Salvage therapy with mitoxantrone,etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia

The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8 mg/m²/day, etoposide 100 mg/m²/day, and cytarabine 1000 mg/m²/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ≥second relapse (p = 0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.     

Idarubicin in combination with etoposide and cytarabine in adult untreated acute non lymphoblastic leukemia

Thirty-one unselected patients with untreated acute non lymphoblastic leukemia (ANLL) ranging in age from 15 to 76 years received two courses of a new high-dose induction regiment consisting of idarubicin, etoposide and cytarabine.Patients who entered complete remission (CR) were then allocated to post-remission intensification (PRI). Patients under 40 years of age with a HLA-compatible donor were given bone marrow transplantation (BMT); those without an HLA identical donor received either autologous BMT (ABMT) or no subsequent therapy.Twenty-five out of 31 patients (80.6%) achieved CR (93.3% in young and 68.7% in old patients) and 14 (56%) after the first cycle. Six patients (five out six > 40 years) died of cerebral hemorrhage and/or infection during the induction phase and four additional patients (three elderly) died on the PRI for the same cause without recurrent disease. Eleven out 25 patients are disease-free survivors 2–34 months (median 10 months) after achievement of CR.In conclusion, this intensive chemotherapy regimen is effective both in young and older patients but the post-remission intensification is too aggressive in elderly patients.     

Idarubicin in refractory acute leukemia

10 patients with resistant or relapsed acute leukemia (9 AML, 1 ALL) were treated with idarubicin (4-demethoxydaunorubicin) in combination with cytosine arabinoside +/- etoposide. All patients had been heavily pretreated. 9 AML-patients had previously received 2-4 cycles of TAD-9 regimen. 2 complete and 1 partial remission were achieved. 1 patient died from septicemia in bone marrow aplasia without leukemic cells. 6 patients did not respond to idarubicin-based salvage treatment. The median survival from start of therapy was 4 months. Idarubicin-based combination chemotherapy is effective in relapsed acute leukemia, even in patients intensively pretreated with anthracyclines.     

High-dose liposomal daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia.

BACKGROUND: Liposomal encapsulation of daunorubicin (DaunoXome, DNX; Nexstar Pharmaceutical, Boulder, CO) changes the pharmacology profile to increase delivery to tumor sites and decrease toxicity. The authors investigated the effect of daunorubicin in combination with ara-C in patients with refractory or recurring acute myelogenous leukemia (AML). PATIENTS AND METHODS Sixty-two patients with refractory or recurring AML received escalating doses of daunorubicin of 75, 100, 125, or 135 mg/m(2) daily for 3 days together with ara-C 1 g/m(2) intravenous continuous infusion daily for 4 days. RESULTS: Eighteen patients (29%) achieved a complete remission (CR) and 7 (11%) a hematologic improvement (i.e., met all criteria for CR except for platelet count < 100 x 10(9)/L) for an overall response rate of 40%. The dose-limiting toxicity was mucositis in 4 in 9 (44%) patients treated at the 150 mg/m(2) dose level, but minimal at 125 mg/m(2) (2 of 32, 6%) or 135 mg/m(2) (1 of 13, 8%). Cardiotoxicity Grade 2 was observed in 4 patients (6%) and Grade 3 or higher in 4 patients (6%). The median CR duration was 63 weeks, and overall survival rate was 25 weeks, with 28% patients alive after 1 year. CONCLUSIONS: The combination of DNX (or liposomal daunorubicin) and ara-C has significant antileukemia activity with acceptable toxicity. Further studies are warranted to investigate the role of high-dose anthracyclines in frontline AML therapy.     

FLAG方案治疗复发及难治成人急性淋巴细胞白血病

目的:观察FLAG方案化疗对复发或难治的成人淋巴细胞白血病的疗效和安全性.方法:对19例复发、难治的成人急性淋巴细胞白血病患者进行氟达拉滨、阿糖胞苷、粒细胞集落刺激因子联合的(FLAG)补救方案化疗.其中5例为原发耐药患者,14例为首次复发患者.结果:给予补救化疗后,8例患者(42.1%)达到完全缓解,10例患者(52.6%)未缓解,1例患者死于感染.完全缓解患者的中性粒细胞数在达到0.5×109/L和1×109/L以上的平均时间分别为开始治疗后的第18(范围为15到24天)和第21天(范围为19到26天),血小板数达到20×109/L和100×109/L以上的平均时间分别为开始化疗后的第22(范围为17到23天)和第31天(范围为26到36天).19例患者中有18例(94.7%)出现了高于38.5℃的发热,其中10例为不明原因发热,8例为感染所致.主要的非血液学不良作用为粘膜炎(16/19或84.2%)和肝毒性的增加(8/19或42.1%),对于这些不良作用,患者一般都可耐受.达到缓解的8例患者接受了第二轮FLAG方案化疗,此后其中4例患者接受了异基因干细胞移植(3例来源于同胞相合供者,1例来源于无关供者),另外4例患者因缓解后出现早期复发而未行移植.19例患者的中位生存期为7个月(范围为1到36个月),8例缓解患者的无病生存期和总生存期分别为6(范围为5到36个月)和10个月(范围为9到36个月).4位接受异基因干细胞移植患者的无病生存期为12个月(范围为7到36个月). 结论:研究中,复发难治的成人急性淋巴细胞白血病患者对于FLAG方案化疗是容易承受的,毒性可以耐受,该方案可使部分患者达到完全缓解,从而接受同种异基因移植治疗.     

Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia

Purpose: Based on reported synergy of the topoisomerase-I (topo-I) inhibitor irinotecan with antimetabolites, irinotecan and cytarabine (Ara-C) were administered sequentially to patients with acute myeloid leukemia (AML) refractory to or relapsed following high-dose Ara-C and anthracycline therapy. Pharmacokinetic and pharmacodynamic studies were performed with the first irinotecan dose. Experimental Design: In vitro synergy of irinotecan followed by Ara-C was confirmed in a human AML cell line as a basis for the clinical trial. Irinotecan was administered daily for 5 days, with Ara-C 1 g/m² 12 h after each irinotecan dose. Irinotecan was initiated at 5 mg/m², and the dose was escalated by 5 mg/m² increments in cohorts of three patients and in individual patients. Pre-treatment samples were studied for topo-I activity and serial samples after the first irinotecan dose were analyzed for pharmacokinetics and for pharmacodynamic effects, including DNA damage and DNA synthesis rate. Results: The irinotecan dose reached 15 mg/m² in three-patient cohorts without reaching the maximum tolerated dose, and reached 30 mg/m² in individual patients. The AUC and C _max of both irinotecan and its active metabolite SN38 increased linearly in proportion to dose, and the mean half-lives of irinotecan conversion to SN38 and SN38 elimination were 6.2 h (CV 171%) and 7.2 h (CV 48%). Irinotecan rapidly induced DNA damage, and DNA synthesis inhibition varied among patients and treatment cycles. All courses resulted in rapid cytoreduction, and two patients achieved complete remission. Topo-I activity did not predict response. Conclusion: Irinotecan can be safely administered with Ara-C. This combination is active in refractory AML and warrants further study.     

成年人复发难治急性淋巴细胞白血病现代化疗

成年人难治复发急性淋巴细胞白血病的治疗对临床实践是一大挑战.治疗策略包括大剂量单药、加强诱导缓解、新药、靶向治疗、免疫治疗等,对一些患者可能有益.缓解后治疗仍需进一步深入研究.     

成年人复发难治急性淋巴细胞白血病现代化疗

 成年人难治复发急性淋巴细胞白血病的治疗对临床实践是一大挑战。治疗策略包括大剂量单药、加强诱导缓解、新药、靶向治疗、免疫治疗等,对一些患者可能有益。缓解后治疗仍需进一步深入研究。     

成年人复发难治急性淋巴细胞白血病现代化疗

成年人难治复发急性淋巴细胞白血病的治疗对临床实践是一大挑战.治疗策略包括大剂量单药、加强诱导缓解、新药、靶向治疗、免疫治疗等,对一些患者可能有益.缓解后治疗仍需进一步深入研究.     

Patient-specific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia

We hypothesized that the steady-state concentration of intracellular cytarabine 5'-triphosphate (ara-CTPss) in leukemia cells is proportional to the dose rate of cytarabine (ara-C) during continuous infusion. To evaluate this possibility, patients with acute myelogenous leukemia in relapse were treated with two sequential schedules of serially increasing ara-C dose rates over a total of 36 hours. Schedule I consisted of serial infusions of 250, 500, and 750 mg/m2 each over 12 hours. Subsequently, patients entered on schedule II received 500, 1,000, and 1,500 mg/m2 serially, each over 12 hours. Steady-state levels of ara-CTP were achieved within four hours after beginning ara-C infusion and, in separate studies of a single ara-C dose rate, were shown to be maintained beyond 36 hours. Four patients treated with schedule I and two patients treated with schedule II showed a linear dose rate-dependent increase-of ara-CTPss at all three dose rates. The cells of one patient on schedule I and two patients on schedule II had a dose rate-dependent ara-CTPss increase only over the first two dose levels, while no increase or lower ara-CTPss was observed at the third dose rate. The ara-CTPss of one patient on schedule II did not change. These results suggest that there is a proportionality between the continuous infusion dose rate of ara-C and the ara-CTPss in circulating leukemia cells within the dose range of 250 to 1,000 mg/m2 over 12 hours. This opens the possibility that pharmacologic determinations may be used to redirect the ara-C dose rate to achieve a desired ara-CTPss level in leukemia blasts during therapy.     

