Cladribine- and decitabine-containing conditioning regimen has a low post-transplant relapse rate in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning regimens. Our study aimed to analyze the risk factors associated with the relapse of relapsed/refractory (R/R), high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) post-transplant and the efficacy of a new conditioning regimen involving decitabine and cladribine. Clinical data of 125 patients with R/R AML, high-risk AML and high-risk MDS who underwent allo-HSCT were collected. In addition, 35 patients with R/R AML, high-risk AML and high-risk MDS received treatment with a new conditioning regimen including decitabine and cladribine. Cox regression analysis was used to identify risk factors associated with OS, RFS and relapse. Among 125 patients who underwent allo-HSCT, CR before allo-HSCT and matched sibling donors were independent protective factors for OS. DNMT3A abnormality was an independent risk factor for both relapse and RFS. Among 35 patients who received a new conditioning regimen containing decitabine and cladribine, only six patients relapsed and 1-year cumulative incidence of relapse was 11.7%. Moreover, this new regimen showed efficient MRD clearance early after allo-HSCT. The combined decitabine- and cladribine-based conditioning regimen showed a low relapse rate and a high survival without an increased incidence of GVHD or adverse effects and thus has potential for use in allo-HSCT for R/R AML, high-risk AML and high-risk MDS.     

地西他滨联合HIA方案治疗复发难治性急性髓系白血病的临床观察

目的 探讨地西他滨（DAC）联合HIA方案（高三尖杉酯碱、阿糖胞苷和去甲氧柔红霉素）和FLAG方案（氟达拉滨、阿糖胞苷和粒细胞集落刺激因子）治疗复发难治性急性髓系白血病（AML）的疗效及不良反应。方法 回顾性分析50例复发难治性AML患者分别采用DAC+HIA方案（观察组,n=17）和FLAG方案（对照组,n=33）作为诱导方案的疗效和不良反应,计算完全缓解率、总有效率（RR）和不良反应发生率。采用Kaplan Meier法进行生存分析并行Log-rank检验。结果 观察组完全缓解率为64.7％,高于对照组的33.3％ （P＜0.05）;观察组和对照组的RR分别为76.5％和60.6％ （P＞0.05）。观察组的中位总生存期（OS）与中位无复发生存期（RFS）均未达,死亡率和复发率为35.3％和18.2％;对照组的中位OS和中位RFS为654 d和612 d,死亡率和复发率为42.4％和45.5％,差异无统计学意义（P＞0.05）。两组不良反应发生率的差异无统计学意义（P＞0.05）,主要不良反应为感染。结论DAC联合HIA方案作为首选治疗复发难治性AML与FLAG方案总体疗效相当,且完全缓解率更高,不良反应可耐受。     

High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia

Background: The bcl-2 oncoprotein is suggested to be directly involved in the emergence of drug resistance by disrupting or delaying the apoptotic program and promoting tumor survival.Patients and methods: In order to define the clinical relevance of the bcl-2 mRNA expression in acute myeloid leukemia (AML) and its correlation to therapy outcome and prognosis, we analyzed 219 AML bone marrow (BM) samples, including 119 patients with de novo AML at presentation, 37 with AML following myelodysplastic syndrome (MDS), as well as 42 BM samples of AML in relapse and 21 in complete remission (CR) using RT-PCR. For performing quantitative measurements of bcl-2 mRNA, we developed a quantitative RT-PCR.Results: Bcl-2 mRNA was detectable in 133 of 156 (84%) patients at diagnosis and 40 of 42 (95%) at relapse. AML patients with high bcl-2 mRNA expression achieved lower CR rates than those with no or low expression. Concerning the long-term outcome, the overall (OS) and disease-free survival (DFS) was significantly worse in AML patients with high expression levels of bcl-2 mRNA. The three-year OS for all newly diagnosed AML patients was 49% and 10% (P = 0.028), respectively, and 71% and 15% (P = 0.0004) for patients <60 years. Comparable significant differences were observed for the DFS.In AML following MDS and patients >60 years, the bcl-2 expression was not associated with remission rate or survival.Conclusions: The expression of bcl-2 mRNA may serve as a prognostic factor predicting remission outcome and long-term prognosis in AML.     

Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience

IntroductionMutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes.Patients and MethodsIn this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML.ResultsPatients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15).ConclusionAmong patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).     

