tests, and neuromuscular symptoms. 5-Azacytidine by continuous infusion has significant activity in refractory acute myelogenous leukemia and should be considered for inclusion in primary remission induction therapy.     

4-demethoxydaunorubicin (idarubicin) in combination with 1-beta-D-arabinofuranosylcytosine in the treatment of relapsed or refractory acute leukemia

We conducted a Phase I-II trial of 4-demethoxydaunorubicin (idarubicin, IDR) in combination with 1-beta-D-arabinofuranosylcytosine (ara-C) in 51 patients with relapsed or refractory acute nonlymphocytic leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia in blast crisis. Only 1 of 12 patients treated at the first dose level (idarubicin, 10 mg/m2/day for 3 days and ara-C, 25 mg/m2 i.v. bolus followed by 200 mg/m2 continuous infusion daily for 5 days) achieved aplasia and complete remission. The dose of idarubicin was subsequently increased to 10 mg/m2/day for 4 days with the ara-C dose held constant. Complete remission incidence for this dose schedule was: 7 of 31 patients with acute nonlymphocytic leukemia, 0 of 5 patients with acute lymphocytic leukemia, 0 of 1 patient with chronic myelogenous leukemia in blast crisis, and 1 of 2 patients with biphenotypic leukemia. Nonhematological toxicity included nausea, vomiting, mucositis, and abnormal liver function tests. Detailed pharmacological studies were performed to determine whether ara-C altered IDR metabolism or that of its main metabolite, 13-hydroxyidarubicinol or IDR clearance. A high degree of variability among patients was apparent and no consistent effect could be demonstrated. In summary, 9 of 37 patients (24%) with relapsed or refractory ANLL, including 1 patient with biphenotypic leukemia, achieved remission. We conclude that idarubicin in combination with ara-C is an active combination in patients with relapsed or refractory leukemia.     

Prevention of chemotherapy-induced leukemia and of leukemia relapses

Fifty percent of patients with the myelodysplastic syndrome, frequently following treatment by radiation or chemotherapy, have prognostically unfavorable deletions of the long arms of chromosomes 5 and 7, or trisomy 8, as have the 25% of patients with acute myeloblastic leukemia where remissions last 6–12 months, and where relapse cannot be prevented. In contrast, patients with prognostically favorable cytogenetics (translocation 15; 17 or 8; 21 or inversion 16) maintenance chemotherapy may prevent relapses. Of chronic myelocytic leukemia patients, 85% can achieve hematological remission with interferon α, and 40% a partial cytogenetic remission, which probably delays relapse.     

Argininosuccinate synthetase gene expression in leukemias: potential diagnostic marker for blastic crisis of chronic myelocytic leukemia.

Argininosuccinate synthetase (ASS) activity is hardly detected in human lymphocytes. In this study, we examined the ASS gene expression of various leukemia cells by a polymerase-chain-reaction method. We demonstrate here that (a) acute lymphocytic and acute myelocytic leukemia cells exhibit the highly elevated expression of the ASS gene and (b) chronic myelocytic leukemia (CML) in blastic crisis also exhibits the increase of ASS gene expression while CML in chronic phase, chronic lymphocytic leukemia and adult T leukemia cells show the similar level to that of normal lymphocytes. These results suggest that the ASS gene expression is of value as a diagnostic marker of acute type leukemia, particularly for blastic crisis of CML.     

VP 16-213 in the treatment of acute leukemia in childhood

Effectiveness and side effects of VP 16-213, a semi-synthetic podophyllotoxin, on acute leukemia and histiocytic medullary reticulosis in childhood was tested. Four cases of refractory acute lymphocytic leukemia, five of acute non-lymphocytic leukemia-one induction failure and 4 in remission--and a case of histiocytic medullary reticulosis were treated with a combination of VP 16-213 (Days 1-5), cytosine arabinoside (Days 1-5) and adriamycin (Day 6). None of the acute lymphocytic leukemia patients yielded a complete response; however, one of them later attained a partial response with modified intermittent administration of VP 16-213 and cytosine arabinoside. A patient with acute non-lymphocytic leukemia who had failed to attain initial remission, achieved a complete response after the second course of the treatment with increased dosages. In the four acute non-lymphocytic leukemia patients in remission, complete remission was maintained more than 4 a months. A case of histiocytic medullary reticulosis demonstrated partial response. The major toxic effects produced by this regimen were marked pancytopenia and vomiting. VP 16-213 appears to be effective for myelocytic and monocytic malignancies in childhood.     