Mitoxantrone in the treatment of relapsed and refractory acute leukemia

Twenty-four patients with acute leukemia and blast crisis of chronic myelocytic leukemia in relapse or refractory to standard chemotherapy were eligible for treatment with mitoxantrone. Mitoxantrone was administered in a dose of 8-13 mg/m2 on five consecutive days. 5 of 20 evaluable patients were induced into complete remission, 1 patient achieved a partial remission. Side effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.     

氟达拉滨联合中剂量阿糖胞苷治疗复发难治性急性髓系白血病效果观察

目的 比较氟达拉滨（FLud）联合中剂量阿糖胞苷（Ara-C）（改良FLAG方案）与CAG 预激方案治疗复发难治性急性髓系白血病（AML）的疗效及患者不良反应.方法 49例复发难治性AML 患者,随机分为两种治疗方案组,改良FLAG治疗方案组：粒细胞集落刺激因子（G-CSF）每天200 μg/m2,第0天至第5天,Flud每天30 mg/m2,第1天至第5天;Ara-C每天1 g/m2,第1天至第5天.CAG预激治疗方案为：G-CSF每天200 μg/m2,第1天至第14天,阿柔比星20 mg/d,第1天至第4天,Ara-C 10 mg/m2,1次/12h,第1天至第14天.结果 改良FLAG组完全缓解（CR）率43 ％（10/23）,部分缓解（PR）率21％（5/23）,有效率64 ％;CAG预激组CR率23％（6/26）,PR率19％（5/26）,有效率42％,两组间比较差异有统计学意义（P＜0.05）;主要不良反应为骨髓抑制、感染,改良FLAG组感染发生率70％（16/23）,CAG组感染发生率为54％（14/26）,两组间比较差异无统计学意义（P＞0.05）.结论 改良FLAG方案可有效治疗复发难治性AML患者,加强感染防控措施,缩短骨髓抑制时间.CAG方案不良反应小,可分层个体化治疗复发难治性AML患者.     

HyperCVAD/MA方案治疗难治/复发成人急性淋巴细胞白血病疗效分析

目的:评估HyperCVAD/MA方案治疗难治/复发成人急性淋巴细胞白血病(ALL)的疗效和安全性.方法:回顾性分析21例2010年1月至2016年6月应用HyperCVAD/MA方案治疗的难治/复发成人ALL患者的有效性和安全性.结果:21例患者的完全缓解(CR)率为47.6％,部分缓解(PR)率为23.8％,总有效率为71.4％.所有患者均发生Ⅲ/Ⅳ度的骨髓抑制,未发生危及生命的出血现象,其他不良反应包括感染、肝肾毒性、胃肠道反应、皮疹等,无治疗相关死亡发生.结论:HyperCVAD/MA方案治疗难治/复发成人ALL的疗效满意,不良反应可控,但长期缓解率仍有待进一步观察.     

FLAG方案治疗成年人复发难治性急性淋巴细胞白血病的疗效观察

 目的　观察FLAG方案在成年人复发难治性急性淋巴细胞白血病（ALL）诱导化疗中的疗效及安全性。方法　对2008年1月至2012年1月收治的复发难治性ALL患者（治疗组）20例,采用FLAG方案补救化疗;选择20例2002年1月至2008年1月住院的复发难治性ALL患者作为对照组,采用首次诱导方案和去甲氧柔红霉素（IDA）联合依托泊苷及大剂量甲基氢化泼尼松方案,比较两组的疗效及不良反应,应用流式细胞术（FCM）以白血病细胞特异分化抗原为标志监测两组微小残留病（MRD）,并与传统骨髓形态学结果进行比较。结果　治疗组和对照组血液学不良反应相似（P＝0.548）,治疗组其他非血液系统不良反应包括肝损伤（4／20）、心脏毒性（1／20）,较对照组（9／20 和4／20）轻;大多数不良反应均可耐受。治疗组CR 8例（40.0 %）,CR患者平均无病生存期和总生存期分别为6个月（4～30个月）和11个月（9～30个月）;对照组CR 7例（35.0 %）,CR患者平均无病生存期和总生存期分别为4个月（3～30个月）和9个月（9～30个月）,两组总生存期差异无统计学意义。治疗组早期复发率[5.0 %（1／20）]和髓外复发率（0）较对照组[20.0 %（4／20）和10.0 %（2／20）]低。结论　FLAG方案治疗成年人复发难治性ALL不良反应可耐受,为患者选择同种异基因移植争取了时间。     

Mitoxantrone and high-dose etoposide for patients with relapsed or refractory acute leukemia.

