急性髓系白血病预后相关因素分析

目的 探讨成年急性髓系白血病(AML)患者的预后影响因素.方法 回顾性分析182例初治AML患者临床资料,探讨患者性别、年龄(以60岁为界)、初治白细胞计数(≥30× 109/L)、骨髓细胞学免疫表型、细胞遗传学、异基因造血干细胞移植(allo-HSCT)和治疗1个疗程获得完全缓解(CR)等因素与总生存(OS)及无事件生存(EFS)的关系.结果 182例AML患者的中位年龄49岁(14～ 80岁),中位随访时间9.7个月(0.5～75.5个月),首次化疗达CR 107例,总有效率为65.9％(120/182),年龄≥60岁、CD64阴性、染色体高危组及首次诱导未达CR患者的总CR率低于无上述因素者.单因素生存分析提示年龄≥60岁、细胞遗传学高危组、CD19阴性、CD11b阳性、CD64阴性、未行allo-HSCT、首次诱导未达到CR的患者OS及EFS较短(P＜0.05),多因素分析显示年龄、细胞遗传学表达、CD11b、CD64、是否行allo-HSCT、首次诱导能否达CR是患者OS的独立预后因素,细胞遗传学表达、CD64表达、是否行allo-HSCT及首次诱导能否达CR是患者EFS的独立预后因素.结论 根据AML相关因素进行预后分析判断,有利于临床医生早期制订个体化治疗方案,对于延长患者生存期有重要意义.     

The prognostic significance of serum beta2 microglobulin levels in acute myeloid leukemia and prognostic scores predicting survival: analysis of 1,180 patients.

PURPOSE: Serum beta(2) microglobulin (beta2M) is prognostic in other hematologic malignancies; therefore, we evaluated its prognostic significance in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: Multivariate analyses were used to examine the effect of pretreatment serum beta2M levels on clinical outcomes in patients with AML. beta2M was associated with poorer survival in older but not younger patients. We thus fit separate Cox survival models in patients above and below age 60 years treated with remission induction therapy containing high-dose cytarabine (n = 1,280). In each age group, 50% of the patients were used to develop the model, which was tested in the other 50%. Resampling methods were also used to validate the independent prognostic significance of covariates. RESULTS: In patients 60 years or older (n = 591), poorer risk cytogenetics; poorer performance status; and higher levels of beta2M, uric acid, and lactate dehydrogenase were each found to independently predict shorter survival and formed the basis of a scoring system. A similar approach was used in patients younger than 60 years (n = 589), with poorer risk cytogenetics, poorer performance status, older age, higher hemoglobin level, and higher leukocyte count predicting a shorter survival and forming the basis of the scoring system. Higher beta2M levels were an adverse independent factor for response, survival, relapse-free survival, and event-free survival in older but not in younger patients. CONCLUSIONS: Serum beta2M levels can help predict outcome in patients > or =60 years with untreated AML, and their use is strongly encouraged.     

Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype

BACKGROUND: CXC chemokine receptor 4 (CXCR4) expression in acute myeloid leukemia (AML) is reported to correlate with FLT3 gene mutation and poorer prognosis. The prognostic significance of CXCR4 expression in patients with AML that have a normal karyotype and no evidence of FLT3 gene mutations was examined. METHODS: The prognostic significance of CXCR4 expression in 122 AML patients with normal karyotype and no evidence of FLT3 gene mutation treated at our institution between 1997 and 2003 was analyzed. All patients received intensive chemotherapy according to institutional protocols; 84% received cytarabine-containing regimens. Bone marrow biopsy or clot specimens obtained before treatment were immunostained for CXCR4. RESULTS: There were 70 men and 52 women with a median age of 62 years (range, 22-82 years). Median follow-up was 18 months (range, <1-97 months). Seventy-six patients achieved complete remission (CR); 39 had recurrence. Sixty-six patients died, including 9 with no evidence of disease. CXCR4 was positive in 70 and negative in 52 patients, with CR rates of 58% and 71%, respectively (P = .09). Multivariate analysis demonstrated that CXCR4 expression, presence of multilineage dysplasia, and high creatinine level predicted poorer overall (OS) and event-free (EFS) survival. CONCLUSIONS.: The results suggest that CXCR4 expression is associated with poor prognosis in AML patients with an unmutated FLT3 gene.     

