FLAG方案治疗复发/难治的急性髓系白血病患者的临床研究

目的研究FLAG方案治疗复发和难治的急性髓系白血病患者的疗效。病例与方法采用FLAG治疗的为复发和难治性的18～60岁的AML患者,急性早幼粒细胞白血病除外。同时选择既往采用非FLAG治疗的患者作为历史对照组。FLAG方案,即:氟达拉滨30mg/m~2,d1～d5,Ara-C 2g,d1～d5,粒细胞集落刺激因子(G-CSF)5μg/ kg d0直到白细胞恢复超过>1.5×10~9/L。结果FLAG治疗组患者21例完全缓解(CR),CR率为53.85%;对照组患者8例完全缓解,CR率为24.24%;FLAG治疗组患者CR率显著高于对照组(P<0.05)。治疗组患者中位随访时间为7个月(0～17个月),中位OS为6个月(0～17个月)。21例CR的患者随访PFS,中位PFS为10个月(4～17个月)。结论FLAG方案是复发、难治的急性髓系白血病患者治疗的较好选择。     

BCL-2抑制剂Venetoclax联合阿扎胞苷治疗难治复发急性髓系白血病1例

<正>近年来出现不少 急性髓系白血病(acute myeloid leukemia, AML)的治疗新药,其中对于年龄<60岁的复发AML,《中国复发难治性急性髓系白血病诊疗指南》(2021年版),建议可选择BCL-2抑制剂Venetoclax(维奈克拉)联合去甲基化的治疗方案,但由于BCL-2抑制剂在国内尚未正式获批,导致临床使用率并不高,我们现报道1例中年女性复发AML患者使用该方案后得到完全缓解的个案,     

三氧化二砷辅助治疗难治或复发急髓白血病的疗效观察

目的:研究三氧化二砷（As2O3）联合小剂量高三尖杉酯碱（homoharringtonine,HHT）、阿糖胞苷（Ara-c）治疗难治或复发性急性髓细胞白血病（relapsed acute myeloid leukemia,RAML）的疗效及不良反应。方法:难治或复发性急性髓细胞白血病患者180例随机分成两组:研究组94例,方案:三氧化二砷10mg/日,d1-5、d8-12静脉滴注,高三尖杉酯碱1mg/日,d1-14静脉滴注,阿糖胞苷25mg,皮下注射2次/日,d1-14。对照组86例,给予标准剂量HA方案:用药剂量疗程同前,不加As2O3。 结果:研究组68例获得完全缓解（CR）,CR率72.3％（68/94）,13例获得部分缓解（PR）,总有效率（ORR）86.2％（81/94）。对照组CR率54.7％（47/86）,9例PR,总有效率65.1％。两组比较研究组完全缓解率、部分缓解率以及总有效率均优于对照组（P＜0.05）,不良反应发生率研究组与对照组无显著差异（P＞0.05）。结论:小剂量阿糖胞苷方案治疗难治复发性AML的疗效比标准剂量HA方案疗效优越,化疗相关不良反应无显著差异。     

CLAG方案治疗复发难治急性髓系白血病的疗效观察

目的:评价CLAG方案（2-CdA+Ara-C+G-CSF）治疗复发难治急性髓系白血病的疗效及安全性。方法:回顾性分析我中心2015年6月至2016年8月应用CLAG方案治疗的12例复发难治急性髓系白血病患者。结果:12例患者均系复发难治急性髓系白血病,根据NCCN急性髓系白血病指南（2017年第1版）细胞遗传学及分子生物学标记,进行危险度分级,其中预后良好组3例,预后中等组5例,预后不良组4例。所有患者均给予1疗程CLAG方案化疗,其中8例（72.7%）达到完全缓解（CR）,2例（18.2%）达到部分缓解（PR）,总有效率（OR）90.9%。所有患者均出现Ⅲ-Ⅳ级血液学毒性,主要毒副反应为粒细胞缺乏及血小板减少所导致的感染和出血,其中肺部感染8例（72.7%）,侵袭性真菌病5例（45.5%）,革兰阴性杆菌败血症2例（18.2%）。6例患者（54.5%）发生Ⅲ-Ⅳ级出血,1例因弥漫性肺泡出血早期死亡。化疗所致恶心呕吐、肝肾毒性、口腔黏膜炎等非血液学毒性均为Ⅰ-Ⅱ级。结论:CLAG方案治疗复发难治性急性髓系白血病有效率较高。化疗所致骨髓抑制较重,但合并感染、出血可控制,非血液学毒性轻微,安全性较好,可作为复发难治急性髓系白血病挽救性治疗的首选方案。     

Phase 2 randomized study of p53 antisense oligonucleotide (cenersen) plus idarubicin with or without cytarabine in refractory and relapsed acute myeloid leukemia

BACKGROUND:

The p53 antisense oligonucleotide cenersen has been shown to sensitize acute myeloid leukemia (AML) stem cells to DNA damaging agents.

METHODS:

To determine whether cenersen merits testing in larger efficacy studies, an exploratory study of cenersen in combination with idarubicin either alone or with 1 of 2 doses of cytarabine was performed in first‐salvage AML patients. Patients who either had failed to respond to a single induction course or had responded to induction but relapsed within 12 months were enrolled. Stopping rules based on an expected 14% complete response (CR) rate were applied to each treatment arm.