Expression of the Wilms' tumor gene (WT1) in human leukemias.

Leukemic cells from seventy patients with various types of human leukemias were examined for expression of the WT1 gene, the Wilms' tumor gene located at chromosome 11p13. WT1 was expressed in 7 of 16 cases of acute lymphoblastic leukemia, 15 of 22 with acute myelogenous leukemia and 8 of 10 in blast crisis of chronic myelogenous leukemia. No detectable WT1 RNA was found in chronic leukemias, including chronic lymphocytic leukemia, plasma cell leukemia, hairy cell leukemia and chronic myelogenous leukemia in chronic phase. The expression pattern of WT1 in these human leukemia samples indicates the involvement of this gene in the early stage of hematological cell differentiation.     

Isoenzyme studies in human leukemia. I. Acid phosphatase

Acid phosphatase (AcP) isoenzymes were investigated in acute lymphocytic leukemia (ALL), malignant Non-Hodgkin-lymphoma (NHL) and acute myelocytic leukemia (AML) by analytical isoelectric focusing in polyacrylamide gels (IEF). By this technique 5 groups of at least 8 isoenzymes were observed. A new subgroup of childhood common ALL (C-ALL) could be defined, lacking acid phosphatase activity by cytochemistry. However, IEF demonstrated the presence of the main isoenzyme band and the cells reacted positively with C-ALL antiserum. AcP isoenzymes of myelocytic and lymphocytic leukemic cells showed similar patterns in IEF. No leukemia specific isoenzyme could be demonstrated. The results indicate that childhood C-ALL cells may represent different differentiation stages.     

Construction of a Protein-Protein Interaction Network for Chronic Myelocytic Leukemia and Pathway Prediction of Molecular Complexes

Background: Chronic myelocytic leukemia is a disease that threatens both adults and children. Great progress has been achieved in treatment but protein-protein interaction networks underlining chronic myelocytic leukemia are less known. Objective: To develop a protein-protein interaction network for chronic myelocytic leukemia based on gene expression and to predict biological pathways underlying molecular complexes in the network. Materials and Methods: Genes involved in chronic myelocytic leukemia were selected from OMIM database. Literature mining was performed by Agilent Literature Search plugin and a protein-protein interaction network of chronic myelocytic leukemia was established by Cytoscape. The molecular complexes in the network were detected by Clusterviz plugin and pathway enrichment of molecular complexes were performed by DAVID online. Results and Discussion: There are seventy-nine chronic myelocytic leukemia genes in the Mendelian Inheritance In Man Database. The protein-protein interaction network of chronic myelocytic leukemia contained 638 nodes, 1830 edges and perhaps 5 molecular complexes. Among them, complex 1 is involved in pathways that are related to cytokine secretion, cytokine-receptor binding, cytokine receptor signaling, while complex 3 is related to biological behavior of tumors which can provide the bioinformatic foundation for further understanding the mechanisms of chronic myelocytic leukemia.     

The first case of Philadelphia chromosome-negative acute promyelocytic leukemia following imatinib for chronic myelogenous leukemia

In chronic myelogenous leukemia, chromosomal abnormalities in Philadelphia-negative cells are rare and usually transient, but can infrequently lead to myelodysplastic syndrome and/or acute myeloid leukemia. We report an 82-ear-old patient with an 11-year history of chronic myelogenous leukemia, in complete cytogenetic response, who developed Philadelphia-negative t(15;17)/PMLRARA acute promyelocytic leukemia. This isolated case reaffirms several important clinicopathologic and biologic aspects of chronic myelogenous leukemia, and sheds a unique light on its Philadelphia-negative hematopoiesis. It also underlines the importance of continued cytogenetic monitoring of patients in complete cytogenetic response for the emergence of new chromosomal abnormalities.