Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients

BACKGROUND:

Standard therapy for older patients with acute myeloid leukemia (AML) has a poor outcome. The authors have designed a combination of clofarabine plus low‐dose cytarabine followed by a prolonged consolidation alternating with decitabine.

METHODS:

Sixty patients with a median age of 70 years (range, 60‐81 years) with newly diagnosed AML were included. They received clofarabine 20 mg/m² intravenously daily for 5 days plus cytarabine 20 mg subcutaneously twice daily for 10 days. Responding patients continued for up to 17 courses of consolidation therapy including decitabine.

RESULTS:

Forty of 59 evaluable patients responded (66%). Complete remission rate was 58%. Median relapse‐free survival (RFS) was 14.1 (95% confidence interval [CI], 6.9 to not estimable), and median overall survival (OS) was 12.7 months (95% CI, 8.8 to not estimable). Median OS of responding patients (complete response [CR]/CR with platelet count <100 × 109/L) was 24.2 months (95% CI, 17 to not estimable). Compared with a historical group of patients who received clofarabine plus low‐dose cytarabine with a shorter consolidation, RFS was not statistically different. Induction mortality was low (7% at 8 weeks) and toxicities manageable.

CONCLUSIONS:

Clofarabine plus low‐dose cytarabine alternating with decitabine in consolidation is active in older patients with newly diagnosed AML. The benefits of a prolonged consolidation remain unproven. Cancer 2012. © 2012 American Cancer Society.     

Clofarabine in the Treatment of Elderly Patients with AcuteMyeloid Leukemia

Background: Elderly patients with acute myeloid leukemia (AML) have a poor outcome because of comorbidities,poor tolerance to intensive chemotherapy and inherently more resistant disease. Clofarabine is asecond generation nucleoside analogue which has shown promising activity in elderly patients with AML. Thisstudy was conducted to review the outcome of treatment with clofarabine in a group of such patients. Methods:The records of 5 elderly patients who were diagnosed to have AML and treated with clofarabine over a 12month period were reviewed retrospectively. Results: There were 2 female and 3 male patients with a medianage of 68 years (range 65-82). At the time of treatment, 2 patients had newly diagnosed AML not consideredsuitable for intensive therapy, while 3 patients had partial or no response to conventional chemotherapy. Theoverall response rate was 100%, all patients achieving a complete remission. Induction and consolidation werewell tolerated. All patients developed neutropenia with a median duration of 20 days (range 17-42). One patientdeveloped hand and foot syndrome and a generalized rash but recovered. There was no mortality and all patientsremained in remission after a median follow-up of 5.2 months (Range 3-10). Conclusion: Clofarabine (alone orin combination) is active in elderly AML patients with an acceptable safety profile and should be considered apotential option in this group.     

Clofarabine for the treatment of acute lymphoblastic leukemia

A marked improvement in the outcome of patients with acute lymphoblastic leukemia has been achieved with chemotherapeutic agents developed between the 1950s and 1970s. As the limits of optimizing the use of old drugs are reached, most adults with acute lymphoblastic leukemia still succumb to their disease and leukemia remains the leading cause of nonaccidental death in children. Salvage regimens, based mostly on different combinations of the same agents used in front-line therapy, carry a high incidence of morbidity and dismal long-term survival rates. New therapeutic strategies are needed. Clofarabine, a next-generation deoxyadenosine analog, has demonstrated significant activity in children and adults with refractory lymphoid and myeloid leukemia in early clinical trials and was granted approval for use in children with acute lymphoblastic leukemia in second or higher relapse. This is the only anticancer drug to receive primary indication for use in children over the past decade. Ongoing studies are exploring the benefit of clofarabine combinations in less heavily pretreated patients and the use of different dose schedules in a variety of hematological malignancies.     

Clofarabine in the treatment of poor risk acute myeloid leukaemia

Clofarabine is a second generation nucleoside analogue. It inhibits DNA repair and activates the mitochondrial apoptotic pathway leading to cell death. In vitro clofarabine has demonstrated synergy with daunorubicin and Ara‐C and in phase II clinical trials has shown promising activity in poor risk Acute myeloid leukaemia (AML) patients. In our institution over a 24 month period 22 AML patients (11 M, 11 F) with poor risk features, deemed unsuitable for standard therapy, were treated with clofarabine, alone (eight patients) or in combination (14 patients) for up to three cycles of treatment. The median age was 67.5 years (24–76) with 16 patients > 60 years. At the time of treatment 18 patients had active AML. Four patients intolerant of standard induction received clofarabine as consolidation. The overall response rate (ORR) for the 18 patients with active AML was 61%, nine patients (50%) achieving a complete response (CR). Induction and consolidation were well tolerated with no unexpected toxicities. Predictably, all patients developed grade 4 neutropenia but the median duration was only 20 days (17–120). Induction mortality was acceptable at 17%. In conclusion, clofarabine (alone or in combination) is active in poor risk AML with an acceptable safety profile and should be considered a potential option in poor risk AML patients. Copyright © 2009 John Wiley & Sons, Ltd.     

