Fludarabine, Arabinosyl Cytosine and Idarubicin (FLAI) for Remission Induction in Poor-Risk Acute Myeloid Leukemia

Progress in treatment of acute myeloid leukemia (AML) is slow and treatment intensification alone has limited effects, particularly in poor-risk cases. Poor-risk cases, that are identified mainly by prior history, leukemic cell mass and cytogenetic abnormalities, share multiple mechanisms of drug resistance that are responsible for treatment failure. Since Pgp-mediated resistance to anthracycline can be reduced with Idarubicin (IDA) and resistance to arabinosyl cytosine (AC) can be reduced with Fludarabine (FLUDA), we tested a combination of high dose AC (2000mg/sqm, 5 doses), FLUDA (30 mg/sqm, 5 doses) and IDA (12mg/sqm, 3 doses) for remission induction and consolidation in 45 consecutive cases of poor-risk AML. The complete remission (CR) rate was 71 % after the first course and 82% overall, with a projected 2-year survival and relapse-free survival of 44% and 50% respectively. Non-hematologic toxicity was very mild, that is very important in elderly patients, but hemopoietic toxicity was substantial, with a time to hematologic recovery of 3 to 4 weeks and two cases of death in CR. Peripheral blood stem cells (PBSC) could be mobilized and collected successfully only in 11 cases. This three-drug combination is effective and has a limited non-hematologic toxicity, but FLUDA may increase the difficulty of obtaining PBSC early after remission induction.     

Doxorubicin in Combination with Verapamil in Advanced Colorectal Cancer: A Phase It Trial

The possibility that verapamil might increase the sensibility of colorectal carcinomas to doxorubicin was studied in 24 patients without previous cytotoxic chemotherapy. The treatment started with oral verapamil, which was escalated up to the individual maximum tolerable dose (defined by prolongation of P-Q in ECG, fall in blood pressure, or dizziness). The median maximum tolerable dose was 600 mg (range 320-1 440 mg). During continued verapamil administration the patients then got weekly infusions of doxorubicin, 25mg/m². The median number of doxorubicin courses was 8 (range 2-22). Among 21 patients evaluable for response and toxicity two partial remissions occurred but no complete remission. The study did not indicate enhanced cardiac, hematological or non-hematological toxicity from the combined treatment.     

A Frontline Approach With Peripherally Inserted Versus Centrally Inserted Central Venous Catheters for Remission Induction Chemotherapy Phase of Acute Myeloid Leukemia: A Randomized Comparison

BackgroundThe incidence of peripherally inserted central catheter (PICC)-related adverse events has been uncertain in the setting of acute myeloid leukemia (AML) compared with the incidence of centrally inserted central catheter (CICC) adverse events.Patients and MethodsWe conducted a monocentric, randomized trial of patients with previously untreated AML. Of the 93 patients, 46 had received a PICC and 47 had received a CICC as frontline intravascular device. Thereafter, all patients underwent intensive chemotherapy for hematologic remission induction. The primary endpoint was catheter-related (CR)-bloodstream infection (BSI) and venous thrombosis (VT) rate. The secondary endpoints catheter malfunction, catheter removal, and patient overall survival.ResultsThe CR-BSI and CR-VT rate in the PICC and CICC groups was 13% and 49%, respectively, with a difference of 36 percentage points (relative risk for CR-BSI or CR-VT, 0.266; P = .0003). The CR-BSI incidence was 1.4 and 7.8 per 1000 catheters daily in the PICC and CICC groups, respectively. Among the CR thromboses, the symptomatic VT rate was 2.1% in the PICC group and 10.6% in the CICC group. In the CICC group, 16 of the 47 patients (34%) had the catheter removed for BSI (n = 5), septic thrombophlebitis (n = 4), VT (n = 2), or malfunction (n = 5) a median of 7 days after insertion. In the PICC group, only 6 of the 46 patients (13%) required catheter removal for VT (n = 2) or malfunction (n = 4). At a median follow-up of 30 days, 6 patients in the CICC group died of CR complications versus none of the patients in the PICC group (P = .012). Using PICCs, the reduction in BSI and symptomatic VT decreased mortality from CR infection and venous thromboembolism. In contrast, the CICC approach led to early catheter removal mostly for difficult-to-treat infectious pathogens.ConclusionOur data have confirmed that BSI and symptomatic VT are the major complications affecting frontline central intravascular device-related morbidity in the leukemia setting. The use of a PICC is safer than that of a CICC and maintains the effectiveness for patients with AML undergoing chemotherapy, with an approximate fourfold lower combined risk of infection or thrombosis at 30 days.     

