复发难治性急性髓系白血病临床高危因素分析及再诱导方案疗效评估

目的 分析复发难治性急性髓系白血病（AML）患者的临床和遗传学高危因素,评估再诱导方案疗效.方法 回顾性分析296例初诊AML患者临床资料,观察其中89例复发难治性AML患者的临床特征,对比不同再诱导化疗方案的疗效.结果 与同期收治AML患者相比,初诊时高龄、复杂核型和Fms样酪氨酸激酶3内部串联重复（FLT3-ITD）基因突变是AML复发难治的高危因素（P＜0.05）.复发难治性AML患者再诱导有效率（完全缓解率＋部分缓解率）为44.90％（35/78）.其中使用原方案或无交叉耐药的新药组成联合化疗方案（方案A）再诱导有效率为35.12％（13/37）;含中、大剂量阿糖胞苷（Ara-C）方案（方案B）再诱导有效率为61.90％（13/21）;由阿柔比星或高三尖杉酯碱、小剂量Ara-C联合粒细胞集落刺激因子（G-CSF）组成的预激方案（方案C）再诱导有效率为45.00％（9/20）.方案B再诱导疗效优于方案A,差异具有统计学意义（P＜0.05）.结论 初诊时高龄、复杂核型和FLT3-ITD基因突变是AML复发难治的重要原因.不同的再诱导方案疗效存在差异,对年轻患者选择含中、大剂量Ara-C方案有助于提高再诱导缓解率.对耐受性差的患者,更适合选择预激方案以提高再诱导缓解率.     

以地西他滨为主方案治疗初发老年人急性髓系白血病近期疗效分析

目的 探讨以地西他滨为主方案治疗初发老年人急性髓系白血病(AML)的临床安全性和有效性.方法 选择2014年6月至2015年12月首都医科大学附属北京潞河医院收治的12例初发老年AML患者,应用地西他滨单药或联合低剂量化疗方案治疗,对12例患者临床资料进行回顾性分析.结果 12例患者中1个疗程达完全缓解(CR)者6例,部分缓解(PR)者5例,未缓解(NR)者1例.6例CR患者中1例在第6个疗程后复发,其余在随访中仍CR;5例PR患者中2例经2个疗程化疗后达CR,1例在第2个疗程化疗后复发,2例在第3个疗程化疗后复发.1例患者经2个疗程化疗后NR,因肺部感染死亡.4例复杂核型患者中3例疗效差,1例达CR,但最终仍复发;其余8例+8、-X或正常核型患者中7例短期达CR.主要不良反应为骨髓抑制和感染,所有患者均能耐受.结论 地西他滨单药或联合低剂量化疗方案治疗初发老年人AML近期疗效好,耐受性好,安全性高,可作为一线治疗方案.     

复发难治性弥漫大B细胞淋巴瘤的生物靶向治疗

含有利妥昔单抗的化疗方案能改善弥漫大B细胞淋巴瘤(DLBCL)患者的预后,然而仍有部分患者在一线应用R-CHOP方案后转为复发难治性DLBCL(RR-DLBCL),且预后不良.对DLBCL及其相关肿瘤基因表达研究证实基因水平的生物靶向治疗能改善RR-DLBCL患者的预后.目前,一些新的靶向治疗成为研究热点.文章就RR-DLBCL的生物靶向治疗进展进行综述.     

沙利度胺联合干扰素、白细胞介素2治疗复发难治急性髓系白血病长期生存二例并文献复习

目的 观察沙利度胺联合干扰素、白细胞介素2治疗复发难治急性髓系白血病(AML)患者长期生存的临床疗效.方法 回顾性分析2例接受沙利度胺联合干扰素、白细胞介素2方案治疗的复发难治AML患者临床资料,并进行文献复习.结果 2例AML患者治疗后达完全缓解并长期生存.结论 沙利度胺联合干扰素、白细胞介素2方案治疗复发难治AML安全、有效.     

