Salvage chemotherapy with low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor priming in patients with refractory or relapsed acute myeloid leukemia with translocation (8;21)

High expression levels of granulocyte colony stimulating factor (G-CSF) receptor were found in the leukemic cells of acute myeloid leukemia (AML) patients with t(8;21). Therapeutic significance of G-CSF receptor on chemotherapy remains to be defined. We evaluate the efficacy and tolerability of CAG regimen, consisting of concurrent use of G-CSF with low-dose cytarabine and aclarubicin, in 36 refractory/relapsed AML patients with t(8;21). The overall complete remission (CR) rate was 75% and median CR duration was 12 months. No significant treatment-related adverse events were observed. These data demonstrate that CAG regimen might be an alternative option in the treatment of AML with t(8;21), especially in older patients or patients with co-morbidities.     

Efficacy and safety of decitabine in combination with G-CSF,low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia

Purpose

This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML.

Experimental Design

All patients in this study were treated with decitabine of 15 mg/m² for 5 days and G-CSF for priming, in combination with cytarabine of 10-mg/m² q12h for 7 days and aclarubicin of 10 mg/day for 4 days (D-CAG).

Results

Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged ≥70 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged ≥70 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%.

Conclusion

D-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (≥70 years).     

Granulocyte-macrophage colony-stimulating factor (GM-CSF) priming with successive concomitant low-dose Ara-C for elderly patients with secondary/refractory acute myeloid leukemia or advanced myelodysplastic syndrome.

Patients with advanced MDS and secondary AML respond poorly to chemotherapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can stimulate proliferation of leukemic blasts and sensitize these cells to the cytotoxic effects of S-phase-specific drugs. This is the first report of safety and efficacy of GM-CSF prior to and during cytarabine in a low-dose, intermittent regimen for elderly patients with poor risk acute myelogenous leukemia or myelodysplastic syndrome. Twenty patients, age 68 to 86 years, each received 250 microg/m2 of GM-CSF (Sargramostatin; Immunex, Seattle, WA, USA) subcutaneously (s.c.) or intravenously (i.v.) for 3 days followed by GM-CSF at the same dose and cytarabine 100 mg/m2 i.v. for 3 days. GM-CSF and cytarabine were both administered for 3 days during weeks 2 and 3 followed by a 3-week rest period. Rates of CR and PR were 20% and 40%, respectively. These included clinically significant resolution of cytopenias and transfusion requirements. Many of the responding patients had been heavily pretreated prior to enrollment. One- and 2-year survival estimates are 44% and 19%, respectively. Myelosuppression was the most significant toxicity. Our findings suggest that this novel combination of GM-CSF with sequential and concomitant low-dose cytarabine can benefit patients with poor risk myeloid malignancies.     

小剂量CHG预激方案治疗老年人急性髓系白血病的临床研究

Objective To explore the efficacy and side effect of inductive chemotherapy with lowdose,cytarabine,homoharringtonine and granulocyte colony-stimulating factor(CHG) in elderly acute myeloid leukemia(AML). Methods Thirty-five elderly patients (age＞60 years) with AML were enrolled for the initial treatment with CHG regimen,The CHG regimen consisted of cytarabine 10 mg/m2 per 12 h by subcutaneous injection,days 1-14,homoharringtonine 1 mg/m2 per day by intravenous continuous infusion,days 1-14,and G-CSF 200 μg/m2 per day by subcutaneous injection 12 h before chemotherapy,days 0-14. G-CSF only was used when white blood cell count(WBC) was less than 20×109/L during the whole course. Results After the first course,12 patients achieved complete response (CR),15 patients achieved partial response(PR),and 8 patients had no response(NR). After the second course,5 of 15 PR patients achieved CR,2 of 8 NR patients achieved PR. The total effective rate was 82 % (29/35). Of those 17 CR patients,eleven patients continued maintenance therapy and remained in remission for 12-34 months with a median CR duration of 18 months,the other 6 patients relapsed and were treated with original regimen,including one achieved CR again,4 achieved PR,and 1 achieved NR. The CHG regimen had mild hematologic toxicities and no severe nonhematologic toxicities. Conclusion CHG regimen is effective and well tolerated in remission for elderly AML.     