伴Fms样酪氨酸激酶3内部串联重复的急性髓系白血病临床特点及预后分析

目的 探讨Fms样酪氨酸激酶3内部串联重复(FLT3-ITD)的急性髓系白血病(AML)患者的临床特点及预后.方法 回顾性分析2011年6月至2014年3月收治的39例FLT3-ITD的AML患者临床资料.结果 FLT3-ITD突变的发生率为11.6％(39/337),39例FLT3-ITD AML患者中,M5所占比例最高(43.6％,17/39),其次为M2(28.2％,11/39);外周血白细胞计数平均为88.63×109/L,其中12例(30.8％)大于100×109/L;骨髓原始细胞比例平均为82.53％,其中33例(84.6％)大于50.00％.13例发生髓外浸润;17例核型正常,9例核型异常,3例未见核分裂象;13例患者伴随NPM1突变,2例伴有KIT突变,3例伴有DNMT3突变.37例接受治疗的患者中,第1个疗程获完全缓解(CR)16例(43.2％),第2个疗程获CR 4例(10.8％),2个疗程累积CR率为54.0％,诱导治疗相关病死率为21.6％ (8/37),死亡原因主要为感染及出血.中位随访时间12个月,20例CR患者的复发率为50.0％(10/20),无复发生存(RFS)率为45.0％(9/20);移植组17例患者的总生存及RFS均优于单纯化疗组的20例患者(P=0.004、0.020).结论 FLT3-ITD AML具有初发时外周血白细胞计数及骨髓原始细胞比例高、与M5亚型高度伴随的临床特点,异基因造血干细胞移植能明显提高患者总生存期及无复发生存期.     

急性白血病细胞P-gp LRP的表达及其临床意义

目的：研究急性白血痛细胞P-糖蛋白（P—gp）、肺耐药蛋白（LRP）的表达情况，观察其表达率与临床症状及化疗缓解率的关系。方法：利用P—gp、LRP单克隆抗体，采用流式细胞技术分别测定15例正常对照和79例急性白血病（AL）患者P-gp、LRP的表达率，分析两种蛋白表达的临床意义。结果：初治急性淋巴细胞白血病（ALL）组P—gp、LRP的表达率均高于初治急性髓细胞白血病（AML）组（P〈0．01），复发／难治ALL组P—gp的表达率与复发／难治AML组相比无显著性差异（P〉0．05），而LRP的表达率较复发／难治AML组的表达率高（P〈0．01）。复发／难治组P—gp、LRP的表达率均高于相应的初治组（P〈0．05）。急性白血病患者P—gp、LRP的表达之间无相关性（L=0．0746，P〉0．05）。急性白血病细胞P—gp^＋／LRP^＋组缓解率低于P—gp^＋／LRP^-、P—gp^-／LRP^＋组（P〈0．05），并明显低于P—gp^-／LRP^-组（P〈0．01）。结论：复发／难治组P—gp、LRP的表达率高于初治组，而两者的表达率无相关性。P—gp、LRP表达阳性的患者缓解率低，且易出现髓外浸润。同时检测P—gp、LRP的表达较单独检测一种蛋白更具有临床意义。     

Glutathione S-transferases (GSTT1 and GSTM1) genes polymorphisms and the treatment response and prognosis in Chinese patients with de novo acute myeloid leukemia

We investigated the prognostic significance of genetic polymorphism for glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase mu 1 (GSTM1) in 254 Chinese patients with de novo acute myeloid leukemia (AML) other than AML-M3. The early death rate after the initiation of chemotherapy was similar between the GSTT1+/GSTM1+ group and GSTT1−/GSTM1− group. The complete remission (CR) rate was higher in GSTM1+ group than in GSTM1− group (OR = 1.88; P = 0.03) after the first course of chemotherapy, and was higher in GSTT1+ group than in GSTT1− group (OR = 2.20; P = 0.02) after the second course of chemotherapy. Overall survival and disease-free survival of CR patients in GSTT1 and GSTM1 double present group was better than in GSTT1- and/or GSTM1-group (P = 0.03 and 0.02, respectively). Our preliminary results warrant testing of a larger number of patients.     

银屑病相关急性白血病39例临床分析

目的 探讨银屑病相关急性白血病患者的临床特征、疗效及预后。方法 收集2011年1月至2016年6月山西医科大学第二医院39例银屑病相关急性白血病住院患者的临床资料,对其临床特点及预后进行分析。结果 39例患者中,男性28例,女性11例,中位年龄42岁（13~76岁）,中位银屑病史10年（1~30年）;急性早幼粒细胞白血病（APL）23例（59.0%）,急性髓系白血病（AML）13例（33.3%）,急性B淋巴细胞白血病（B-ALL）3例（7.7%）;复发9例,其中APL 4例,AML 4例,B-ALL 1例。单因素分析显示,PML-RARα融合基因异构体类型和银屑病史为APL复发患者的影响因素（均P〈0.05）,但多因素分析显示两者均不是独立危险因素（均P〉0.05）。银屑病相关APL和AML患者的完全缓解（CR）率分别为96%（22/23）、46%（6/13）,3年总生存（OS）率分别为96%、44%,3年无复发生存（RFS）率分别为77%、38%。结论 银屑病相关急性白血病患者以APL居多,预后较好;银屑病相关AML、ALL患者CR率及长期生存率低,后期应考虑进行异基因造血干细胞移植。     

Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup.