Among 35 patients with relapsed or refractory acute myelogenous leukemia (AML) who received salvage chemotherapy, 28 were treated with mitoxantrone (7.5 mg/m2/d intravenously [IV] over 1 hour for 5 days) and etoposide (VP-16) (2 g/m2 over 4 days either as a daily infusion or as two daily doses). Seven patients received mitoxantrone (6 mg/m2/d for 5 days) and VP-16 (1500 mg/m2 over 3 days). The median duration of the initial complete remission (CR) was 6 months and 83% of the patients had initial CR that lasted 12 months or less. Forty-six percent of the patients were undergoing a second or subsequent salvage attempt. Eight patients (23%) achieved CR; seven of these CR were obtained after one course of therapy. Twelve patients (33%) died and 15 patients (42%) had disease that was resistant to treatment. Patients undergoing a first salvage attempt had a higher incidence rate of CR than those undergoing a second or subsequent salvage attempt (37% versus 6%; P = 0.03). CR rates were also higher in patients with a favorable (translocation 8;21 or 15;17) or diploid karyotype compared with other patients (32% versus 8%; P = 0.10). The median survival time was 2 months for all patients and 8 months for patients achieving CR. Mucositis occurred in 74% of the patients and was severe in 32%. Diarrhea and rash occurred in less than 33% of the patients. Fever was noticed in all but 1 of the patients and documented infections occurred in 65% of the patients. Six patients had pancytopenia or thrombocytopenia that lasted more than 42 days from the initiation of treatment. Although mitoxantrone and high-dose VP-16 is an effective antileukemic regimen, it is associated with a high incidence of mucositis. Strategies that are used to limit mucosal damage may improve the tolerance of this combination.     

FLAG方案治疗难治性和复发性急性白血病的临床分析

 目的 观察由氟达拉滨（Flud）、阿糖胞苷（Ara-C）、粒细胞集落刺激因子（G-CSF）组成的FLAG方案治疗难治性、复发性急性白血病（AL）的疗效及毒副作用。方法 用FLAG方案治疗复发性ALL 7例,难治性和复发性AML3例,慢性粒细胞白血病（CML）急变2例。结果 5例（42 %）获完全缓解（CR）,1例部分缓解（PR）,且均为复发ALL。每个疗程均出现Ⅳ度血液学毒性,74 %、48 %疗程分别有发热、出血。治疗相关性死亡率17 %。非血液学毒性主要有恶心（或呕吐）、腹泻、睑结膜充血、皮疹或皮肤潮红、一过性肝损害、药物性发热。结论 FLAG方案对复发和难治性AL有一定的疗效。骨髓毒性严重,非血液学毒性轻微。     

氟达拉滨联合阿糖胞苷及粒细胞集落刺激因子治疗儿童难治及复发性急性白血病

 【摘要】　目的　观察氟达拉滨（Flud）联合阿糖胞苷（Ara-C）及粒细胞集落刺激因子（G-CSF）（FLAG）方案治疗儿童难治及复发性急性白血病（AL）的疗效及患者不良反应。方法　9例复发及难治性AL患儿接受了FLAG方案治疗,Flud 每天30 mg／m2,第1天至第5天,静脉滴注30 min;Ara-C每天2 g／m2,Flud应用后4 h静脉滴注,第1天至第5天。G-CSF 5 μg?kg-1?d-1,中性粒细胞＜0.5×109／L时开始应用,用至中性粒细胞 ≥1×109／L。9例患儿中急性髓系白血病（AML）8例,急性淋巴细胞白血病（ALL）1例;难治性AL 5例,复发性AL 4例。结果　9例患儿中经1个疗程化疗达完全缓解（CR）6例,部分缓解（PR）2例,总有效（CR+PR）率 88.9 %（8／9）。6例CR患者中2例行造血干细胞移植,现均无瘤生存;患者主要不良反应是感染、骨髓抑制和胃肠道反应。结论　FLAG方案治疗儿童难治及复发性AL缓解率高,不良反应可以耐受,是治疗儿童难治及复发性AL的一个选择,为后续的造血干细胞移植提供了机会。