Venetoclax联合LDAC方案治疗复发难治性急性髓细胞白血病的疗效及对血清VEGF、survivin表达水平的影响

目的 探究Venetoclax(VEN)联合低剂量阿糖胞苷(LDAC)方案治疗复发难治性急性髓细胞白血病(AML)的疗效及对血清血管内皮生长因子(VEGF)、凋亡存活蛋白(survivin)表达水平影响。方法 选择82例复发难治性AML患者,按照化疗方法不同分为观察组(n=41,VEN+LDAC治疗)和对照组(n=41,安慰剂+LDAC治疗),评价2组近期疗效、不良反应、生存时间及治疗前后血清VEGF、survivin表达水平。结果 治疗1个标准化疗方案后,观察组总缓解率高于对照组(95.12%vs 80.49%,P<0.05)。治疗后2组血清VEGF、survivin表达水平均下降,且观察组低于对照组(P<0.05)。2组患者发生低钾血症、恶心呕吐、肺部感染、白细胞减少、血小板减少等不良反应概率无显著差异(P>0.05)。治疗后随访1年,2组死亡率无显著差异(P>0.05),但观察组中位生存时间较对照组更长(P<0.05)。结论VEN联合LDAC方案治疗复发难治性AML能有效提高临床缓解率和延长生存时间,降低血清VEGF、survivin水平,且不良反应...     

复方浙贝颗粒联合吉姆单抗为主化疗治疗难治性急性髓系白血病四例

 目的　观察复方浙贝颗粒联合吉姆单抗为主化疗治疗难治性急性髓系白血病（AML）的临床疗效。方法　以2008年12月至2009年12月收治的4例难治性AML患者为研究对象,应用吉姆单抗为主化疗方案,于化疗前3 d开始服用复方浙贝颗粒,连服14 d。化疗1个周期后评价疗效。结果　第1例完全缓解（CR）,4个月后因疾病复发死亡;第2例CR,维持巩固5个月后疾病复发,再次诱导无效,复发后3个月死亡;第3例无效,于复发后8个月死亡;第4例CR。结论　复方浙贝颗粒联合吉姆单抗为主化疗治疗难治性AML可获一定疗效。     

FLAG方案与CAG方案治疗复发、难治性急性髓系白血病的疗效比较

目的:评价并比较FLAG方案与CAG方案治疗复发、难治性急性髓系白血病(acute myeloid leukemi-a,AML)的疗效及安全性。方法:将2004年1月至2011年3月于我院接受化疗的复发、难治性AML患者74例,按治疗方案分成FLAG组和CAG组,对2组的疗效及不良反应进行分析比较。结果:FLAG组完全缓解率(CR)为61.5%,总有效率为76.9%;CAG组CR为35.4%,总有效率为50%,组间比较差异有显著性意义(P<0.05)。原发难治AML、复发性AML、M1型、M2型、M5型及由骨髓增生异常综合征(myelody splastic syn-drome,MDS)转化而来的复发、难治性AML的CR率和总有效率,FLAG组均高于CAG组,组间比较差异有显著性意义(P均<0.05)。2组的血液学不良反应主要是骨髓抑制,非血液学不良反应较少。结论:CAG方案和FLAG方案均为复发、难治性AML的有效治疗方案,但FLAG方案CR率和总有效率高,不良反应可耐受,可进一步扩大临床应用。     

替雷利珠单抗桥接脐血移植治疗复发难治急性髓系白血病1例并文献复习

目的探讨替雷利珠单抗联合脐血移植在复发难治急性髓系白血病(AML)中的效果。方法回顾性分析2021年11月苏州大学附属第一医院收治的1例复发难治AML患者再诱导治疗失败后使用替雷利珠单抗桥接脐血移植的诊治过程。结果患者, 男性, 59岁, 诊断为复发难治AML。初始予地西他滨+维奈克拉方案诱导化疗后达完全缓解, 后予地西他滨+中剂量阿糖胞苷、中剂量阿糖胞苷+伊达比星等方案巩固治疗。16个月后疾病复发, 先后予克拉屈滨+阿扎胞苷+维奈克拉联合化疗和高三尖杉酯碱+阿糖胞苷+粒细胞集落刺激因子方案再诱导化疗均未缓解, 之后使用替雷利珠单抗治疗, 肿瘤负荷明显降低, 桥接脐血移植后获得完全缓解。移植后给予阿扎胞苷维持治疗。随访9个月, 患者持续缓解, 无严重移植相关并发症。结论替雷利珠单抗联合脐血移植挽救性治疗复发难治AML具有潜在应用价值。     