PURPOSE: To evaluate prognostic factors for relapse-free survival (RFS) and overall survival (OS) and to assess the impact of different postremission therapies in adult patients with core binding factor (CBF) acute myeloid leukemias (AML). PATIENTS AND METHODS: Individual patient data-based meta-analysis was performed on 392 adults (median age, 42 years; range, 16 to 60 years) with CBF AML (t(8;21), n = 191; inv(16), n = 201) treated between 1993 and 2002 in prospective German AML treatment trials. RESULTS: RFS was 60% and 58% and OS was 65% and 74% in the t(8;21) and inv(16) groups after 3 years, respectively. For postremission therapy, intention-to-treat analysis revealed no difference between intensive chemotherapy and autologous transplantation in the t(8;21) group and between chemotherapy, autologous, and allogeneic transplantation in the inv(16) group. In the t(8;21) group, significant prognostic variables for longer RFS and OS were lower WBC and higher platelet counts; loss of the Y chromosome in male patients was prognostic for shorter OS. In the inv(16) group, trisomy 22 was a significant prognostic variable for longer RFS. For patients who experienced relapse, second complete remission rate was significantly lower in patients with t(8;21), resulting in a significantly inferior survival duration after relapse compared with patients with inv(16). CONCLUSION: We provide novel prognostic factors for CBF AML and show that patients with t(8;21) who experience relapse have an inferior survival duration.     

大剂量阿糖胞苷巩固治疗急性髓系白血病患者的疗效及预后分析

目的:探讨大剂量阿糖胞苷（HDAC）用于急性髓系白血病(AML)患者完全缓解后巩固治疗的安全性及预后分析。方法:回顾性分析2016年03月至2020年03月就诊空军军医大学第二附属医院血液科的49例接受HDAC方案作为巩固治疗的AML患者,观察巩固治疗中三系细胞减少持续时间、输血量及治疗中的不良事件,记录OS及RFS时间,并进行基因突变与预后分析。结果:49例患者共进行121个疗程,中位2.7（1~4）个疗程。巩固化疗期间共发生感染34例次（28.1%）。2年RFS率及OS率分别为64.3%、76.8%。多因素分析结果提示巩固化疗次数和伴有FLT3-ITD基因突变是影响患者复发的独立预后不良因素（P值分别为0.019和0.024）。而复发是影响OS的独立预后不良因素（P=0.008）。结论:HDAC用于AML患者巩固治疗的安全性好。巩固治疗≤2次是导致疾病复发的不良因素,伴有FLT3-ITD基因突变不能从HDAC中获益。     

HFE gene mutations in patients with acute leukemia

An increased incidence of HFE gene mutations has been described in hematologic malignancies. In the present study, we investigated the allelic frequency of HFE gene mutations in 154 adult patients with acute leukemia (AL) [107 acute myeloid leukemia (AML), 20 acute promyelocytic leukemia (APL) and 27 acute lymphoblastic leukemia (ALL)]. The allelic frequency of the H63D mutation was 29% in AL patients and 25% in the healthy controls [P = 0.41; odds ratio (OR) = 1.20; 95% confidence interval (CI) = 0.77 - 1.93]. No difference was found between controls and AML or APL patients, whereas the H63D mutation was significantly more frequent in ALL than controls (44% vs. 25%, P = 0.04; OR = 2.37; 95% CI = 1.05 - 5.36). The overall comparison of the mutation among the three subtypes of AL demonstrated a higher allelic frequency in ALL (P = 0.02). In conclusion, our data demonstrate a correlation between the presence of the H63D mutation and the occurrence of ALL in adult patients.     

Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations.