CD26: A Prognostic Marker of Acute Lymphoblastic Leukemia in Children in the Post Remission Induction Phase

Background: ALL is an irredeemable disease due to the resistance to treatment. There are several influenceswhich are involved in such resistance to chemotherapy, including oxidative stress as a result of the generation ofreactive oxygen species (ROS) and presence of hypodiploid cells. Cluster of differentiation 26 (CD26), also knownas dipeptidyl peptidase-4, is a 110 kDa, multifunctional, membrane-bound glycoprotein. Aim and objectives: Theaim of this study was to evaluate the clinical significance of serum CD26 in patients with acute lymphoblasticleukaemia patients in the post remission induction phase, as well as the relationship between CD26 activity andthe oxidative stress status. Materials and Methods: CD26, total antioxidant status (TAS), total oxidant status(TOS), and oxidative stress index (OSI), in addition to activity of related enzymes myeloperoxidase, glutathiones-transferase and xanthine oxidase, were analysed in sixty children with acute lymphoblastic leukaemia inthe post remission induction phase. Results: The study showed significant elevation in CD26, TOS and OSIlevels in patients with acute lymphoblastic leukaemia in the post remission induction phase in comparison tohealthy control samples. In contrast, myeloperoxidase, glutathione-s-transferase and xanthine oxidase activitieswere decreased significantly. A significant correlation between CD26 concentration and some oxidative stressparameters was evident in ALL patients. Conclusions: Serum levels of CD26 appear to be useful as a newbiomarker of oxidative stress in children with acute lymphoblastic leukaemia in the post remission inductionphase, and levels of antioxidants must be regularly estimated during the treatment of children with ALL.     

Prognostic Factors in Acute Promyelocytic Leukemia: A Retrospective Study of 67 Cases

In a cohort of 67 adult patients with newly diagnosed untreated acute promyelocytic leukemia (APL), the initial clinical and biological parameters were submitted to multivariate analysis for potential prognostic significance. Median age of the patients was 40 years and the hematologic characteristics of the patients were those regularly seen. Complete remission (CR) was achieved in 43 cases (64%). Fourteen patients died within 4 weeks of diagnosis, due to severe hemorrhage. Factors predictive of hemorrhagic death in the multivariate analysis were hyperuricemia (p = 0.001), splenomegaly (p = 0.009), anemia (p = 0.02), high serum levels of LDH (p = 0.02), increased prothrombin time (p = 0.04), and hypercreatininemia (p = 0.05). Pretreatment patient characteristics for poor prognosis and achieving CR were hyperuricemia (p = 0.0002), splenomegaly (p = 0.01), anemia (p = 0.02), and lymphadenopathy (p = 0.04). The median disease-free survival (DFS) was 15.6 months. Poor prognostic factors for DFS were hyperuricemia (p = 0.007), and splenomegaly (p = 0.03). Maintenance chemotherapy had no statistically significant impact on CR duration. Median survival duration was 10 months. Poor prognostic factors for survival were hyperuricemia (p = 0.0005), and elevated serum LDH levels (p = 0.01).     

Efficacy and Safety of Metronomic Chemotherapy Versus Palliative Hydroxyurea in Unfit Acute Myeloid Leukemia Patients: A Multicenter,Open-Label Randomized Controlled Trial

Background: Management of unfit AML patients is a therapeutic challenge. Most hematologists tend to avoid aggressive treatment leaving patients with a choice of best supportive care. We hypothesized that metronomic chemotherapy could be an alternative treatment for unfit AML patients. Methods: A multi-center randomized controlled trial was conducted in seven university-affiliated hospitals in Thailand. Unfit AML patients were recruited and followed up from December 2014 to December 2017. Patients were randomly assigned to receive either metronomic chemotherapy or palliative hydroxyurea. Overall survival rates were compared using Cox’s proportional hazard survival analysis.Results: A total of 81 eligible patients were randomly allocated and included for ITT analysis. The OS rate was higher in group receiving metronomic chemotherapy than in group receiving palliative treatment at 6 and 12 months with borderline significance (6 months HR 0.60; 95%CI 0.36, 1.02; p-value 0.060; 12 months: HR 0.66; 95%CI 0.41, 1.08; p-value 0.097). Conclusion: Metronomic chemotherapy could prolong survival time of unfit AML patients, especially in the first 12 months after diagnosis without increasing treatment-associated adverse events.     