小剂量CHG预激方案治疗老年人急性髓系白血病的临床研究

 目的　探讨小剂量CHG预激方案[小剂量阿糖胞苷（Ara-C）、高三尖杉酯碱（HHT）联合粒细胞集落刺激因子（G-CSF）]对老年急性髓系白血病（AML）的治疗疗效和毒副作用。方法　选择 年龄＞60岁的AML初治患者共35例,采用CHG方案治疗：在化疗前12 h皮下注射粒细胞集落刺激因子（G-CSF）200 μg／m2后,应用14 d,HHT 1 mg／m2,第1天至第14天,1次／d;Ara-C 10 mg／m2,第1天至第14天,皮下注射,每12 h 1次。治疗过程中,WBC＞20×109／L时暂停使用G-CSF,但不停化疗,待WBC回落后再继续使用。对完全缓解（CR）者后期可选择不同方案交替巩固化疗。结果　第1个疗程后12例患者获得CR,15例获得部分缓解（PR）,8例未缓解（NR）。第2个疗程后,15例PR患者5例取得CR,8例NR患者有2例获得PR,总有效率83 %（29／35）。17例获得CR的患者中11例按计划巩固强化治疗未复发,生存期为12～34个月,中位生存18个月;6例复发,经过原方案诱导后1例CR、4例 PR、1例NR。CHG方案血液学毒性低,非血液学毒性不明显。结论　初治的老年AML患者采用小剂量CHG预激方案诱导缓解的疗效较好、不良反应可耐受。     

小剂量CHG预激方案治疗老年人急性髓系白血病的临床研究

Objective To explore the efficacy and side effect of inductive chemotherapy with lowdose,cytarabine,homoharringtonine and granulocyte colony-stimulating factor(CHG) in elderly acute myeloid leukemia(AML). Methods Thirty-five elderly patients (age＞60 years) with AML were enrolled for the initial treatment with CHG regimen,The CHG regimen consisted of cytarabine 10 mg/m2 per 12 h by subcutaneous injection,days 1-14,homoharringtonine 1 mg/m2 per day by intravenous continuous infusion,days 1-14,and G-CSF 200 μg/m2 per day by subcutaneous injection 12 h before chemotherapy,days 0-14. G-CSF only was used when white blood cell count(WBC) was less than 20×109/L during the whole course. Results After the first course,12 patients achieved complete response (CR),15 patients achieved partial response(PR),and 8 patients had no response(NR). After the second course,5 of 15 PR patients achieved CR,2 of 8 NR patients achieved PR. The total effective rate was 82 % (29/35). Of those 17 CR patients,eleven patients continued maintenance therapy and remained in remission for 12-34 months with a median CR duration of 18 months,the other 6 patients relapsed and were treated with original regimen,including one achieved CR again,4 achieved PR,and 1 achieved NR. The CHG regimen had mild hematologic toxicities and no severe nonhematologic toxicities. Conclusion CHG regimen is effective and well tolerated in remission for elderly AML.     

小剂量阿糖胞苷阿克拉霉素和粒细胞集落刺激因子联合治疗骨髓增生异常综合征转化急性白血病的临床疗效

目的探讨小剂量阿糖胞苷、阿克拉霉素和粒细胞集落刺激因子联合治疗骨髓增生异常综合征(MDS)转化急性白血病的临床疗效。方法选取2005年3月至2014年3月间江苏省南通市如东县人民医院血液内科收治的122例MDS转化的急性白血病患者,采用随机数字表法随机分为观察组和对照组,每组61例。观察组患者采用小剂量阿糖胞苷、阿克拉霉素和粒细胞集落刺激因子联合治疗,对照组患者采用常规化疗治疗,比较两组患者的临床疗效。结果观察组患者治疗的总有效率为90.2%(55/61),显著高于对照组的70.5%(43/61),差异有统计学意义(P<0.05)。观察组患者的不良反应发生率为14.8%(9/61),显著低于对照组的41.0%(25/61),差异有统计学意义(P<0.05)。结论小剂量阿糖胞苷、阿克拉霉素和粒细胞集落刺激因子联合治疗MDS转化的急性白血病的临床疗效较常规化疗治疗好,且具有较高的安全性。     