To explore the validity and prognostic significance of minimal residual disease detection by quantitative polymerase chain reaction (qPCR) in patients of acute myeloid leukemia (AML) bearing Nucleophosmin (NPM1) mutations, we quantified mutants in 194 bone marrow samples from 38 patients with a median follow-up time of 20.6 months. Following induction chemotherapy, a median of 2.78 log decline in mutant copy number was observed. Relapse was always accompanied by significant increase of mutant numbers (P<0.001). After achieving complete remission (CR), the mutant copy number was significantly higher in patients with subsequent relapse than in those remaining in continuous CR (P<0.001). Presence of detectable mutants after treatment predicted relapse if no further chemotherapy was administered. Furthermore, the patients with any rise of mutant signals during serial follow-up had 3.2-fold increase of relapse risk compared to those with persistently low or undetectable signals (P<0.001). Patients who could achieve mutant reduction to <0.1% of internal control had significantly longer overall survival (OS) (P=0.004) and relapse-free survival (RFS) (P<0.001). Failure to achieve 2 logs of reduction after consolidation predicted shorter OS (P=0.01) and RFS (P=0.001). In conclusion, qPCR monitoring may have prognostic impact in AML patients with NPM1 mutations.     

CCDC8和TGF-β1在非小细胞肺癌中的表达及临床意义

目的 探讨CCDC8和TGF-β1在非小细胞肺癌中的表达及其与临床病理特征的关系。方法 比较TCGA数据库正常肺组织与肿瘤组织中CCDC8和TGF-β1的表达量,分析非小细胞肺癌中CCDC8和TGF-β1表达的相关性。免疫组织化学染色检测204例常规石蜡包埋非小细胞肺癌组织CCDC8、TGF-β1表达并分析其与肺癌临床病理特征关系。利用Kaplan-Meier法绘制生存曲线,应用Cox回归分析CCDC8、TGF-β1表达与患者总生存期(OS)的关系。结果 TCGA数据中正常肺组织CCDC8与TGF-β1表达较肿瘤组织中高(P＜0.05),非小细胞肺癌患者CCDC8表达与TGF-β1表达呈正相关(P＜0.0001);鳞癌中CCDC8低表达患者OS长(HR=1.32,P=0.0437)。204例非小细胞肺癌组织中,CCDC8表达与TGF-β1表达呈正相关(P=0.023)。Cox单因素分析鳞癌中CCDC8表达与OS有关(P=0.013);而CCDC8和TGF-β1表达与腺癌患者生存无关(P=0.967,P=0.816)。Cox多因素分析TNM分期、CCDC8表达是肺鳞癌患者预后因子(P=0.016)。结论 非小细胞肺癌中CCDC8表达与TGF-β1表达正相关,CCDC8可能是肺鳞癌患者预后因子。     

Clinical Significance of Co-expression of Aberrant Antigens in Acute Leukemia: A Retrospective Cohort Study in Makah Al Mukaramah,Saudi Arabia

Background: Aberrant phenotypes in acute leukemia have variable frequency and their prognostic andpredictive relevance is controversial, despite several reports of clinical significance. Aims: To determinethe prevalence of aberrant antigen expression in acute leukemia, assess clinical relevance and demonstrateimmunophenotype-karyotype correlations. Materials and Methods: A total of 73 (40 AML and 33 ALL) newlydiagnosed acute leukemia cases presenting to KAMC, Kingdom of Saudi Arabia, were included. Diagnosis wasbased on WHO criteria and FAB classification. Immunophenotyping by flow cytometry, conventional karyotypingand fluorescence in situ hybridization for gene rearrangements were performed. Results: Aberrant antigens weredetected in 27/40 (67.5%) of AML and in 14/33 (42.4%) in ALL cases. There were statistically significant higherTLC in Ly+ AML than in Ly-AML (p=0.05) and significant higher blast count in ALL with aberrant antigensat presentation and day 14 (p=0.005, 0.046). There was no significant relation to clinical response, relapse freesurvival (RFS) or overall survival (p>0.05), but AML cases expressing ≥2 Ly antigens showed a lower medianRFS than those expressing a single Ly antigen. In AML, CD 56 was expressed in 11/40. CD7 was expressed in7/40, having a significant relation with an unfavorable cytogenetic pattern (p=0.046). CD4 was expressed in 5/40.CD19 was detected in 4/40 AML associated with M2 and t (8; 21). In ALL cases, CD33 was expressed in 7/33and CD13 in 5/33. Regarding T Ag in B-ALL CD2 was expressed in 2 cases and CD56 in 3 cases. Conclusions:Aberrant antigen expression may be associated with adverse clinical data at presentation. AML cases expressing≥2 Ly antigens may have shorter median RFS. No specific cytogenetic pattern is associated with aberrant antigenexpression but individual antigens may be related to particular cytogenetic patterns. Immunophenotype-karyotypecorrelations need larger studies for confirmation.