Prognostic scoring model based on multi-drug resistance status and cytogenetics in adult patients with acute myeloid leukemia

Clinical heterogenicity exists within an acute myeloid leukemia (AML) patient group with the same cytogenetic risk. Multi-drug resistance (MDR) is also regarded as one of the potential prognostic factors for AML. Accordingly, the prognostic scoring model can be generated based on both consideration of cytogenetic risk and the MDR status for AML. The CR rate, event-free (EFS) and overall survival (OS) were analysed according to cytogenetic risk, MDR status and clinical factors. Prognostic score was calculated by the sum of MDR status (0 for negative, 1 for positive) and dichotomized scoring for cytogenetic risk (0 for favorable/intermediate and 1 for unfavorable cytogenetics). MDR expression was noted in 36.6% of the patients and associated with a lower CR rate (p = 0.037). MDR, cytogenetics and the use of SCT were identified as independent prognostic factors for EFS and OS. The CR rate of the group scored with 0, 1 and 2 was 81.4, 66.7, and 44.4%, respectively (p = 0.050). The prognostic scoring model depicted a discriminating role in terms of EFS (p < 0.0001) and OS (p = 0.0001). The prognostic scoring model based on cytogenetic risk and MDR provided an improved method for evaluating the prognosis in AML and helped to stratify the risk of patients with the same cytogenetic risk.     

Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients

BackgroundChemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival (OS) of ≤1 year. Elderly patients often present with cardiac comorbidity. Gemtuzumab ozogamicin (GO) is active in elderly (≥60 years) patients with relapsed AML with low cardiac toxicity.Patients and methodsThis randomized phase II study compared a standard combination of ara-C and daunorubicin (DNR; 7+3) versus ara-C plus gemtuzumab ozogamicin (7+GO) as the first course of induction therapy. Primary objectives were comparison of blast clearance on day 16, event-free survival (EFS), and remission duration. OS, complete remission (CR), and tolerability were secondary objectives.ResultsOne hundred and nineteen patients with de novo AML, treatment-related AML, AML with a history of myelodysplastic syndrome (MDS), or high-risk MDS entered the study. Median age of 115 patients (intent-to-treat population) was 69 years. Protocol outlined a second course 7+3 for patients without blast clearance and two courses of high-dose ara-C consolidation upon CR. Both treatments were equally effective in blast clearance, CR, EFS, remission duration, or OS (median: 7+3, 9 months; 7+GO, 10 months). Induction death rate was higher in the GO group due to veno-occlusive disease.ConclusionThe study did not show significant superiority of 7+GO over standard 7+3.     

Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group.

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.     

Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome

BACKGROUND:

Secondary acute myeloid leukemia (AML) from an antecedent myelodysplastic syndrome (MDS)/myeloproliferative neoplasm is associated with a poor prognosis. The authors evaluated predictive factors in patients with secondary AML treated with anthracycline‐based induction therapy.

METHODS:

This was a retrospective review of secondary AML patients treated with induction therapy. Age, International Prognostic Scoring System, Eastern Cooperative Oncology Group performance status, cytogenetics, duration of MDS/myeloproliferative neoplasm, and prior MDS/myeloproliferative neoplasm treatment were evaluated for their impact on complete response (CR), CR with low platelets, and overall survival (OS).