自体外周血造血于细胞移植联合Mylotarg治疗急性髓系白血病一例并文献复习

目的 探讨减少急性髓系白血病(AML)自体外周血造血干细胞移植(auto-PBSCT)后复发的新方法.方法 报道1例auto-PBSCT联合抗CD33,单抗(Mylotarg)治疗的AML患者,并通过长期随访了解治疗效果.结果 该患者无瘤生存3年.结论 auto-PBSCT联合Mylotarg可能为auto-PBSCT后减少白血病复发提供新的治疗方案,同时为Mylotarg的临床应用提供新途径.     

序贯性大剂量阿糖胞苷合并氨甲喋呤治疗难治性急性白血病

作者运用大剂量阿糖胞苷(AraC)合并氨甲喋呤(MTX)序贯性给药(S-HAM)方法治疗22例难治性急性髓细胞白血病(AML)及急性淋巴细胞白血病(ALL),评价其临床疗效及副作用。 22例难治性白血病病人,男11例,女11例,其中AMC 18例,ALL 4例,年龄17～66岁,平均37岁。AML、ALL按FAB协作组诊断标准诊断。难治性急性白血病的诊断标准为:①AML或ALL经常规方案化疗两个疗程无效;②第一次完全缓解后6个月以内复发;③第一次完全缓解后超过6个月以后复发,但对原诱导方案无效;④复发两次或两次以上。     

阿扎胞苷联合CAG方案再诱导治疗儿童复发难治急性髓系白血病临床观察

目的:探讨阿扎胞苷联合CAG（阿糖胞苷+阿柔比星+粒细胞集落刺激因子）方案再诱导儿童复发难治急性髓系白血病（AML）的疗效和安全性。方法:回顾性分析2018年11月至2019年8月福建医科大学附属协和医院收治的3例接受阿扎胞苷联合CAG方案再诱导治疗的复发难治AML患儿的临床资料,分析疗效、预后及不良反应发生情况。结果:3例患儿中,2例为复发AML（分别距开始治疗18个月和8个月后复发）,1例为难治AML（2个疗程标准化疗不能达完全缓解）。在2个疗程阿扎胞苷联合CAG方案再诱导后,2例达完全缓解,1例达部分缓解,之后均桥接造血干细胞移植（HSCT）。随访16~21个月（距首次阿扎胞苷联合CAG方案再诱导的时间）,患儿均为无白血病生存。除了血液学不良反应及感染外,阿扎胞苷未增加其他不良反应。结论:阿扎胞苷联合CAG方案诱导儿童复发难治AML有较高的再缓解率和安全性,及时桥接HSCT可取得较好的预后。     

Long-term results of conventional-dose salvage chemotherapy in patients with refractory and relapsed Hodgkin's disease (Croatian experience).

BACKGROUND: The aim of this study was to analyze outcome of patients with Hodgkin's disease (HD) in whom first-line chemotherapy with mustine/vincristine/procarbazine/prednisone (MOPP) had failed. PATIENTS AND METHODS: From January 1982 to December 1989 among 210 patients treated with MOPP and radiotherapy to initial bulky sites, 65 patients were primary refractory to or relapsed after initial treatment. RESULTS: Twenty-nine of 65 patients (44%) were primary refractory to initial chemotherapy, 20 relapsed within 12 months after complete remission (CR) and 16 relapsed after CR that lasted more than 12 months. Patients with primary refractory HD and early relapse (<12 months after CR) were treated with doxorubicin/bleomycin/vinblastine/darcarbazine. In patients with late relapse (>12 months after CR) MOPP was repeated. The median follow-up for all patients was 115 months. The overall response rate was 63%. Thirty-three patients (51%) achieved a second CR and eight patients (12%) partial response. Remission rate was greatest in patients with late relapse (CR >12 months) (75 versus 55% for early relapse versus 35% for primary refractory HD) (P <0.01). At 10 years, overall and failure-free survival rates were 21 and 16%, respectively. Patients who were in first remission longer than 12 months had a superior overall survival (37 versus 18% for early relapse) and failure-free survival (24 versus 10% for early relapse). No patient with primary refractory HD was alive beyond 52 months after initial treatment failure (P <0.01). Main prognostic factors were duration of the first remission and tumor bulk at relapse. CONCLUSIONS: Our results confirm previous observations that a significant proportion of patients with HD who experience induction treatment failure cannot be cured with conventional treatment and probably need more aggressive therapy.     