RESULTS:

Fifty‐three patients were treated, and none of the arms was terminated for lack of activity. Nearly all patients received a single course unless they responded. Ten of the 53 (19%) patients responded (8 CR and 2 CR with incomplete platelet recovery). There was a positive trend for a better response rate with increasing intensity of chemotherapy in the patients refractory to front‐line treatment compared with those who had relapsed previously. One‐third (17/53) of the patients received cenersen inhibitors (acetaminophen and/or high dose antioxidants) during treatment, and none of these responded to treatment. No unique toxicity was attributed to cenersen.

CONCLUSION:

The results of this study suggested that the combination of cenersen with chemotherapy may have clinical efficacy, and additional studies are warranted to explore its full potential. Cancer 2011;. © 2011 American Cancer Society.     

FLAG方案治疗小儿复发难治性急性白血病临床研究

目的探讨FLAG方案（氟达拉滨,阿糖胞苷,粒细胞集落刺激因子）治疗小儿复发难治性急性白血病的疗效。方法采用FLAG方案[氟达拉滨30mg／（m^2·d）X5＋阿糖胞苷2g／（m^2·d）×5d＋粒细胞集落刺激因子5μg/（kg·d）]治疗21例2—13岁的小儿复发难治性急性白血病,其中急性非淋巴细胞性白血病（AML）15例,急性淋巴细胞性白血病（ALL）6例。首次复发（R1）后首选FLAG方案者8例,次选10例,原发难治2例,第三次缓解（CR3）后FLAG巩固治疗1例。结果21例患儿中1例作为缓解后巩固治疗,1例因化疗后感染死亡而无法评估FLAG应用后缓解率;其他19例可评估患儿中9例（47％）获完全缓解（CR）,3例（16％）部分缓解（PR）,7例（37％）无效（NR）,总有效率63％。其中AMLCR率57％,ALL为20％;R1后首选FLAG方案者CR率为57％,次选为20％。应用FLAG后患儿中性粒细胞〉0．5×10^9／L的中位时间为21（12～36）天,血小板〉20×10^9/L的中位时间为19．4（13～30）天。21例患儿中18例合并感染（86％）,除1例死亡外其余均得到有效控制,治疗相关死亡率为4．76％。FLAG治疗后7例患儿进行了造血干细胞移植治疗,目前2例无病存活,分别已移植后无病生存14个月和56个月,其他4例死于移植相关并发症,1例死于移植后复发。另外14例非移植患儿中1例因FLAG相关感染死亡,7例因NR而放弃治疗或合并感染死亡,FLAG治疗有效的6例患儿中2例放弃治疗,4例复发死亡。本组患儿FLAG治疗后中位生存时间5个月。结论FLAG方案治疗小儿复发难治性白血病疗效肯定,毒副作用可以耐受;AML选择FLAG的疗效优于ALL;复发后首选FLAG治疗效果好于次选者。     

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Adult patients with relapsed/refractory (R/R) B‐precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T‐cell engager (BiTE) immuno‐oncology therapy with dual specificity for CD19 and CD3 that redirects patients’ CD3‐positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open‐label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B‐precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/day during weeks 2‐4, with a 2‐week treatment‐free interval (6‐week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose‐limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5‐6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL.     

CLAG方案和MEA方案治疗复发/难治急性髓系白血病的疗效比较

目的:探讨CLAG方案（克拉屈滨+阿糖胞苷+重组人粒细胞刺激因子）和MEA方案（米托蒽醌+依托泊苷+阿糖胞苷）在治疗难治/复发急性髓系白血病（RR-AML）患者中的疗效及其安全性,并分析在难治性AML患者中应用两种方案的优劣性,为RR-AML的治疗提供依据。方法:回顾性分析44例RR-AML患者,比较CLAG组（n=20）和MEA组（n=24）临床疗效,并观察两种方案的不良反应发生情况,进一步比较CLAG方案和MEA方案在治疗20例难治性AML患者中的临床疗效。结果:CLAG组患者的完全缓解(CR)率40.0 %（8/20）高于MEA组29.2 %（7/24）,但是两组之间比较,差异并无统计学意义（χ2=1.104,P=0.766）;CLAG组患者中位无进展生存期（PFS）和总生存期（OS）均优于MEA组,并且差异性显著有统计学意义（χ2=6.834,P=0.004;χ2=6.883,P=0.001）;CLAG组肺部感染发生率较MEA组高,且差异有统计学意义（χ2=8.826,P=0.033）,粒细胞缺乏发生率亦高于MEA组,但差异无统计学意义（P＞0.05）。难治性AML患者CLAG方案治疗的中位OS、PFS均优于MEA方案治疗患者,但差异均无统计学意义（χ2=1.037,P=0.820;χ2=0.463,P=1.000）。结论:CLAG方案可作为RR-AML患者一线挽救治疗方案,不良反应可控,以期再次达到CR,获得造血干细胞移植机会。     

A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m², rituximab 375 mg/m² (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography–computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.     

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.     

Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open‐label phase 1 study

Gilteritinib, a novel, highly specific, potent fms‐like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open‐label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once‐daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty‐four Japanese patients with R/R AML received once‐daily oral gilteritinib in 1 of 6 dose‐escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose‐limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug‐related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose‐proportional PK profile. Among patients with mutated fms‐like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild‐type fms‐like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.