High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia

Background: The bcl-2 oncoprotein is suggested to be directly involved in the emergence of drug resistance by disrupting or delaying the apoptotic program and promoting tumor survival.Patients and methods: In order to define the clinical relevance of the bcl-2 mRNA expression in acute myeloid leukemia (AML) and its correlation to therapy outcome and prognosis, we analyzed 219 AML bone marrow (BM) samples, including 119 patients with de novo AML at presentation, 37 with AML following myelodysplastic syndrome (MDS), as well as 42 BM samples of AML in relapse and 21 in complete remission (CR) using RT-PCR. For performing quantitative measurements of bcl-2 mRNA, we developed a quantitative RT-PCR.Results: Bcl-2 mRNA was detectable in 133 of 156 (84%) patients at diagnosis and 40 of 42 (95%) at relapse. AML patients with high bcl-2 mRNA expression achieved lower CR rates than those with no or low expression. Concerning the long-term outcome, the overall (OS) and disease-free survival (DFS) was significantly worse in AML patients with high expression levels of bcl-2 mRNA. The three-year OS for all newly diagnosed AML patients was 49% and 10% (P = 0.028), respectively, and 71% and 15% (P = 0.0004) for patients <60 years. Comparable significant differences were observed for the DFS.In AML following MDS and patients >60 years, the bcl-2 expression was not associated with remission rate or survival.Conclusions: The expression of bcl-2 mRNA may serve as a prognostic factor predicting remission outcome and long-term prognosis in AML.     

CD34抗原、bcl-2蛋白表达与急性髓性白血病化疗耐药

目的　检测急性髓性白血病 (AML)中CD34 ,bcl 2的表达 ,并评价其临床意义及CD34 ,bcl 2间可能存在的关系。方法　免疫细胞化学APAAP法。结果　CD34 、bcl 2表达与AML外周血WBC数。骨髓原始细胞比例、CUF L等临床特征无关 ;而继发性AMLCD34 水平显著高于原发性AML患者 (P <0 .0 5 ) ;但bcl 2水平在原发 ,继发AML中无差别。原发性AML中CD34 水平与化疗疗效无关 (P >0 .0 5 ) ;无论原发AML或AML中 ,bcl 2表达均与化疗耐药有关。结论　CD34 并非一个能独立耐药相关的因素 ,而bcl 2可以独立决定化疗反应 ;CD34 和bcl 2无相关性。     

The incidence,risk factors,and survival of acute myeloid leukemia secondary to myelodysplastic syndrome: A population‐based study

To determine the incidence, risk factors, and relative survival of acute myeloid leukemia (AML) secondary to myelodysplastic syndrome (MDS) in the Surveillance, Epidemiology, and End Results (SEER) database. Retrospective analysis of all patients with new MDS onset in the SEER‐18 database from 2001 to 2013. We identified 36 558 patients with primary MDS. The rate of secondary AML (sAML) was 3.7% among patients 40 years or younger and 2.5% among those older than 40 (P = .039). The median transformation interval was significantly shorter for the younger group (4.04 vs 13.1 mo; P < .001). For both age groups, median overall and cancer‐specific survival were significantly longer for patients who did not develop sAML. Although the younger patients survived longer than the older patients, sAML development had a more negative effect on the survival of younger patients. Female sex, age, and World Health Organization (WHO) type MDS with single lineage dysplasia (MDS‐SLD) were associated with a decreased risk of sAML for older but not younger patients. Among older patients with MDS, a married status, Black race, female sex, shorter time to sAML, and WHO type MDS‐SLD or MDS with ringed sideroblasts were favorable prognostic factors for survival. In the SEER database, the rate of sAML among patients with MDS is lower than that in previous reports, but these patients still have worse survival. Risk assessment should include clinical and demographic factors.     

The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral,outpatient therapy

The therapeutic potential of arsenic derivatives has long been recognized and was recently rediscovered in modern literature. Early studies demonstrated impressive activity of this compound in patients with relapsed acute promyelocytic leukemia (APL). Over the last 2 decades, intravenous arsenic trioxide has been used successfully, both alone and in combination with other agents, for the treatment of APL and, with some success, of other myeloid neoplasms. Arsenic trioxide is currently part the standard of care for patients with APL. More recently, oral formulations of this compound have been developed and are entering clinical practice. In this review, the authors discuss the evolution of arsenic in the treatment of APL and other myeloid neoplasms. Cancer 2016;122:1160–8. © 2015 American Cancer Society.     