RESULTS:

The authors evaluated 61 secondary AML patients who received induction chemotherapy; 59% (36 patients) achieved CR/CR with low platelets (95% confidence interval [CI], 46%‐71%), and median OS was 6.5 (95% CI, 3.9‐8.1) months. Three factors were associated with lower CR/CR with low platelets and OS: poor risk cytogenetics, prior treatment with hypomethylating agents or lenalidomide, and longer time to transformation to AML. Of those treated with hypomethylating agents or lenalidomide, 32% achieved CR/CR with low platelets versus 78% in the group not treated with a hypomethylating agent or lenalidomide (odds ratio [OR], 0.13; 95% CI, 0.04‐0.42). Median OS for those treated with a hypomethylating agent or lenalidomide was 3.7 versus 10.5 months for those not treated with a hypomethylating agent or lenalidomide (P < .0001). The CR/CR with low platelets rate for those with intermediate risk cytogenetics was 70% versus 35% for those with poor risk (OR, 4.33; 95% CI, 1.38‐13.6). Those with poor risk cytogenetics had a median OS of 2.8 versus 7.5 months for those with intermediate risk (P = .01).

CONCLUSIONS:

Prior treatment with hypomethylating agents or lenalidomide, poor risk cytogenetics, and longer time to transformation to AML are independent negative predictive factors for response and OS in patients with secondary AML after induction therapy. Cancer 2011. © 2010 American Cancer Society.     

High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma - results of a comprehensive meta-analysis

BACKGROUND: Randomized controlled trials (RCTs) reported conflicting results on the impact of high-dose chemotherapy (HDCT) and autologous stem cell transplantation in the first-line treatment of patients with aggressive non-Hodgkin lymphoma (NHL). METHODS: We performed a systematic meta-analysis to assess the efficacy HDCT compared to conventional chemotherapy in aggressive NHL patients with regard to complete response (CR), overall survival (OS), event-free survival (EFS), toxicity, and impact of the age-adjusted International Prognostic Index (aaIPI) risk factors. We searched the Cochrane Library, MEDLINE and other databases (1/1990 to 1/2005). Hazard ratio (HR), relative risks (RR) and 95% confidence intervals (CIs) were calculated using the fixed effect model. RESULTS: Fifteen RCTs including 2728 patients were identified. HDCT improved CR when compared to conventional chemotherapy (RR 1.11, CI 1.04-1.18). Overall, there was no evidence for HDCT to improve OS (HR 1.05, 95% CI 0.92-1.19) or EFS (HR 0.92, 95% CI 0.80-1.05) when compared with conventional chemotherapy. However, subgroup analysis indicated OS differences (p=0.032) between good (HR 1.46, 95% CI 1.02-2.09) and poor risk (HR 0.95, 95% CI 0.81-1.11) patients. Conflicting results were reported for poor risk patients, where some studies reported improved and others reduced OS and EFS after HDCT. CONCLUSION: There was no evidence that HDCT improved OS and EFS in good risk NHL patients. The evidence for poor risk patients is inconclusive. HDCT should not be further investigated in good risk patients with aggressive NHL but high quality studies in poor risk patients are warranted.     

Long-term follow-up of advanced-stage low-grade lymphoma patients treated upfront with high-dose sequential chemotherapy and autograft.

Long-term outcome, after first line intensified high-dose sequential (i-HDS) chemotherapy, was evaluated in 46 patients, aged < or =65 years, with advanced low-grade lymphoma. Seventeen patients had small lymphocytic lymphoma (SLL), 29 had follicular lymphoma (FL), 10 of them with histologic transformation. I-HDS included: (1) tumor debulking, by 2 APO+2 DHAP courses; (2) sequential administration of high-dose (hd) etoposide, methotrexate, and cyclophosphamide, followed by peripheral blood progenitor cell (PBPC) harvest; (3) hd-mitoxantrone + melphalan with PBPC autograft. Ten FL patients had their PBPC immunologically purged ex vivo. There were two treatment-related deaths; five FL patients had short-lasting response followed by disease progression, five SLL reached a stable PR; overall, 34 patients (74%) reached CR. At a median follow-up of 4.3 years, the estimated 9-year OS and EFS were 84% and 45%, respectively. No significant differences were observed in the OS among patients at low, intermediate or high IPI score, with an estimated OS projection of 95%, 78%, and 75%, respectively. FL had longer survival without evidence of residual disease (9-year EFS: 59%) as compared to SLL patients (8.8-year EFS: 17%); however, both groups had prolonged survival and no need of salvage treatment, as shown by the time to disease progression curve, projected to 66% and 62% for SLL and FL, respectively. The results indicate that hd-approach in low-grade lymphoma: (1) is associated with longer progression-free survival as compared to conventional therapies; (2) may imply higher tumor mass reduction in FL as compared to SLL patients; (3) offers long life expectancy, with potential survival benefits at least for patients at intermediate/high IPI score.     

Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia.

The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid (ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged >or=61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n=122) or no ATRA (standard-arm, n=120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n=31) or 1-year oral maintenance therapy (n=30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P=0.05). Event-free (EFS) and overall survival (OS) were significantly better in the ATRA-compared to the standard-arm (P=0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P<0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML.     

Predictive value of karyotype on outcome of autotransplants for acute myeloid leukemia in second remission

The impact of karyotype on the outcome of patients who undergo autotransplant for acute myeloid leukemia (AML) in second remission (CR2) has not been explored. We evaluated the outcomes of 40 patients who proceeded to autotransplant for AML in CR2 at 2 centers. The median age at autotransplant was 50 years (18-64 years) and the median duration of first remission was 15 months (0.8-51 months). High-dose therapy was melphalan 140-160 mg/m2 plus etoposide 60 mg/kg with or without total body irradiation (22), a busulfan-based regimen (17), and cyclophosphamide alone (1). Six patients (15%) died of treatment-related causes within the first 100 days. Event-free and overall survival at 3 years were both 38% (95% confidence interval 23-53%). At a median follow-up of 76 months (2?-?170) in surviving patients, 13 (32.5%) are alive and disease free. Graft purging did not significantly influence survival outcome (P=0.94), although platelet engraftment was significantly delayed (P=0.02). The relative risk of an event (relapse or death) for the karyotype risk groups was favorable 1.0; intermediate 4.2 (1.2-14.7); adverse 9.9 (1.5-63.9); unknown 2.3 (0.6-8.8) (P=0.028). We conclude that patients with AML in CR2 who undergo autotransplant can have durable remissions and those with a good risk karyotype are the most likely to obtain long-term disease-free survival.     

77例老年急性髓性白血病患者的预后因素分析

背景与目的:老年急性髓性白血病(acutemyelogenousleukemia,AML)有独特的生物学及临床特征,患者对治疗的反应差、生存期短。本研究旨在探讨老年AML的预后因素。方法:对上海市第一人民医院1994～2005年收治的77例老年AML患者可能影响预后的因素进行Kaplan-Meier生存分析,然后对有意义的因素进行Cox比例风险模型分析。结果:可评价患者72例。年龄60～70岁者中位生存期(350天)显著长于年龄>70岁者(60天)(P<0.001),CR率显著提高(71.4%vs.29.4%,P=0.001);生存状态(performancestatus,PS)0或1分者中位生存期(402天)显著长于2、3、4分者(31天)(P<0.001),CR率显著提高(75.0%vs.15.0%,P<0.001);原发者中位生存期(98天)显著长于继发者(32天)(P=0.007),CR率显著提高(50.0%vs.0%,P=0.023);使用亚标准剂量的蒽环类药物者中位生存期(293天)显著长于减量使用者(35天)(P=0.006),CR率显著提高(63.6%vs.33.3%,P=0.02)。骨髓原始细胞(bonemarrowblastcell,BMblast)比率≤50%者中位生存期(98天)显著长于>50%者(55天)(P=0.006);预后良好核型者中位生存期(293天)显著长于预后不良或正常核型者(31天)(P=0.005);CD34阴性者中位生存期(201天)显著长于阳性者(36天)(P<0.001)。外周血白细胞数量(peripheralbloodwhitebloodcellcount,PBWBC)大于10×109/L者CR率(50.0%)显著高于PBWBC小于10×109/L者(25.0%)(P=0.043);化疗者CR率(50.0%)显著高于支持治疗者(0%)(P=0.001)。Cox比例风险模型分析显示影响生存期的7个因素均具有独立性和统计学意义。结论:年龄>70岁、PS为2～4分、骨髓原始细胞比率>50%、继发性、不良核型、CD34 以及蒽环类药物剂量强度是影响患者生存期的主要预后因素,蒽环类药物剂量显著影响CR率。     