地西他滨联合半量CAG和单用CAG方案治疗老年人急性髓系白血病效果比较

目的 探讨地西他滨联合半量CAG方案和单用CAG方案治疗老年人急性髓系白血病(AML)的疗效及不良反应.方法 回顾性分析山东省菏泽市立医院2013年8月至2017年8月收治的42例老年AML患者(急性早幼粒细胞白血病除外)临床资料,患者年龄65～75岁.根据化疗方案分为治疗组和对照组,治疗组20例采用地西他滨联合半量CAG方案(重组粒细胞集落刺激因子+阿糖胞苷+阿柔比星),对照组22例单用CAG方案.结果 1个疗程后治疗组患者完全缓解(CR) 13例,部分缓解(PR)3例,未缓解(NR)4例,总有效(CR+PR)率为80.0％(16/20);对照组CR 8例,PR 2例,NR 12例,总有效率为45.5％(10/22),两组总有效率比较差异有统计学意义(x2=3.707,P=0.035).两组骨髓恢复时间、输注红细胞及血小板量比较,差异均无统计学意义(均P＞ 0.05).结论 地西他滨联合半量CAG方案治疗老年AML患者的效果优于单用CAG方案,不良反应均可耐受,可作为老年人AML的首选治疗方案.     

小剂量地西他滨联合CAG方案治疗老年人急性髓系白血病及中高危骨髓增生异常综合征临床分析

目的 探讨小剂量地西他滨(DAC)治疗老年人急性髓系白血病(AML)和中高危骨髓增生异常综合征(MDS)的临床价值.方法 对19例老年AML和中高危MDS患者使用小剂量DAC(10 mg/d,连用7 d)联合CAG方案[重组粒细胞集落刺激因子(G-CSF)+阿糖胞苷(Ara-C)+阿柔比星]进行治疗;1个疗程后对疗效及不良反应进行综合评估;对患者进行生存期跟踪随访.结果 1个疗程治疗后,完全缓解8例,部分缓解7例;4个疗程治疗后,完全缓解13例(68.4%),总体反应率达到78.9%(15/19),化疗相关不良反应少.随访42个月,生存12例,中位生存时间为13.5个月(3~42个月).结论 对于中高危MDS和老年AML患者,小剂量DAC联合CAG方案有较好的疗效、较高的安全性、较低的经济负担,有利于改善患者的治疗依从性.     

Continuous drip infusion of low dose cytarabine and etoposide with granulocyte colony-stimulating factor for elderly patients with acute myeloid leukaemia ineligible for intensive chemotherapy

BACKGROUNDS AND OBJECTIVES: The optimal strategy for the management of elderly patients with acute myeloid leukaemia (AML) is still controversial. We previously reported the effectiveness of low dose cytarabine (Ara-C) and etoposide (VP-16) (AV therapy) for those elderly AML patients ineligible for intensive chemotherapy. We initiated the present feasibility study to improve the efficacy by using glanulocyte-colony stimulating factor (G-CSF) with AV therapy (AVG therapy). PATIENTS AND METHODS: The eligibility for enrolment was AML patients according to the World Health Organization (WHO) criteria who were over 60 years of age and who had difficulty in tolerating intensive chemotherapy due to their poor performance status (PS) or some comorbidities. They were given continuous drip infusion of Ara-C (20 mg/body) and VP-16 (50 mg/body) for 7-14 days, and were also simultaneously administered G-CSF (150 microg/m2) once daily. RESULTS: The median age of consecutively enrolled 25 patients was 73 years. Eighteen (72%) patients achieved complete remission (CR). The 1-year overall survival (OS) and the 3-year OS rates were 69% and 22%, respectively. The 1-year disease free survival (DFS) rate in CR patients was 44%. The major regimen related toxicities of grade 3 or 4 were only febrile neutropenia in 15 patients (60%). No regimen-related mortality was observed. CONCLUSION: AVG therapy was therefore found to be an effective and well-tolerated regimen for remission induction in elderly AML patients with poor PS or comorbidity.     

