较高剂量柔红霉素诱导老年急性髓性白血病缓解的疗效分析

目的 探讨较高剂量柔红霉素(DNR)对诱导老年急性髓性白血病（AML）缓解及疗效的作用。方法 随机将123例老年AML分为三组,分别给予标准剂量、低于标准剂量和高于标准剂量的DNR,联合阿糖胞苷（Ara-c）作为首次诱导缓解方案,对比分析化疗产生的不良反应、完全缓解率和两年生存情况。结果 DNR高于标准剂量组血液学毒性反应的发生较标准剂量组未明显增加,而缓解所用时间短（P<0.01）、完全缓解率（63.4% vs 29.3%）和两年无事件生存率（58.5% vs 26.8%）提高（P值均<0.05）。结论 较高剂量DNR可作为诱导老年AML缓解较理想的选择。     

急性髓系白血病CD123表达及其与FLT3-ITD突变的临床意义

目的:探讨急性髓系白血病(AML)患者中CD123表达及其与FLT3-ITD突变同步检测的临床意义。方法:采用流式细胞仪检测32例AML患者CD123表达,聚合酶链反应(PCR)检测FLT3-ITD突变。结果:32例AML中24例CD123表达阳性,阳性率75.0%,对照组表达阴性。CD123+患者诱导化疗完全缓解(CR)率37.5%,低于CD123-患者(75.0%)(P<0.05)。CD123+患者18个月生存率20.8%,低于CD123-患者(62.5%)(P<0.05)。32例AML中有6例FLT3-ITD突变阳性,阳性率18.8%,其中4例伴有CD123表达阳性,均未获完全缓解,生存期6～8个月。结论:CD123可能作为诊断急性髓系白血病独立参考依据之一及评估预后指标。CD123表达阳性及FLT3-ITD突变同时存在的AML患者生存期更短,预后更差。FLT3-ITD突变阳性患者CD123表达阳性率增高,FLT3-ITD突变在CD123+白血病干细胞最终形成中的意义值得深入探讨。     

Drug delivery in acute myeloid leukemia

Background: Acute myeloid leukemia was among the first malignancies to be cured by drug therapy alone, but overall survival rates remain unsatisfactory and have changed little over the past 20 years. Conventional chemotherapeutic regimens, which almost invariably include cytarabine and anthracyclines, are untargeted, and more specific therapies are needed. Objective: We have chosen acute myeloid leukemia as a disease prototype to review established and novel targeted approaches in leukemia treatment. Methods: Our selection of the reviewed literature focused on drug delivery aspects. Conclusion: While the toxicity profile of chemotherapeutics has been improved by liposomal formulations and antibody conjugation for leukemia-directed uptake, their efficacy has probably not changed significantly. Drugs with an alternative mode of action, including kinase inhibitors, hold great promise. Further improvements may result from the characterization of novel acute myeloid leukemia (AML) cell surface receptors and of leukemic stem cells, as well as from the design of leukemia-targeted gene therapy vectors.     

Cytarabine and daunorubicin for the treatment of acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML) is the most common acute forms of leukemia in adults. It has a poor long-term survival with a high relapse rate and at relapse, is commonly resistant to available therapies. The current combination of daunorubicin (DNR) for three days and cytarabine (Ara-C) as a continuous infusion for seven days, more commonly known as ‘3 + 7? has remained essentially unaltered over the last forty-four years and remains the standard induction regimen internationally.

Areas covered: This paper will briefly review clinically important trials related to ‘3 + 7?. Somatic mutations in AML that are linked to chemoresistance to ‘3 + 7?will be discussed. Other topics covered include the novel ratiometric agent containing daunorubicin and cytarabine, CPX-351, and midostaurin in FLT3 mutated AML.

Expert opinion: ‘3 + 7? continues to be the backbone of therapy for AML. However, genetic risk stratification should be used to determine patients who are unlikely to respond to standard intensive chemotherapy and hence, should be enrolled onto a clinical trial upfront. This will facilitate development of newer effective treatment strategies in AML. Patients with mutations that are associated with chemoresistance should be offered therapies which may circumvent or overcome these pathways.     

Novel CD123-aptamer-originated targeted drug trains for selectively delivering cytotoxic agent to tumor cells in acute myeloid leukemia theranostics

Since conventional chemotherapy for acute myeloid leukemia (AML) has its limitations, a theranostic platform with targeted and efficient drug transport is in demand. In this study, we developed the first CD123 (AML tumor marker) aptamers and designed a novel CD123-aptamer-mediated targeted drug train (TDT) with effective, economical, biocompatible and high drug-loading capacity. These two CD123 aptamers (termed as ZW25 and CY30, respectively) can bind to a CD123 peptide epitope and CD123?+?AML cells with high specificities and KD of 29.41?nM and 15.38?nM, respectively, while has minimal cross reactivities to albumin, IgG and trypsin. Further, TDT is self-assembled from two short primers by ligand-modified ZW25 that acted as initiation position for elongation, while intercalated by doxorubicin (Dox). TDT is capable of transporting high capacity of Dox to CD123?+?cells and retains the efficacy of Dox, while significantly reducing drug uptake and eased toxicity to CD123? cells in vitro (p?in vivo. These suggest that CD123 aptamer and CD123 aptamer-mediated targeted drug delivery system may have potential applications for selective delivery cytotoxic agents to CD123-expressing tumors in AML theranostics.     