Role of autophagy in acute myeloid leukemia therapy

Despite its dual role in determining cell fate in a wide array of solid cancer cell lines, autophagy has been robustly shown to suppress or kill acute myeloid leukemia cells via degradation of the oncogenic fusion protein that drives leukemogenesis. However, autophagy also induces the demise of acute leukemia cells that do not express the known fusion protein, though the molecular mechanism remains elusive. Nevertheless, since it can induce cooperation with apoptosis and differentiation in response to autophagic signals, autophagy can be manipulated for a better therapy on acute myeloid leukemia.     

Targeted therapy of acute myeloid leukemia

Advances in the understanding of the genetic underpinnings of acute myeloid leukemia are rapidly being translated into novel treatment strategies. Genomic profiling has highlighted the importance of the epigenetic machinery for leukemogenesis by identifying recurrent somatic mutations involving chromatin-modifier proteins. These genetic alterations function as dynamic regulators of gene expression and involve DNA-methyltransferase 3A, methyltransferase DOT1L, enhancer of zeste homologue 2, isocitrate dehydrogenases 1 and 2 and bromodomain-containing proteins. New therapeutic targets are also emerging from further delineation of cell signaling networks in acute myeloid leukemia blasts mediated by PIM kinases, polo-like kinase 1, cell surface protein CD98 and nucleocytoplasmic shuttling receptors, among others. Early results of targeted therapies directed at these molecular mechanisms are discussed in this review and their potential to improve the outcomes of patients by allowing the use of more effective and less toxic treatments.     

LD-HA方案在急性髓系白血病治疗中的应用

上世纪80年代,由于缺乏有效的支持治疗（如抗生素、输血、细胞因子等）,小剂量化疗药物治疗急性髓系白血病（acute myeloid leukemia,AML）成为当时的一个研究热点,特别是小剂量阿糖胞苷化疗方案的应用,取得了良好效果。1984年Body等体外证明了小剂量三尖杉酯碱有诱导HL-60细胞分化成熟的作用。1985年黄昌亮等国内外率先报告了LD-HA方案治疗AML的疗效,目前已成为不适合标准治疗方案的急性髓系白血病患者主要选择性方案之一,本文就LD-HA临床应用、疗效及存在问题作一综述。     

Clinical implications of acute myeloid leukemia presenting as myeloid sarcoma

In this retrospective study, we aim to analyze the characteristics, treatments, and overall survival of all patients presenting with isolated myeloid sarcoma (MS) or MS with concomitant acute myeloid leukemia (AML) compared with all patients with AML, treated during the same period. We identified patients with AML with or without MS at diagnosis, presenting to our medical center between the years 1990 and 2005. There was no statistically significant difference between the groups regarding gender, age, cytogenetic risk groups, rate of complete remission, number of cycles of chemotherapy needed to achieve complete remission, and rate of first relapse. The time to death in the MS group was not significantly different (p = 0.60) from the AML group, and radiotherapy did not affect the median time to death. Transplantation prolonged survival in both groups (p = 0.018 and p < 0.0001, respectively). Patients with MS at diagnosis might benefit from upfront aggressive treatment with hematopoietic stem cell transplantation. Copyright © 2011 John Wiley & Sons, Ltd.     

预激方案治疗老年急性髓性白血病的临床疗效

目的：探讨小剂量高三尖衫酯碱（HHT）、阿糖胞苷（Ara-c）联合粒细胞集落刺激因子（G-CSF）即HAG方案治疗老年急性髓细胞白血病（acute myelocytic leukemia,AML）的临床疗效。方法：36例老年AML中M14例,M213例,M45例,M59例,MDS转化AML 5例,均行HAG方案治疗。给予Ara-C 10mg/m2,12小时1次,皮下注射14天;HHT 1mg/m2.d,静滴14天;G-CSF150μg/d,皮下注射,在首次注射Ara-C前12小时给予,至最后一次注射Ara-C前12小时停用。WBC〉20×109/L时暂停G-CSF,待WBC回落后继续使用。对照组22例只采用HA方案化疗,即Ara-C10mg/m2,12小时1次,皮下注射14天;HHT 1mg/m2.d,静滴14天。观察两组疗效。结果：HAG方案组总CR率72.2%,有效率达77.8%。对照组总CR率36.4%,有效率59.1%,P=0.007,差异有统计学意义。结论：预激方案治疗老年急性髓性白血病疗效好,不良反应轻。     

急性髓系白血病靶向治疗的研究进展

近年来,治疗急性髓系白血病（acute myeloid leukemia,AML）的新药层出不穷,目前已经有几种新的靶向药物获得FDA批准。本文综述了包括针对FLT3信号通路的靶向药物、针对CD33抗原的靶向药物、针对BCL-2基因的靶向药物、针对IDH基因的靶向药物、针对免疫检查点的靶向药物以及CPX-351等药物的作用机制及临床研究进展,为AML未来治疗选择的扩大化、精准化和个性化提供了思路。     