索拉非尼靶向治疗FLT3-ITD阳性急性髓系白血病

FMS样酪氨酸激酶-3（FLT3）近膜区的的内部串联重复序列（FLT3 internal tandem duplications, FLT3/ITD）突变是急性髓系白血病中常见的基因突变类型,与急性髓系白血病（acute myeloid leukemia, AML）的发生发展及不良预后有密切关系。目前多靶点酪氨酸激酶抑制剂药物的研究成为近几年来治疗FLT3/ITD阳性AML研究的热点,尤其是对多靶点抑制剂索拉非尼（sorafenib）的研究较为深入。本文通过学习国内外相关文献资料,综述酪氨酸激酶抑制剂索拉非尼在治疗FLT3/ITD 阳性AML的疗效和作用机制方面的研究进展。     

MTRR基因A66G多态性与儿童急性淋巴细胞白血病关系的Meta分析

目的 评估甲硫氨酸合成酶还原酶（MTRR）基因A66G多态性与儿童急性淋巴细胞白血病（ALL）发生风险的关系。方法 全面检索PubMed、Elsevier、Embase、中文期刊全文数据库（CNKI）和万方数据库,收集探索MTRR基因A66G多态性与儿童ALL发生关系的病例对照研究,纳入符合入选标准的文献并评估其质量。优势比（ORs）及95%可信区间（CIs）评估关联强度。应用RevMan 5.2软件对纳入研究进行异质性检验和效应值合并,漏斗图评估发表性偏倚,敏感性分析采用逐一排除的方法以评估结果的稳定性。结果 共纳入7篇文献,包括儿童ALL患者2 326例,对照3 090例。异质性检验结果表明纳入研究间无显著异质性,采用固定效应模型合并数据。Meta分析结果示,在整体人群纯合子模型和显性模型发现MTRR A66G多态性与儿童ALL风险有关联（GG vs. AA: OR=0.81, 95%CI: 0.69~0.95, P=0.009; AG+GG vs. AA: OR=0.87, 95%CI: 0.77~0.98, P=0.03）;根据种族 进行亚组分析时在白种人群中发现显著性关联（AG vs. AA: OR=0.84, 95%CI: 0.72~0.99, P=0.04; GG vs. AA: OR=0.79, 95%CI: 0.66~0.95, P=0.01; AG+GG vs. AA: OR=0.82, 95%CI: 0.71~0.96, P=0.01）。漏斗图未检测出显著性发表性偏倚,敏感性分析表明结果稳定可靠。结论 目前Meta分析表明MTRR基因A66G多态性与儿童ALL发生风险存在关联,尤其在白种人群。     

Acute Myeloid Leukemia in the Elderly: A Critical Review of Therapeutic Approaches and Appraisal of Results of Therapy

In the elderly, acute myeloid leukemia (AML) is characterized by a poorer prognosis than in younger patients, due to either host related factors (poor performance status, co-morbid diseases, organ function impairment) or the biology of leukemia itself (high incidence of adverse cytogenetic abnormalities, high frequency of preceding myelodysplastic syndromes, intrinsic resistance to cytotoxic drugs). Current therapeutic results are mostly unsatisfactory and studies reporting high rates of complete remission are probably influenced by selection biases as suggested by the low rate of elderly patients inclusion into cooperative trials. Availability of intensive support including hematopoietic growth factors could stimulate clinicians to manage an increasing number of elderly patients with AML with aggressive programs. However, chemotherapy in the elderly is difficult, costly and usually associated with high morbidity and mortality rate. Therefore, all efforts should be made to identify those subset of elderly patients in whom aggressive treatment may result in a true improvement of disease free and overall survival. The critical analysis of our five years experience, as reported here, seems to suggest that older AML patients displaying unfavourable prognostic factors at diagnosis (i.e., adverse karyotype and high serum LDH levels), but clinically eligible for intensive chemotherapy, do not actually benefit from an aggressive approach. A blind attempt to treat these patients aggressively may be associated with a life threatening toxicity not counterbalanced by an actual survival advantage. We suggest therefore that aggressive treatment should be reserved for elderly AML cases in whom the presence of good prognostic factors at diagnosis predicts that the loss of some patients due to toxicity may be balanced by the achievement of a substantial proportion of long term survivors. Finally, given the biological and clinical heterogeneity of elderly AML patients, a more precise prognostic categorization of these patients would be particularly useful in interpreting future therapeutic results.     