CAG预激方案治疗急性髓系白血病及骨髓增生异常综合征

 目的　探讨小剂量阿糖胞苷（Ara-C）、阿克拉霉素（Acla）联合粒细胞集落刺激因子（G-CSF）（CAG方案）治疗急性髓系白血病（AML）及骨髓增生异常综合征（MDS）的临床疗效及患者不良反应。方法　选择初治或复发难治的AML与MDS患者54例,采用CAG方案化疗;获得完全缓解（CR）后选择不同方案交替巩固化疗。结果　CAG预激化疗治疗AML及MDS总有效39例（72.2 %）,CR 26例（48.1 %）,部分缓解（PR）13例（24.1 %）;化疗相关不良反应：粒细胞及血小板减少发生率40.7 %（22／54）,重症感染发生率24.1 %（13／54）。1例并发肝功能损害死亡。36例年龄＜60岁的患者总有效28例（77.8 %）,18例年龄≥60岁的患者总有效11例（61.1 %）,差异有统计学意义（P＜0.05）。结论　CAG方案治疗AML与MDS-原始细胞过多难治性贫血（RAEB）的疗效肯定,不良反应小,无病生存期长,是高效低毒的新型化疗方案。     

CAG预激方案治疗急性髓系白血病及骨髓增生异常综合征

Objective To explore the efficacy and side effect of CAG (G-CSF, aclarubicin and cytarabine) priming chemotherapy for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods 54 patients with AML at diagnosis and relapse or MDS were'enrolled for the initial treatment with CAG regimen. Patients who have achieved complete remission (CR) were treated with various regimens. Results The total effective rate was 72.2 %, complete remission rate was 48.1% and partial remission rate was 24.1%. The incidence of granulocyte deficiency was 40.7 %(22/54). The severe infection rate was 24.1%(13/54). One case died of function damage in liver. The study includes 36 patients below 60 years, 18 patients above 60 years, and overall effective cases are 28 (77.8 %), 11 (61.1%),respectively. There was significant difference (P ＜0.05). Conclusion CAG regimen is effective and well tolerated in remission for AML and MDS-RAEB.     

地西他滨联合CAG或HAAG方案治疗老年白血病疗效比较

目的:观察地西他滨(DAC)+CAG方案与地西他滨(DAC)+HAAG方案治疗初治老年急性非淋巴细胞白血病(AML)的疗效与安全。方法:回顾性分析我院血液科近5年的58例老年初治急性非淋巴细胞白血病患者,其中35例接受DAC+CAG方案诱导化疗,23例接受DAC+HAAG方案诱导化疗。结果:DAC+CAG及DAC+HAAG组缓解率分别为51.4%及60.9%,差异无统计学意义(P=0.592),两组有效率分别为62.9%及69.6%,差异无统计学意义(P=0.779)。经过平均12个月(1~60个月)的随访,两组的2年存活率分别为23.5%及33.3%,差异无统计学意义(P=0.591)。结论:DAC+CAG与DAC+HAAG方案对于诱导老年急性非淋巴细胞白血病缓解的疗效差异并不明显,两种方案对患者的长期生存并无明显影响。     

Arsenic trioxide and low-dose cytarabine in older patients with untreated acute myeloid leukemia, excluding acute promyelocytic leukemia

BACKGROUND: Acute myeloid leukemia (AML) carries a dismal prognosis in older patients. In this study, the authors evaluated the safety and efficacy of arsenic trioxide combined with low-dose cytarabine in untreated patients aged >or=60 years with AML. METHODS: In a phase 1/2 design, arsenic trioxide was administered intravenously at a dose of 0.25 mg/kg on Days 1 through 5 and on Days 8 through 12, and low-dose cytarabine was given subcutaneously twice daily on Days 1 through 14 in escalating doses to a target of 10 mg/m(2) per dose. Of 64 patients who had pathologically confirmed AML, excluding patients with acute promyelocytic leukemia and using World Health Organization criteria, the median age was 71 years, 10 patients (16%) had treatment-related AML, 40 patients (63%) had an antecedent myelodysplastic syndrome or myeloproliferative disorder, and 35 patients (55%) had unfavorable cytogenetics. Thirty-four patients (53%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. RESULTS: Complete remission was achieved in 21 of 61 patients (34%), including 15 of 50 patients (30%) who had secondary or treatment-related AML, 10 of 33 patients (30%) who had unfavorable cytogenetics, and 6 of 34 patients (18%) who had a poor baseline performance status. The mortality rate within the first 4 weeks was 8%. Neutropenic fever was observed in >80% of patients, and 41% of patients had bacteremia. Nonhematologic toxicity generally was mild and reversible and included fatigue, nausea, diarrhea, rash, peripheral edema, and elevated transaminases. There were no clinically significant cardiac arrhythmias. CONCLUSIONS: The addition of arsenic trioxide to low-dose cytarabine appeared to improve responses in elderly patients who had AML compared with either agent alone, and a randomized trial of the combination versus single-agent low-dose cytarabine is ongoing.     