Prognostic factors and treatment effects on survival in acute myeloid leukemia of M6 subtype: A retrospective study of 54 cases

Background:Since 1976, erythroleukemia has been included within the FAB classification system of acute myeloid leukemia (AML) which designates it as M6 AML. This report describes the data of 54 patients with newly diagnosed M6 AML, consecutively seen in our hospital between May 1976 and May 1999. Patients and methods:There were 40 males and 14 females. Median age was 59 years. Pancytopenia was the most common feature at diagnosis. Twenty-six percent of cases presented with secondary AML. Karyotype was successfully performed in 35 cases. Eleven patients presented with normal karyotype, nine with simple karyotypic abnormalities, and fifteen with major karyotypic abnormalities. Fifty of the fifty-four patients received one or two courses of induction chemotherapy combining anthracyclines with cytarabine according to different successive protocols. One elderly patient only received low-dose cytarabine, and three patients died before any chemotherapy could be given. Results:Complete remission (CR) was achieved in 29 cases (54%, 95% confidence interval (CI): 40%–67%). As post-remission therapy, four patients could be allografted, and two underwent autologous transplantation. All other treated patients received continuation chemotherapy. Twenty-one patients have relapsed (72%). Median time to relapse was six months. Among those patients, only eight achieved a second CR (38%). The median disease-free survival (DFS) was eight months (95% CI: 4–10 months) with a five-year survival rate of 17%. Median overall survival (OS) was nine months (95% CI: 5–12 months) with a five-year survival rate of 13%. In univariate analysis, poor prognostic factors for DFS were secondary AML (P = 0.05) and initial platelet count <50 × 109/l (P = 0.02). Poor prognostic factors for OS were age 60 years (P = 0.005), secondary AML (P = 0.05), initial blastic fever (P = 0.0004), and initial haemoglobin level <90 g/l (P = 0.03). All factors, but haemoglobin level, remained significant in the multivariate analysis. Although it was not statistically significant, there was a trent for a better prognosis of M6 patients presenting with normal karyotype as compared to those displaying chromosomal abnormality. Conclusions:This retrospective analysis points to a somewhat heterogenous group of AML in terms of clinical and biological features, and outcome. Distinctive subgroups can be identified according to prognostic factors related to survival. A larger multicenter study with well-defined diagnostic criteria is warranted to further clarify treatment effects.     

Study of the levels of expression of two oncogenes, c-myc and c-myb, in acute and chronic leukemias of both lymphoid and myeloid lineage

Total cellular RNA from a series of leukemic cell populations, both myeloid and lymphoid, as well as from normal circulating lymphocytes was analysed for the expression of two cellular oncogenes, c-myc and c-myb, by Northern blot hybridization assay. Expression of c-myc but not of c-myb was observed in unstimulated normal lymphocytes. Stimulation by PHA was shown to activate the expression of both genes. Remarkably different levels of expression of c-myc were observed in ALL, whereas in CLL the expression of c-myc was uniformly low or absent. Differential expression of c-myc was detected in AML as well as in CML, c-myb was differentially expressed in AML and ALL, and absent in CLL and CML. Other single cases of hemopoietic disorders were studied, but the expression of the two oncogenes was low or absent. Neither evident genome amplification nor genome rearrangements were detected in the cell DNAs digested with restriction endonucleases.     

BCL6、KLF5、NCL基因在儿童急性淋巴细胞白血病中异常表达的特点

目的:研究转录因子基因BCL6、KLF5及核仁蛋白基因NCL在急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患儿骨髓细胞中的表达情况及其在不同疾病状态下的表达特点。方法:选取北京儿童医院2004年1月至2005年12月住院ALL患儿100例,另取由于骨骼畸形而在北京儿童医院进行外科手术的5例非ALL患儿作对照;以基因芯片检测ALL患儿骨髓细胞中异常表达基因,GeXP多重基因表达分析系统检测BCL6、KLF5、NCL基因在另外选取的10例配对ALL患儿初诊及缓解期的表达变化。结果:基因芯片筛查发现,在100例各亚型ALL标本中,BCL6和KLF5mRNA表达均下调,NCLmRNA表达均上调。BCL6和KLF5mRNA在10例ALL初诊患儿骨髓细胞中表达较低,完全缓解后表达升高(0.380±0.16vs0.850±0.10,0.074±0.021vs0.228±0.049;均P<0.01);NCLmRNA在ALL初诊患儿骨髓细胞中表达较高,完全缓解后表达降低(0.234±0.054vs0.151±0.055,P<0.01)。在10例配对患者儿中,TEL-AML1阳性及E2A...     

Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome

In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.     