Pegylated Liposomal Doxorubicin (Caelyx®) as Adjuvant Treatment in Early-Stage Luminal B-like Breast Cancer: A Feasibility Phase II Trial

Background: Adjuvant chemotherapy for Luminal B-like breast cancers usually includes anthracycline-based regimens. However, some patients are reluctant to receive chemotherapy because of side-effects, especially alopecia, and ask for a “less intensive” or personalized approach. Patients and methods: We conducted a phase II feasibility trial to evaluate pegylated liposomal doxorubicin (PLD, Caelyx^®) as adjuvant chemotherapy. Patients who received surgery for pT1–3, any N, and luminal B-like early-stage breast cancer (EBC) candidates for adjuvant chemotherapy were included. PLD was administered intravenously at 20 mg/m² biweekly for eight courses. Endocrine therapy was given according to menopausal status. Trastuzumab was administered in HER2-positive disease. The primary endpoint was to evaluate the feasibility of this regimen, defined as the ability of a patient to achieve a relative dose intensity (RDI) of at least 85% of the eight cycles of treatment. Secondary endpoints included adverse events (AEs), tolerability, breast cancer-free survival, disease-free survival, and overall survival. Results: From March 2016 to July 2018, 63 patients were included in the trial. Median age was 49 years (range: 33–76), with mostly pre- and peri-menopausal (65%) and stage I–II (94%). Only 5% of patients had HER2-positive EBC. Median RDI was 100% (range: 12.5–100%; interquartile range, IQR: 87.5–100%). The proportion of patients meeting the primary endpoint was 84% (95% confidence interval, CI: 73–92%). Overall, 55 out of 63 enrolled patients completed treatment (87%, 95% CI: 77–94%). Most common AEs were palmar-plantar erythrodysesthesia (12.2%), fatigue (10.4%), and mucositis (8.5%). Only 13% of patients had G3 AEs. None had alopecia. After a median follow-up of 3.9 years (range: 0.3–4.7) two distant events were observed, and all patients were alive at the date of last visit. Conclusions: The trial successfully met its primary endpoint: the regimen was feasible and well tolerated and could be considered for further evaluation as a treatment option for patients with contraindications to standard anthracyclines or requiring a personalized, less intensive approach.     

Antifungal Prophylaxis in AML Patients Receiving Intensive Induction Chemotherapy: A Prospective Observational Study From the Acute Leukaemia French Association (ALFA) Group

BackgroundAlthough recommended in patients with acute myeloblastic leukaemia (AML) after induction chemotherapy, real-life use of antifungal prophylaxis (AFP) is different among centres.Materials and MethodsThis is an ancillary study to a randomized trial on intensive induction chemotherapy in AML patients (ALFA-0702/NCT00932412), where AFP with posaconazole was recommended. IFIs were graded by investigators and by central reviewers according to the revised EORTC definitions. Experts conclusions were compared to the investigators’ ones.ResultsA total of 677 patients were included. Four AFP strategies were reported: Group-1: no AFP (n = 203, 30%), Group-2: posaconazole (n = 241, 36%), Group-3: posaconazole with other AFP (n = 142, 21%), Group-4: other AFP (n = 91, 13%). Experts graded more IFI than investigators: proven/probable IFI, 9.0% (n = 61) versus 6.2% (n = 42). The cumulative incidence at day60 of probable/proven IFI was 13.9% (Group-1); 7.9% (Group-2); 5.6% (Group-3); and 6.6% (Group-4). IFI onset was 26 (19-31) days after induction in Groups 2-3, versus 16 (9-25) days in Group 1 and 20 (12-24) days in Group 4 (P< .001). After a median follow-up of 27.5 months (0.4-73.4), the mortality rate was 38.3%, with 5.4% attributed to IFI. In multivariate analysis, IFI occurrence was an independent risk of death (HR5.63, 95%-CI 2.62-12.08, P< .001). EORTC recommendations were applied in only 57% of patients. In patients without IFI, the rate of AML complete remission was higher.ConclusionsIn AML patients, AFP delayed the onset of IFI in addition of decreasing their rate. The frequent misidentification of IFI impacts their appropriate management according to recommendations. hematological remission was more frequent in patients without IFI.     