含高三尖杉酯碱方案治疗初治急性髓系白血病46例效果和生存分析

目的探讨以高三尖杉酯碱（HHT）为主的化疗方案治疗急性髓系白血病（AML）的缓解率,评价AML不同染色体核型、基因突变对总生存（OS）率、无事件生存（EFS）率的影响。方法将80例初治AML患者用随机信封法分为HAA、HDA、DA、IA方案治疗组,比较各组诱导完全缓解（CR）率,并将AML患者分为染色体核型“好、中、差”三组,分别比较OS、EFS。结合患者是否表达预后较差的基因突变,利用染色体与基因型两者总体评价OS、EFS。结果用含有HHT方案治疗初治AML46例,总CR率78．3％（36／46）,高于DA方案组总CR率66．7％（10／15）及IA方案组的63．2％（12／19）,三种方案组CR率差异无统计学意义（P〉0．05）。不同染色体核型对于生存具有较大影响,染色体核型“差”者OS、EFS较染色体核型“好”或“中”者下降程度显著。结合染色体和基因型分组对于显示预后总体OS、EFS的下降趋势更明显。结论含HHT的治疗方案CR率与传统DA、IA方案相似,提示高三尖杉酯碱治疗的有效性。不同染色体及基因突变对于AML预后具有较大影响。     

大剂量依托泊苷联合自体造血干细胞移植挽救性治疗进展期淋巴瘤的临床观察

背景与目的：淋巴瘤复发是进展期淋巴瘤患者的主要死因,常规化疗疗效不佳。本研究旨在评估大剂量依托泊苷(VP16)联合自体造血干细胞移植治疗进展期淋巴瘤的疗效。方法：40例进展期淋巴瘤患者均接受大剂量VP16 10～15 mg/(kg·d)静脉滴注,持续2 d化疗,并在化疗后接受G-CSF 5～10 μg/kg皮下注射,至白细胞计数>4×109/L,采集患者干细胞并冻存于-80 ℃深低温冰箱中;40例患者均接受自体造血干细胞移植。结果：VP16治疗后中位随访时间39 d(17～172 d),40例患者中12(30%)例对大剂量VP16无反应,28(70%)例有反应。自体干细胞移植后,中位随访28个月(4～66 d)。40例患者中,16(40%)例达到完全缓解,其中对VP16有反应的28例患者,15(53.6%)例达到完全缓解,4(14.3%)例部分缓解,9(32.1%)例死于疾病进展,对VP16无反应的12例患者,仅1(8.3%)例达到完全缓解。1(8.3%)例部分缓解,10(83.4%)例死于疾病进展。对VP16有反应的患者1年的无事件生存率(event-free survival,EFS)为56.7%,总体生存率(overall survival,OS)为69.0%,2年EFS为52.0%,OS为63.0%。无反应的患者1年EFS为16.7%,OS为25.0%,2组数据相比,差异有统计学意义(P<0.01)。结论：大剂量VP16联合自体造血干细胞移植能使对大剂量VP16有反应的患者带来较高的EFS和OS,可作为难治性淋巴瘤患者挽救性治疗的选择之一。     

Salvage therapy in refractory acute myeloid leukemia: prediction of outcome based on analysis of prognostic factors