Phase I study of liposomal daunorubicin in patients with acute leukemia

The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acute leukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity and probably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapy in acute leukemias. We conducted a phase I study of liposomal daunorubicin (Daunoxome® DNX) in patients with refractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m² on each cycle, to a total dose of 225, 300, 450, and 600 mg/m², respectively. At least three patients were included at each dose level before escalating to the next level, and patients could receive more than one course at the next dose level. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven received two courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines. The dose-limiting toxicity was mucositis which occurred (grade 3–4) in 3 of 5 patients treated at 200 mg/m², 2 of 9 treated at 150 mg/m² and 1 of 6 at 100 mg/m². Other non-hematologic toxicity was mild and infrequent. There was no change in post-LVEF among 9 patients with available data and no significant cardiac events were documented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blast phase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved a third complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m² and has significant anti-leukemia activity.     

Chemotherapy options for previously untreated acute myeloid leukemia

Introduction: Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite many large trials examining the choice and dosing of these agents.

Areas covered: We will review the major published clinical trials for untreated AML that have established the dosing choice and schedule for intensive therapy, as well as trials for patients not eligible for more intensive therapy. We will also discuss treatment considerations for subgroups of patients.

Expert opinion: While one or two cycles of anthracycline and cytarabine-based combination regimens remain the standard of care for younger and older patients with AML deemed fit to receive induction chemotherapy, controversy remains regarding the optimal selection and dosing schedule for anthracyclines. Low-intensity regimens, such as low-dose cytarabine and hypomethylating agents, can achieve a complete response even with adverse risk features, and can be used in a fit subset of older patients not eligible for clinical trial or transplant. Incorporation of new targeted agents, such as tyrosine kinase and small-molecule inhibitors, combined with better selection of drugs for unique patient cohorts, will likely be necessary to substantially improve outcomes in AML.     

较小剂量柔红霉素诱导老年急性髓细胞白血病临床观察

目的：探讨较小剂量柔红霉素（DNR）诱导老年急性髓细胞白血病（AML）缓解的临床疗效。方法：将80例老年AML患者随机分为治疗组（40例）和对照组（40例）,两组患者均采用DA化疗方案,治疗组患者柔红霉素采用较小剂量30mg/（m2·d）,对照组患者柔红霉素采用标准剂量45mg/（m2·d）,随访2个疗程,比较两组患者的临床疗效和Ⅲ度以上骨髓抑制、感染、胃肠道反应等药物不良反应。结果：治疗组患者完全缓解16例,缓解率为40%,对照组患者完全缓解18例,缓解率为45%,两组患者完全缓解率比较差异无统计学意义（P〉0.05）;治疗组患者不良反应11例,占28%,对照组患者不良反应18例,占45%,对照组不良反应发生率明显高于治疗组,两组患者比较差异有统计学意义（P〈0.05）。结论：较小剂量柔红霉素诱导老年AML,疗效满意,药物不良反应少,值得临床推广。     

Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia

Introduction: Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. Despite the known clinical efficacy in relapsed/refractory acute myeloid leukemia (AML), GO was withdrawn from the market in 2010 due to increased early deaths witnessed in newly diagnosed AML patients receiving GO + intensive chemotherapy. In 2017, new data on the clinical efficacy and safety of GO administered on a fractionated-dosing schedule led to re-approval for newly diagnosed and relapsed/refractory AML.

Areas covered: Addition of fractionated GO to chemotherapy significantly improved event-free survival of newly diagnosed AML patients with favorable and intermediate cytogenetic-risk disease. GO monotherapy also prolonged survival in newly diagnosed unfit patients and relapse-free survival in relapsed/refractory AML. This new dosing schedule was associated with decreased incidence of hepatotoxicity, veno-occlusive disease, and early mortality.

Expert commentary: GO represents the first drug-antibody conjugate approved (twice) in the United States for AML. Its re-emergence adds a valuable agent back into the armamentarium for AML. The approval of GO as well as three other agents for AML in 2017 highlights the need for rapid cytogenetic and molecular characterization of AML and incorporation into new treatment algorithms.     

CD56在急性髓细胞白血病的表达及意义

目的：探讨CD56在急性髓细胞白血病（AM L ）患者中的表达及意义。方法采用多色流式细胞术对102例初诊A M L的患者进行免疫表型检测,分析CD56在A M L患者中的表达及其与其他分化抗原的相关性。结果102例AM L患者中,23例（22.5％）表达CD56。伴有淋系抗原表达的AML（Ly＋ AML）组CD56表达率高于Ly －AML组（χ2＝9．54,P＜0．01）,Pearson相关性分析显示,CD56的表达与伴淋系抗原的表达呈正相关（ r＝0．304,P＜0．05 ）,而与年龄、性别、CD7、CD34、CD117及人类白细胞抗原 DR 的表达无明显相关性。CD56＋ AML 组的完全缓解（CR）率低于CD56－AML组（42.1％ vs ．74.5％）（χ2＝6．91,P＜0．05）。多因素Logistic回归分析显示,CD56是影响AML 患者 CR率的独立危险因素（P＜0．05）。CD56＋ AML 的无病生存期（DFS）较CD56－AML短（χ2＝18．97,P＜0．01）。COX回归多因素分析结果提示,CD56是影响AML患者DFS的独立危险因素（P＜0．01）。结论 CD56＋ AML患者CR率明显降低,DFS明显缩短,预后较差。CD56可作为评估AML患者预后的指标。     