Prospective Monitoring of Minimal Residual Disease in Acute Myeloid Leukemia with Inversion(16) by CBFβ/MYH11 RT-PCR: Implications for a Monitoring Schedule and for Treatment Decisions

Minimal residual disease in patients with acute myeloid leukemia (AML) with inversion(16) can be monitored by CBFβ/MYH11 RT-PCR. While the association between molecular remission (MR) in bone marrow (BM) and peripheral blood (PB) and long-term clinical remission (CR) seems to be established, there are insufficient data on the kinetics of CBFβ/MYH11. We have performed a prospective study in order to generate a reasonable and sufficient schedule for PCR-monitoring. 11 patients with AML and inversion (16) in complete hematological remission have been prospectively monitored by CBFβ/MYH11 RT-PCR in their BM and PB during an observation period of 7 to 67 months (median 32 months). Patients were followed during consolidation chemotherapy with repetitive cycles of high-dose Ara-C and after autologous or allogeneic stem cell transplantation in 2^nd CR or refractory AML. MR never coincided with achievement of CR but occurred between 2 and 8 months after hematological remission. All patients in continuous CR were PCR-negative after 1-8 (median 4) months. Two patients relapsed despite MR for 10 to 15 months. Molecular relapse preceded hematological relapse by 3 to 5 months. Three out of four patients who were not in MR after 8 months relapsed. Allogeneic stem cell transplantation was able to eradicate minimal residual disease in 4/4 patients. In 2 patients a temporary reconversion to PCR-positivity was reversed by reduction of immunosuppression. 1 patient did not become PCR-negative until compete withdrawal of immunosuppression. We suggest that BM and PB should be examined after the last consolidation treatment. In case of MR, PB should be examined every 1 to 2 months and BM examination should be done only in case of PCR-positivity in PB in order to confirm the molecular relapse and to identify an impending cytogenetic and/or hematological relapse. CBFβ/MYH11 RT-PCR monitoring is able to predict relapse 3 to 5 months prior to overt hematological relapse, offers a window of opportunity for preemptive therapy of molecular relapse and confers implications for immunotherapy in the setting of allografting.     

Successful treatment of two relapsed patients with t(11;19)(q23;p13) acute myeloid leukemia by CLAE chemotherapy sequential with allogeneic hematopoietic stem cell transplantation: Case reports

The prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) is poor, with a 3-year overall survival rate of 10%. Patients with translocation (t)(11;19)(q23;p13) have a higher risk of relapse and there is no optimal regimen for these patients. The present study treated two young patients with t(11;19)(q23;p13) AML, who relapsed after one or two cycles of consolidation, with a salvage treatment consisting of sequential cladribine, cytarabine and etoposide (CLAE) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Both neutrophil and platelet engraftments were achieved within 15 days, and no severe transplant-related complications and graft-versus-host diseases were observed. Following allo-HSCT, both patients achieved complete hematologic and cytogenetic remission. Decitabine was used for the prophylaxis of relapse. The two patients remained alive and disease-free for 100 days following allo-HSCT. The results presented here suggest that CLAE regimen sequential with allo-HSCT may be effective in treating patients with R/R AML, with t(11;19)(q23;p13). However, further studies and a larger sample size are required to validate the effectiveness of this treatment regimen.     