Acute myeloid leukemia (AML) non-responsive to initial chemotherapy is generally of poor prognosis. High-dose cytarabine (HD-AraC) has been proposed as salvage therapy in combination with amsacrine. The aim of the current study was first to assess the toxicity and the efficacy of such a combination therapy, and secondly to determine prognostic factors allowing to predict whom patients could benefit of such a treatment. Out of 91, 45 patients referred to our institution have been treated by HD-AraC (3 g/m(2)/12h from day 1 to 4) combined with amsacrine (90 mg/m(2) per day from day 5 to 7) as a salvage regimen. Forty-five of the 91 patients (49%, 95% confidence interval (CI): 39-60%) achieved complete remission (CR). Thirty-five patients were refractory to the salvage therapy and 11 patients died from toxicity during aplasia. Median disease-free survival (DFS) was 11.5 months (95% CI: 6-16 months). After CR achievement, 26 patients received consolidation therapy according to the protocol in which they were included. Nineteen patients with an HLA-identical sibling donor underwent allogeneic bone marrow transplantation. At time of analysis, 27 of the 45 patients (60%) who achieved CR have relapsed. Median overall survival (OS) was 7.5 months (95% CI: 6-15 months). There was 12 long survivors (13%). In univariate analysis, initial karyotype was the main prognostic factor as well as in terms of CR achievement (P=0.002) than in terms of DFS (P=0.01) or OS (P=0.009). CR achievement was negatively influenced by higher WHO performance status index (P=0.006), higher LDH level (P=0.02), and higher CD34 expression by leukemic cells (P=0.03) at diagnosis, and presence of circulating blasts (P=0.001), platelet count <80 x 10(9)/l (P=0.0001), and polymorphonuclear (PMN) percentage <30% (P=0.01) at time of starting salvage therapy. DFS was negatively influenced by secondary AML (P=0.01), weight loss > or =5% (P=0.03), and higher white blood cell (WBC) count (P=0.03) at time of diagnosis. Age over 60 years (P=0.002), prior history of toxic exposure (P=0.01), higher CD34 expression (P=0.02), weight loss > or =5% (P=0.006), and WHO performance status index > or =2 (P=0.01) at diagnosis, and platelet count <80 x 10(9)/l (P=0.02) at time of salvage therapy were the main prognostic factors associated with shorter OS. In multivariate analysis, karyotype grouping at diagnosis (P=0.006) and blood count before salvage therapy (P=0.001) were of prognostic value for CR achievement. Karyotype remained of prognostic value for DFS and OS (P=0.007 and <0.0001, respectively).We conclude that HD-AraC combined with amsacrine was as a useful salvage regimen in AML non-responding to a first intensive course of chemotherapy. Using objective parameters of proven significance (karyotypic grouping and blood count before salvage), we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices. Patients with favorable risk cytogenetics and those with intermediate risk cytogenetics and favorable blood count (PMN > or =30%, no circulating blasts, and platelet count > or =80 x 10(9)/l) before salvage therapy had a similar outcome than those achieving CR after only one course of chemotherapy. All other patients displayed a poor outcome. This suggests their orientation at an earlier time to alternate therapeutic programs based on investigational drugs.     

Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML.

The aim of this study was to compare the pattern of karyotype abnormalities of therapy-related acute myeloid leukemia (t-AML) (n=93) with de novo AML (n=1091), and to evaluate their impact on prognosis. Favorable, intermediate, and unfavorable cytogenetics were observed in 25.8, 28.0, and 46.2% of t-AML, and in 22.2, 57.3, and 20.4% of de novo AML. The median overall survival (OS) was shorter in t-AML than in de novo AML (10 vs 15 months, P=0.0007). Favorable and unfavorable cytogenetics had a prognostic impact with respect to OS in both t-AML (P=0.001 and 0.0001) and de novo AML (P<0.0001 and <0.0001). To define the overall prognostic impact of cytogenetics and t-AML, a multivariate Cox's regression analysis was performed for OS with favorable cytogenetics, unfavorable cytogenetics, t-AML, age, and white blood cell (WBC) count as covariates. All parameters proved to be independently related to OS (P=0.001 for t-AML, P<0.0001 for all other parameters). Within patients with t-AML, there were significant correlations between OS and both unfavorable (P<0.0001) and favorable cytogenetics (P=0.001), while age and WBC count had no impact on OS. In conclusion, these data indicate that cytogenetics are an important prognostic parameter in t-AML. Furthermore, t-AML is an unfavorable factor independent of cytogenetics with respect to survival.     