Decitabine for acute myeloid leukemia

Decitabine (Dacogen^®, Eisai Inc., NJ, USA) is a nucleoside analogue DNA methyltransferase inhibitor first synthesized and documented to have antileukemic efficacy over 40 years ago. Over the years, the dosing of decitabine has been refined, such that for acute myeloid leukemia, a 5-day schedule of 20 mg/m² is now commonly utilized. Owing to its relatively modest nonhematologic toxicity when administered in this manner, single agent decitabine has shown the greatest promise in antileukemic efficacy for the management of older individuals and others who are not candidates for more intensive therapy. Whether or not single-agent decitabine is more safe and effective than existing therapies for older individuals, which markers best predict for response, and what drugs combine most effectively with decitabine, are all areas of active investigation at this time.     

预激方案治疗老年急性髓性白血病的临床疗效

目的:探讨小剂量高三尖衫酯碱(HHT)、阿糖胞苷(Ara-c)联合粒细胞集落刺激因子(G-CSF)即HAG方案治疗老年急性髓细胞白血病(acute myelocytic leukemia,AML)的临床疗效。方法:36例老年AML中M14例,M213例,M45例,M59例,MDS转化AML 5例,均行HAG方案治疗。给予Ara-C 10mg/m2,12小时1次,皮下注射14天;HHT 1mg/m2.d,静滴14天;G-CSF150μg/d,皮下注射,在首次注射Ara-C前12小时给予,至最后一次注射Ara-C前12小时停用。WBC>20×109/L时暂停G-CSF,待WBC回落后继续使用。对照组22例只采用HA方案化疗,即Ara-C10mg/m2,12小时1次,皮下注射14天;HHT 1mg/m2.d,静滴14天。观察两组疗效。结果:HAG方案组总CR率72.2%,有效率达77.8%。对照组总CR率36.4%,有效率59.1%,P=0.007,差异有统计学意义。结论:预激方案治疗老年急性髓性白血病疗效好,不良反应轻。     

抗CD123抗体靶向治疗急性髓系白血病

白血病干细胞（leukemic stem cells,LSCs）被认为是白血病发生、发展、耐药、复发的根源,如何彻底根除LSCs已成为白血病治疗研究的一个重要方向。CD123是LSCs表面相对特异的抗原,针对其研发的靶向抗体治疗药物可有效杀伤急性髓系白血病（acute myeloid leukemia,AML）的LSCs,本文对抗CD123抗体靶向治疗AML的最新进展做一综述。     

急性髓细胞白血病细胞遗传学诊断研究进展

大多数急性髓细胞白血病患者可检出不同类型的染色体核型异常,通过染色体核型分析技术和分子生物学技术可以检测出这些染色体畸形,由此发展了急性髓细胞白血病的细胞遗传学诊断,再结合细胞形态学和免疫学技术等,最终确定白血病的分型,以便更好的指导治疗、判断预后以及检测微小残留病变等.     

Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia

BACKGROUND: Outcome after recurrence of childhood acute myeloid leukemia (AML) is poor. We performed this study to identify prognostic factors for recurrence and for survival after recurrence of AML. METHODS: The clinical characteristics, biological features, treatment modalities, and outcomes of children with de novo AML who were enrolled on 3 consecutive clinical protocols from 1987 to 2002 at St. Jude Children's Research Hospital were studied. Regression modeling was used to identify prognostic factors for recurrence and for survival after recurrence. RESULTS: The outcome after recurrence was poor, with a 5-year survival estimate of only 23.3% +/- 5.7%. Multivariable analysis indicated that male sex (P = .005), autologous stem cell transplant before recurrence (P = .097), each additional month from diagnosis to recurrence (P = .041), and stem cell transplant after recurrence (P < .001) were associated with a better survival after recurrence, whereas M5 or M7 morphology (P = .001) were significantly predictive of a lower survival estimate after recurrence. CONCLUSIONS: Survival after recurrence was poor in children with AML. Novel therapies are urgently needed to prevent or to treat recurring AML.     

得力生联合化疗治疗急性髓性白血病疗效观察

目的:观察得力生注射液联合化疗治疗急性髓性白血病的疗效。方法:将62例患者随机分为治疗组和对照组,治疗组给予得力生注射液联合化疗,对照组单用化疗,观察临床疗效及造血恢复时间。结果:在第一疗程化疗后完全缓解率、部分缓解率、总有效率两组无显著性差别;达到完全缓解所需时间两组分别为25.9±6.6天、30.0±7.6天,治疗组短于对照组(P<0.05);治疗组骨髓抑制期也明显短于对照组(P<0.05)。结论:得力生注射液可提高急性髓性白血病的化疗效果,保护骨髓、促进造血恢复。