急性骨细胞白血病CD11b表达的临床意义

目的　研究急性髓细胞白血病（AML）CD11b表达的临床意义。方法　采用碱性磷酸酶抗碱性磷酸酶复合物法（APAAP）,测定80例AML患者细胞膜表面CD11b的阳性表达。结果　CD11b     

Curative chemotherapy for acute myeloid leukemia: the development of high-dose ara-C from the laboratory to bedside

Summary In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C × t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c × T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c × T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1–3 gm/m²) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C × t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.     

Clofarabine: a new treatment option for patients with acute myeloid leukemia

Clofarabine is a rationally designed, second-generation deoxyadenosine analog that incorporates characteristics of two other purine analogs, fludarabine and cladribine. It has shown efficacy in hematologic malignancies such as acute lymphoblastic leukemia, acute myeloid leukemia and myelodysplastic syndrome. It has already been approved for use in pediatric acute lymphoblastic leukemia after two lines of previous therapy. Clinical trials have also shown clofarabine to have activity both as a single agent and in combination with other cytotoxic drugs in adult myeloid leukemia. This compound seems to have efficacy in older patients, as well as those with adverse cytogenetics.     

Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloid leukaemia

AIMS

It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed ‘the inocculum effect’. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated.

METHODS

Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR.

RESULTS

A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r² = 0.11, P < 0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P < 0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect.

CONCLUSION

This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.     

CD123在急性白血病骨髓干祖细胞中的表达及其临床意义

目的检测细胞表面抗原CD123（IL-3受体α链）在急性白血病（AL）患者骨髓干祖细胞中的表达,并探讨其与患者预后的关系。方法采用流式细胞术检测43例初治的AL患者及13例正常对照组的骨髓CD34阳性细胞中CDl23的表达情况;同时根据AL患者的年龄、细胞遗传学改变、发病时外周血白细胞数量将其按不同预后分为高危、标危、低危3组,其中高危15例,标危15例,低危13例,分析CD123表达与AL患者预后的相关性。结果43例AL患者CD34＋CDl23＋/CD34＋平均水平为38.24%,显著高于对照组平均表达水平1.90%;3组AL患者CD34＋CDl23＋/CD34＋均显著高于对照组（P〈0.05）;高危组患者CD34＋CDl23＋/CD34＋显著高于标危组和低危组,差异具有统计学意义（P〈0.05）;标危组患者CD34＋CDl23＋/CD34＋显著高于低危组,差异具有统计学意义（P〈0.05）。结论在AL患者骨髓干祖细胞中,CD123异常过度表达;在高危组、标危组、低危组的表达逐渐降低,提示CD123的表达与AL患者的预后相关,临床可通过检测该指标判断AL患者预后。     

HAG方案治疗老年急性髓系白血病16例疗效分析

目的探讨老年急性髓系白血病（AML）的治疗方法。方法应用HAG预激方案（阿糖胞苷10mg·m^-1,每12h皮下注射1次,第1～14d;高三尖杉酯碱1mg·m^-2·d^-1,第1—14d,静脉滴注;粒细胞集落刺激因子300μg·d^-1,第1—14d皮下注射）,治疗老年急性髓系白血病16例,观察疗效及毒副作用结果16例患者中,达到完全缓解5例,部分缓解2例,早期死亡3例,骨髓抑制比常规化疗抑制较轻,未见严重心、肝、肾等重要器官损害。结论HAG方案治疗老年AML效果较好,化疗耐受性高。     

The efficacy of sapacitabine in treating patients with acute myeloid leukemia

ABSTRACT

Introduction: Acute myeloid leukemia (AML) remains a poor prognosis hematological malignancy. The introduction of aggressive chemotherapy with allogeneic stem cell transplantation has resulted in improved clinical outcomes in younger patients. However, the treatment results in unfit elderly AML population remain disappointing. New strategies should be introduced to improve the prognosis in this group of patients.

Areas covered: This review presents and discusses the mechanism of action, safety and efficacy of sapacitabine in AML patients.

Expert opinion: Sapacitabine, a novel nucleoside analog, seemed to be a promising new agent for AML treatment. Its oral bioavailability and tolerable toxicity profile allow the drug to be used in an outpatient setting, especially in elderly unfit patients. Sapacitabine is known to have antileukemic activity in randomized clinical trials. In AML patients, sapacitabine monotherapy offered no advantage over low-intensity cytarabine treatment, and the combination of sapacitabine with decitabine was not significantly more effective than decitabine alone. However, the oral administration of sapacitabine allows it to be used in AML maintenance therapy.