A phase II study of timed sequential therapy of acute myelogenous leukemia (AML) for patients over the age of 60: two cycle timed sequential therapy with topotecan, ara-C and mitoxantrone in adults with poor-risk AML

Acute myeloid leukemia (AML) in the elderly is a serious problem characterized by poor response to therapy and short survival. To improve response to therapy, a timed sequential therapy (TST) approach was designed utilizing topotecan, cytosine arabinoside (ara-C) and mitoxantrone based on multiple studies suggesting that topotecan and mitoxantrone are effective in older patients. Thirty-two adults, >or=60-year-old (median age 69) were included. None had favorable cytogenetics and 44% had and antecedent myelodysplastic syndrome (MDS) or 2 degrees AML. Fifty-nine percent achieved a complete response (CR). Median overall survival (OS) was 6.5 months (95% confidence interval (CI): 3.1-12.0 months; range, 15 days to 25.3 months). Disease-free survival (DFS) for the 19 patients achieving a CR was 7.7 months (95% CI: 6.1-13.7 months; range, 2.9-25.3 months). There were no differences in OS or DFS between cytogenetic or disease etiology groups. Although TST was well tolerated, long-term results in this group of patients are not satisfactory and new approaches are needed.     

The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia--analysis of 848 patients.

We studied the impact of cytogenetics and kind of induction/consolidation therapy on 848 adult acute myeloid leukemia (AML) patients (age 15-83). The patients received three types of induction/consolidation regimen: standard (daunorubicin and cytosine arabinoside (3/7); two cycles); intensive (idarubicin, cytosine arabinoside and etoposide (ICE), plus mitoxantrone and intermediate-dose Ara-C (NOVIA)); and low-dose (low-dose cytosine arabinoside). CR patients under 60 years of age, if an HLA-identical donor was available received allogeneic stem cell transplantation (allo-SCT); otherwise, as part of the program, they underwent autologous (auto)-SCT. CR rates significantly associated with 'favorable' (inv(16), t(8;21)), 'intermediate' ('no abnormality', abn(11q23), +8, del(7q)) and 'unfavorable' (del (5q), -7, abn(3)(q21q26), t(6;9), 'complex' (more than three unrelated cytogenetic abnormalities)) karyotypes (88% vs 65% vs 36%, respectively; P = 0.0001). These trends were confirmed in all age groups. On therapeutic grounds, intensive induction did not determine significant increases of CR rates in any of the considered groups, with respect to standard induction. Low-dose induction was associated with significantly lower CR rates. Considering disease-free survival (DFS), multivariate analysis of the factors examined (including karyotype grouping) showed that only age > 60 years significantly affected outcome. However, in cases where intensive induction was adopted, 'favorable' karyotype was significantly related to longer DFS (P = 0.04). This was mainly due to the favorable outcome of t(8;21) patients treated with intensive induction. Patients receiving allo-SCT had significantly longer DFS (P = 0.005); in particular, allo-SCT significantly improved DFS in the 'favorable' and 'intermediate' groups (P = 0.04 and P = 0.048, respectively). In conclusion our study could provide some guidelines for AML therapy: (1) patients in the 'favorable' karyotype group seem to have a longer DFS when treated with an intensive induction/consolidation regimen, adopted before auto-SCT instead of standard induction; this underlines the importance of reinforcement of chemotherapy, not necessarily based on repeated high-dose AraC cycles. Allo-SCT, independently of induction/consolidation therapy, should be considered an alternative treatment; (2) patients in the 'intermediate' karyotype group should receive allo-SCT; (3) patients in the 'unfavorable' karyotype group should be treated using investigational chemotherapy, considering that even allo-SCT cannot provide a significantly longer DFS, but only a trend to a better prognosis.     