High expression of Inositol 1,4,5-trisphosphate receptor,type 2 (ITPR2) as a novel biomarker for worse prognosis in cytogenetically normal acute myeloid leukemia

Inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) is a key regulator for the activity of calcium ion transmembrane transportation, which plays a critical role in cell cycle and proliferation. However, the clinical impact of ITPR2 in cytogenetically normal acute myeloid leukemia (CN-AML) remained unknown. Several microarray datasets were used to evaluate the association between ITPR2 expression and clinical and molecular characteristics. ITPR2 showed a higher expression in CN-AML patients than normal persons. In a cohort of 157 CN-AML patients, high ITPR2 expression (ITPR2^high) was associated with dramatically shorter overall survival (OS; P = 0.004) and event-free survival (EFS; P = 0.01), which were also shown in the European Leukemia Net (ELN) intermediate-I genetic category (OS: P = 0.0066; EFS: P = 0.009). Multivariable analyses adjusting for known prognostic factors confirmed ITPR2^high to be associated with shorter OS (P = 0.0019) and EFS (P = 0.012). The prognostic value of ITPR2 was further validated in another cohort of 162 CN-AML patients (P = 0.007). In addition, first gene/microRNA expression signatures were derived that associated with ITPR2^high on the genome-wide scale, which provided many indications to illustrate the possible mechanisms why ITPR2 could function. These results could aid to identify new targets and design novel therapeutic strategies for CN-AML patients.     

A Phase 2 study of combination therapy with arsenic trioxide and gemtuzumab ozogamicin in patients with myelodysplastic syndromes or secondary acute myeloid leukemia

BACKGROUND:

Higher‐risk myelodysplastic syndromes (MDS) are similar pathobiologically to acute myeloid leukemia (AML), particularly in older adults. AML therapies thus may have activity in MDS. In the current study, phase 2 study data of arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) in CD33‐positive patients with MDS and secondary AML (sAML) were presented.

METHODS:

Between June 2004 and February 2006, 30 patients with higher‐risk MDS or sAML received ATO (at a dose of 0.25 mg/kg intravenously for 5 days during Week 1, then twice weekly during Weeks 2‐12) and GO (at a dose of 3 mg/m² on Day 8) for 1 or 2 cycles of 12 weeks each. The primary endpoint was response as per MDS or AML International Working Group (IWG) criteria. Adverse events were collected throughout treatment. Patients were followed for a minimum of 3 years for survival.

RESULTS:

The median patient age was 69 years. A total of 18 patients had MDS, 12 had sAML, and 19 had been previously treated. Seventeen patients (57%) completed ≥1 cycle, and 7 patients (23%) completed 2 cycles. IWG responses occurred in 9 patients (30%) according to IWG MDS criteria (including 2 of 7 patients who failed hypomethylating agents) and 3 of 12 AML patients (25%) according to IWG AML criteria. Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) thrombocytopenia occurred in 47% of patients, neutropenia in 63%, and anemia in 37% of patients. The median overall survival was 9.7 months (28.6 months in responders and 7.6 months in nonresponders; P <.001). Patients who completed 2 cycles of therapy spent a median of 13 days in the hospital.

CONCLUSIONS:

Combination therapy with ATO and GO was found to have acceptable response rates and toxicity, and may be a viable treatment option to standard induction therapy, particularly for patients who fail therapy with hypomethylating agents. Cancer 2011. © 2010 American Cancer Society.     

A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome

BACKGROUND:

The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndrome.

METHODS:

Induction consisted of idarubicin 12 mg/m² a day on days 1‐3, cytarabine 1.5 g/m² intravenously continuously daily on days 1‐4 (days 1‐3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m² a day on days 1‐2, cytarabine 0.75 g/m² a day on days 1‐3, and tipifarnib 300 mg twice a day for 14 days every 4‐6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4‐6 weeks was continued for 6 months.

RESULTS:

With a median follow‐up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities.

CONCLUSIONS:

The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor‐risk AML. Cancer 2011. © 2010 American Cancer Society.     

Acquired methemoglobinemia in leukemia: Its etiopathogenesis and possible effects on red cell structure and function

Significant methemoglobinemia has been observed in 79% (66/84) cases of leukemia, irrespective of their morphologic types. The mean methemoglobin (Hi) levels were 5.60, 3.22, 4.49 and 2.25% in acute myeloblastic, chronic granulocytic, acute lymphoblastic and chronic lymphocytic leukemia respectively, against the normal mean of 1.10%. Twenty-two cases had values higher than 5% out of which 7 had more than 10% Hi.Strong evidence is presented in this paper to suggest that methemoglobinemia is acquired in leukemia as a result of greatly increased in vivo oxidation of hemoglobin by oxidants generated by the leukemic cells, in spite of a normal Hi-reducing system in the red cells. Higher Hi levels are encountered in the acute leukemias, probably because immature leucocytes produce greater amounts of oxidants compared to the more mature ones. The possible effects of methemoglobinemia and associated red cell membrane lipid and protein peroxidation on the structure and function of red cells are discussed in the light of the pre-existent decreased oxygen carrying capacity of these cells in leukemia due to anemia.