局部晚期非小细胞肺癌诱导化疗后同期放化疗与同期放化疗疗效及安全性Meta分析

目的 不可手术局部晚期非小细胞肺癌经诱导化疗后同期放化疗的获益情况尚缺乏证据.本研究通过对比不可切除局部晚期非小细胞肺癌经诱导化疗后同期放化疗与同期放化疗2种治疗模式下的疗效及安全性,望寻求对局部晚期非小细胞肺癌更有效的治疗方法,为临床治疗手段提供理论依据.方法 计算机检索The Cochrane Library、PubMed、Embase、Web of Science、CBM和CNKI,同时辅佐其他检索途径,搜集2016-06前所有关于局部晚期非小细胞肺癌诱导化疗后同期放化疗与同期放化疗治模式的随机对照试验(randomized controlled clinical study,RCT).质量评价参考2008年Cochrane质量评价标准,统计学分析应用Review Manager 5.2软件.结果 共纳入11个RCT.诱导化疗后同期放化疗与同期放化疗治模式总有效率差异无统计学意义,OR=1.30,95％CI为0.96～1.77,P=0.10;1(OR=1.51,95％CI为0.97～2.43,P=0.07)和2(OR=1.34,95％CI:1.00～1.79,P=0.05)年生存率差异无统计学意义,3年生存率差异有统计学意义,OR=1.43,95％CI:1.02～2.01,P=0.04;Ⅲ～Ⅳ级不良反应中,放射性食管炎(OR=1.96,95％CI:1.06～3.62,P-0.03)和白细胞降低(OR=1.84,95％CI:1.24～2.74,P=0.002)差异有统计学意义,放射性肺炎(OR=1.31,95％CI:0.62～2.77,P=0.48)和恶心呕吐(OR=1.46,95％CI:0.82～2.59,P=0.19)差异无统计学意义.结论 诱导化疗后同期放化疗组Ⅲ～Ⅳ级放射性食管炎、放射性肺炎及白细胞降低发生率较同期放化疗组增多,但无毒性相关死亡,而诱导化疗组3年生存率较同期放化疗组提高,可考虑为临床应用.     

Effect of the Thiotepa Dose in the TBF Conditioning Regimen in Patients Undergoing Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission: A Report From the EBMT Acute Leukemia Working Party

BackgroundAllogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of thiotepa, administered as part of the thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR.Patients and MethodsIn a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months.ResultsOn univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups.ConclusionT2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.     

急性非早幼粒细胞白血病患者早期颅内出血预警评分系统的建立及应用CSCD

目的回顾性分析急性非早幼粒细胞白血病(ANPL)早期颅内出血(ICH)的高危因素,建立预警评分系统。方法纳入1 281例ANPL成人患者(模型组)和378例成人患者(验证组),所有患者均随访12月。模型组数据归纳ICH发生的相关因素并建立风险评分系统,验证组数据对风险评分系统进行验证(评分系统对验证组的每例患者进行评分,分为高、中、低风险),并通过绘制ROC曲线评价该评分系统的预测效能。结果单、多因素分析表明,ANPL早期ICH的独立危险因素为WBC≥30.00×10~9/L、FIB<2.92 g/L和PT≥12.91 s。用上述3个因素依据各自权重建立新的预警评分系统,该评分系统ROC曲线下面积为0.774(95%CI:0.688~0.859)。验证组证实,该评分系统ROC曲线下面积为0.715(95%CI:0.559~0.872)。结论新建预警评分系统能较好预测ANPL早期ICH的发生,可指导临床及早识别潜在危重患者。     

FLT3 Inhibition as Therapy in Acute Myeloid Leukemia: A Record of Trials and Tribulations

Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis. Approximately one quarter of the patients with AML also carry an internal tandem duplication (ITD) mutation in the gene encoding FMS-like tyrosine kinase 3 (FLT3), which has a significantly deleterious impact on prognosis. The ITD mutation renders FLT3 constitutively active and leads to uncontrolled proliferation of the leukemic blast. Over the course of the last decade, a variety of compounds have been developed in preclinical and clinical studies as potent inhibitors of FLT3. Many of the earlier agents under investigation, such as lestaurtinib, midostaurin, and sunitinib, were initially developed as inhibitors of other tyrosine kinases and as targeted therapies in a variety of malignancies. These compounds have been demonstrated to have some efficacy in clinical trials of AML, mainly manifesting as transient decreases in circulating blasts correlating with effective in vivo suppression of the FLT3 target. Nevertheless, the cumbersome pharmacokinetics of some compounds and the suboptimal specificity and potency of others have limited their therapeutic efficacy. In the last few years, newer, more potent and specific agents have been under investigation, with the leading example being AC220. This agent has shown significant promise in early phases of clinical investigation, and is currently in more advanced clinical trials. Hope remains that FLT3 inhibition will be become an effective therapeutic adjunct to our current treatment approach to AML.