Trisomy 8 as sole anomaly or with other clonal aberrations in acute myeloid leukemia: impact on clinical presentation and outcome

One hundred and fifty-four acute myeloid leukemia patients with trisomy 8 were studied for their clinical and biological characteristics, and treatment outcome. Forty-seven patients presented with trisomy 8 as the sole aberration, 107 with trisomy 8 associated with other cytogenetic abnormalities (13 with favorable, 54 with intermediate, and 40 with unfavorable risk cytogenetics). Overall complete remission (CR) proportion was 48%. Median disease-free survival (DFS) and overall survival (OS) were 7.8 and 8.3 months, respectively. In multivariate analysis, age >or=60 years (P<0.0001) and association with unfavorable karyotype (P=0.03) were of poor prognostic value for CR achievement. Age >or=60 years (P<0.0001) and antecedents of dysmyelopoiesis (P=0.02) were of poor prognostic value for OS. Patients with trisomy 8 alone did not show any difference in terms of outcome as compared with those in whom trisomy 8 was associated to intermediate risk cytogenetics (P=0.0002). Trisomy 8 in addition to favorable karyotype maintained a good clinical outcome, while trisomy 8 in addition to unfavorable cytogenetics showed the worst prognosis.     

Prognostic Significance of Fms-Like Tyrosine Kinase 3 Internal Tandem Duplication Mutation in Non-Transplant Adult Patients with Acute Myeloblastic Leukemia: A Systematic Review and Meta-Analysis

Background: Fms-like tyrosine kinase-3, internal tandem duplication (FLT3-ITD) mutation, is a known predictor for worse outcome in patients with acute myeloblastic leukemia (AML). However, the prognostic significance of FLT3-ITD mutation in adult, non-transplant patients is still unclear therefore we conducted a systematic review and meta-analysis to explain this issue. The main outcome was overall survival (OS), while additional outcomes included event-free survival (EFS). Methods: Seven Databases (ScienceDirect, Scopus, PubMed, Cochrane, SpringerLink, ProQuest, and EBSCOhost) were searched up to August 2020.  Studies investigating the prognostic value of AML in adults with FLT3-ITD mutational status were selected. Studies which patients had received transplantation, diagnosed with acute promyelocytic leukemia (APL) or secondary AML were excluded. The selected studies were divided into subgroups based on their cytogenetic profile. Summary hazard ratios (HR) and 95% confidence intervals (CI) were calculated using fixed-effects models. Heterogeneity tests were conducted and presented in I2 value. Forest plot was presented to facilitate understanding of the results. Publication bias was analyzed by Funnel Plot test. Results: A total of ten studies describing research conducted from 1999 to 2020, met the inclusion criteria for this study. Nine studies reported OS and four studies reported EFS in HR. The highest HR for OS is 6.33 (95% CI, 2.61-15.33; p < 0.001), for EFS is 3.58 (95% CI, 1.59 – 8.05); p = 0.002)., while the lowest for OS is 1.33 (95% CI, 0.88-2.01; P = 0.174) and for EFS is 1.29 (95% CI, 0.75-2.23; p = 0.34). Nine studies were included in meta-analysis with HR for OS 1.91 (95% CI, 1.59–2.30, p < 0.00001), whereas 4 studies were included in meta-analysis for EFS with HR 1.64 (95% CI, 1.25–2.14; p = 0.0003). Conclusion: FLT3-ITD mutation is associated with worse prognosis in adult, non-transplant patients with AML, both for OS and EFS.