HAA方案诱导治疗初治及复发、难治急性髓系白血病临床分析

  目的　探讨HAA方案诱导治疗初治及复发、难治急性髓系白血病（AML）的疗效和安全性。方法　回顾性分析行HAA方案治疗的66例AML患者的资料,按临床病理因素进行分层分析,观察疗效及不良反应情况。结果　66例患者中初治AML 45例,可评价疗效41例,诱导化疗后36例完全缓解,1例部分缓解,总有效率为90.2 %（37／41）;难治复发AML 21例,其中9例获得完全缓解,有效率为42.9 %（9／21）。HAA方案在性别、年龄、入院时白细胞数目和疾病亚型各分层内缓解率差异无统计学意义（均P＞0.05）。14例初治完全缓解病例随访2～19个月,中位随访10个月,持续缓解中位时间为9个月（2～17个月）,其中5例（35.7 %）巩固化疗期间复发。HAA方案的骨髓抑制中位时间为14 d（3～23 d）。主要不良反应为不同程度的恶心、呕吐[20 %（13／66）],腹痛、腹泻[9 %（6／66）]及化疗相关感染[53 %（35／66）],未见其他严重的非血液学不良反应。结论　HAA方案对于初治及复发、难治AML均能获得较高的有效率,且安全性较好。     

Gemtuzumab Ozogamicin Combined With Intensive Chemotherapy in Patients With Acute Myeloid Leukemia Relapsing After Allogenic Stem Cell Transplantation

BackgroundMore than one-third of patients with acute myeloid leukemia (AML) will relapse after allogenic hematopoietic cell transplant (allo-HCT). The main challenge is to overcome disease resistance to achieve a new complete remission while avoiding excessive toxicity. Gemtuzumab ozogamicin (GO), a conjugate of calicheamicin linked to the humanized monoclonal anti-CD33 antibody, has been used for refractory or relapsed AML with promising response rates, but liver toxicity of GO has long been considered a limiting factor.Patients and MethodsWe included 18 consecutive patients with AML relapsing after a first allo-HCT and treated with fractioned GO (fGO) and intensive chemotherapy. The median age was 40 years (range, 18-65).ResultsThe overall response rate was 72% (13/18), including 7 complete remissions. No death was attributed to treatment toxicity. The main liver toxicity was transient and consisted of transaminase level elevation and hyperbilirubinemia. No cases of veno-occlusive disease were observed after the GO treatment. From the time of salvage treatment initiation, 1- and 2-year OS rates were 54% (95% confidence interval, 28%-74%) and 42% (95% confidence interval, 19%-63%), respectively.ConclusionsOur study suggests the feasibility, efficacy, and safety of an fGO-based salvage regimen combined with intensive chemotherapy in patients with CD33+ AML in the case of early relapse after an allo-HCT.     

维奈克拉在复发 难治性急性髓细胞白血病治疗中的应用

复发/难治性急性髓细胞白血病（relapsed/refractory acute myeloid leukemia,R/R AML）患者预后差、死亡率高,是AML治疗的难点之一。BCL-2抑制剂维奈克拉在2018年被美国食品药品监督管理局（FDA）批准用于治疗老年或不能耐受强化治疗的AML患者。近年来,含维奈克拉的方案用于治疗R/R AML展现出一定的疗效,包括联合去甲基化药物、化疗药物、分子抑制剂和桥接同种异基因造血干细胞移植（allogenic hematopoietic stem cell transplantation,allo-HSCT）。此外,allo-HSCT后衔接维奈克拉维持治疗可有效预防AML移植后复发,并能够延长复发患者的生存期。维奈克拉的不良反应发生率低,患者对其具有较好的耐受性。本文主要围绕维奈克拉用于R/R AML的治疗疗效和不良反应的最新进展进行综述。      