小剂量高三尖杉酯碱+阿糖胞苷方案诱导治疗不同危险度分层急性髓系白血病效果分析

目的 探讨小剂量(LD)-高三尖杉酯碱+阿糖胞苷(HA)方案诱导治疗急性髓系白血病(AML)(除外M3)的临床效果.方法 对52例接受LD-HA方案诱导治疗的AML患者资料进行回顾性分析,并依据分子生物学和细胞遗传学危险度分级,观察临床疗效、不良反应,随访长期生存,以同期49例伊达比星+阿糖胞苷(IA)方案治疗患者为对照.结果 1个疗程后,LD-HA组总有效(OR)率为71.2%(37/52)[完全缓解(CR)率50.0%(26/52),部分缓解(PR)率21.2%(11/52)],IA组OR率为53.1%(26/49)[CR率44.9%(22/49),PR率8.2%(4/49)],两组OR率差异无统计学意义(P=0.068).按危险度分层,LD-HA组高危组的OR率高于IA组[100%(11/11)比66.7%(12/18)],差异有统计学意义(P<0.05);LD-HA组和IA组的低危组和中危组OR率差异无统计学意义(P>0.05).LD-HA组心脏毒性及骨髓抑制均较IA组轻,不适合标准方案的AML患者亦对其耐受良好.结论 LD-HA方案诱导治疗AML时,高危组OR率高,化疗相关不良反应发生率低,安全性较高.与标准方案相比,LD-HA对于高危AML患者可能更有效.     

An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia

To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3. We describe here a Thr617Asn mutation in the transmembrane domain of the non-tyrosine kinase receptor for granulocyte colony-stimulating factor (G-CSF) in the blast cells of two out of 555 AML patients examined. The mutant receptor conferred growth factor independence on factor-dependent Ba/F3 cells. In the absence of ligand, immunoblotting showed weak phosphorylation of JAK2, STAT3, ERKs 1 and 2 and the receptor itself, and there was approximately 70% of maximal growth in a proliferation assay. All signals were significantly enhanced in the presence of G-CSF. Retroviral transduction of mutant receptor into primary hematopoietic CD34+ cells induced G-CSF independent myeloid differentiation as assessed by the development of neutrophils and surface expression of CD11b and CD14. These results confirm the importance of the transmembrane domain for receptor function and suggest that introduction of an asparagine residue can cause sufficient stabilization of helix-helix interactions in the absence of ligand to activate downstream signaling pathways involved in directing proliferation and differentiation.     

Pilot study of Mylotarg,idarubicin and cytarabine combination regimen in patients with primary resistant or relapsed acute myeloid leukemia

PURPOSE: Mylotarg has moderate activity as a single agent in patients with CD33-positive refractory or relapsed acute myelogenous leukemia (AML). A combination of an anthracycline and cytarabine (ara-C) is the core of most AML induction regimens. We conducted a pilot study of Mylotarg combined with idarubicin and ara-C in patients with refractory or relapsed AML. METHODS: Mylotarg was administered at 6 mg/m(2) intravenously on days 1 and 15, idarubicin 12 mg/m(2) daily on days 2 through 4, and ara-C at 1.5 g/m(2) daily on days 2 through 5 (MIA) RESULTS: Of 14 patients were treated, 4 (29%) had primary resistant AML, and 10 (71%) relapsed AML. The median age of the patients was 61 years (range 34-74 years). MIA induced complete remission (CR) in three patients (21%) and CR with incomplete platelet recovery (CRp) in three patients (21%). The median survival was 8 weeks (range 2-64 weeks), and the median failure-free survival of CR patients was 27 weeks (range 11-64 weeks). All patients developed grade 3/4 myelosuppression - severe sepsis occurred in ten patients (71%). Other grade 3/4 nonhematologic toxicities included hepatic transaminitis, oral mucositis, and diarrhea. Two patients (14%) developed hepatic venoocclusive disease (VOD). CONCLUSIONS: The addition of Mylotarg to idarubicin and ara-C is feasible. MIA has significant activity in patients with refractory AML. Hepatotoxicity and VOD are significant toxicities of Mylotarg-based combinations.