复发难治急性髓系白血病靶向治疗研究进展

当前复发难治急性髓系白血病（AML）的治疗仍然具有挑战性，复发难治AML患者还没有标准的治疗方法。目前研究认为参与涉及小分子靶向治疗、免疫治疗和表观遗传治疗等新疗法的临床试验可能是最好的选择，但临床试验治疗的有效性和不良反应尚未得到广泛评估，患者的长期生存尚不清楚，所以复发难治AML患者的预后仍然很差。未来研究方向将集中在新颖、有效和有针对性的治疗组合，以及低毒性、个性化和精准化的治疗策略上。文章综述了复发难治AML靶向治疗研究的最新进展。     

Definition of refractoriness against conventional chemotherapy in acute myeloid leukemia: a proposal based on the results of retreatment by thioguanine, cytosine arabinoside, and daunorubicin (TAD 9) in 150 patients with relapse after standardized first line therapy

Response to salvage therapy at first and second relapse was analyzed in 150 patients with acute myeloid leukemia (AML) to improve the characterization of relapsed AML and to deduce from this analysis a proposal for the definition of refractoriness against conventional therapy. Salvage treatment consisted of a repetition of the TAD 9 regimen which was already applied as induction protocol at initial diagnosis. All patients were recruited from the multicenter 1982 trial of the German AML Cooperative Group and had thus received a standardized first line treatment. Response at first relapse was significantly related to the duration of the first remission. From 38 patients relapsing within 6 months after successful induction therapy, only 11 (28%) achieved a second complete remission as compared to 58 of 98 (59%) cases with later occurring relapses (p less than 0.01). This difference was due to a significantly higher incidence of persistent leukemia in the former group and not biased by differences in early death rates. No other variable was found predictive for the response to salvage treatment including age, WBC, serum LDH, morphologic subtype, presence or absence of DNA aneuploidy as detected by flow cytometry or maintenance chemotherapy. A low remission rate of 28% was also obtained in the 14 patients at second relapse. These data indicate that patients with a duration of their first remission of more than 6 months cannot be considered as being refractory against standard chemotherapy while patients with early relapses and second recurrences have a response rate of less than 30% due to refractory disease. Hence, the following criteria are proposed for the definition of refractoriness against standard chemotherapy in advanced AML: (a) nonresponse to first-line induction therapy, (b) early relapse within 6 to 12 months of first remission, (c) relapse after 6 to 12 months of first remission and failure on a reinduction attempt with established regimens, (d) second and subsequent relapses. These criteria may provide a useful rationale for the selection of the most appropriate treatment at relapse. They may also serve as eligibility criteria for clinical phase I/II studies and will facilitate interstudy comparisons.     

Gemtuzumab ozogamicin (Mylotarg) in children with refractory or relapsed acute myeloid leukemia

BACKGROUND: Gemtuzumab ozogamicin (GO) is an immunoconjugate consisting of the CD33 antibody and calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. PATIENTS AND METHOD: We report 12 children with multiple relapsed or refractory AML receiving GO as compassionate use. 11 children had initially been treated according to the AML-BFM 93 or 98 protocol, 1 girl received relapse treatment (liposomal daunorubicin/FLAG) due to secondary AML. After relapse, 10 children received an intensive relapse therapy (AML-BFM 97 or international AML-Relapse Study 2001/01). 2 of them had been transplanted in first or second CR before GO therapy. RESULTS: 5 of 12 children responded to treatment with blast reduction to below 5%, but no child achieved CR after GO. Time until reoccurrence of blasts in almost all children with GO response was 3-8 months. In 5 children stem cell transplantation (SCT) was performed after GO therapy. 4 of them suffered from further progression of AML, 1 boy is in second remission with a follow-up of 8 months. 2 children had severe side effects. An anaphylactic reaction with severe hypotension was managed by catecholamine support and intensive care. In 1 girl, who relapsed after SCT in first remission, a veno-occlusive disease of the liver occurred, but could be treated successfully with defibrotide. CONCLUSION: GO therapy can induce blast reduction in children who have no further conventional treatment options. Frequency and severity of adverse events are limited, and therapy seems to be feasible for children with a sufficient general condition. Controlled studies are necessary to learn more about efficacy and side effects, especially implications for further therapy.