Chidamide,Decitabine,Cytarabine,Aclarubicin,and Granulocyte Colony-stimulating Factor Therapy for Patients with Relapsed/Refractory Acute Myeloid Leukemia:A Retrospective Study from a Single-Center

Objective Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia.However,their efficacy in patients with relapsed/refractory acute myeloid leukemia(R/R AML)remains unclear.Methods Clinical data of R/R AML patients who received a CDCAG regimen(chidamide,decitabine,cytarabine,aclarubicin,and granulocyte colony-stimulating factor)from July 1,2018 to October 31,2021 at our center were retrospectively assessed,and the safety and efficacy of the CDCAG regimen were evaluated.Patients were followed up until November 30,2021,with a median follow-up of 21.6 months(95%CI:10.0–33.2 months).Results A total of 67 patients were enrolled.Two patients died within 3 weeks after the initiation,and therefore only 65 patients underwent the assement for clinical response and survival.It was found that 56.9%patients achieved complete remission with a median overall survival(OS)of 9.6 months.The median OS of responders was 25.9 months,while that of non-responders was 5.0 months(P<0.0001).Patients with gene mutations had a superior overall response rate(ORR)(80.4%vs.45.5%,P=0.043)compared to those without gene mutations.The presence of DNA methyltransferase 3 A(DNMT3A),ten-eleven translocation-2(TET2),and isocitrate dehydrogenase 1/2(IDH1/2)mutations did not affect the response rate(88.2%vs.68.9%,P=0.220)and reflected a better OS(not attained vs.9.0 months,P=0.05).The most common non-hematologic adverse events were pulmonary infection(73.1%),followed by febrile neutropenia(23.9%)and sepsis(19.4%).Conclusions The CDCAG regimen was effective and well-tolerated in R/R AML patients,increasing the potential for allogeneic hematopoietic stem cell transplantation.Moreover,patients with DNMT3A,TET2,and IDH1/2 mutations might benefit from this regimen.

Decitabine for Relapsed Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse after allogeneic hematopoietic stem cell transplantation（allo-HSCT） remains a main question on treatment failure. Current strategies for management that usually include salvage chemotherapy, donor lymphocytic infusion and second transplantation. Our study assessed the efficacy of decitabine（DAC） for treating patients with acute lymphoblastic leukemia（ALL） who relapsed after allogeneic hematopoietic stem cell transplantation（allo-HSCT）. We retrospectively analyzed the outcomes of 12 patients with relapsed ALL after allo-HSCT who received DAC therapy. Nine patients received DAC combined with chemotherapy and donor stem cell infusion, and 3 patients received single-agent DAC. Ten of the 12 patients achieved complete remission（CR）, 1 achieved a partial remission（PR）, and 1 had no response（NR） after treatment at the latest follow-up（LFU）, the median survival was 11.2 months（range, 3.8–34, 7 months）. The 1-and 2-year overall survival（OS） rates were 50%（6/12） and 25%（3/12）, respectively. Five patients were still alive; 4 had maintained CR and 1 was alive with disease. Patients with Philadelphia chromosome-positive ALL had higher survival rate than patients with Philadelphia chromosome-negative ALL（57.1% vs. 20%）. No aggravated flares of graft-versus-host disease（GVHD） were observed during DAC treatment. Therefore, DAC may be a promising therapeutic agent for ALL recurrence after allo-HSCT.

Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia:a registry study

Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT04176393)was conducted to assess the pharmacokinetic(PK)characteristics,safety,and efficacy of ivosidenib in Chinese patients with relapsed or refractory(R/R)mIDH1 AML.Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression.Ten subjects underwent intensive PK/progressive disease(PD)assessments.All subjects had the clinical response assessed at screening,every 28 days through month 12,and then every 56 days.Between November 12,2019,and April 2,2021,30 patients were enrolled;26(86.7%)had de novo AML and 18(60.0%)were transfusion-dependent at baseline.Following single and repeated doses of ivosidenib,median time to maximum plasma concentration(T_(max))was 4.0 and 2.0 hours,respectively.The inter-individual variability of pharmacokinetic exposure was moderate to high(coefficient of variation[CV],25%–53%).No obvious accumulation was observed after repeated doses at cycle 2 day 1.Regarding the clinical response,the CR+CRh rate was 36.7%(95%confidence interval[CI]:19.9%–56.1%),the median duration of CR+CRh was 19.7 months(95%CI:2.9 months–not reached[NR]),and median duration of response(DoR)was 14.3 months(95%CI:6.4 months–NR).Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months,as compared with primary data cutoff,and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

PRPS2 mutations drive acute lymphoblastic leukemia relapse through influencing PRPS1/2 hexamer stability

Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia(ALL),yet the underlying mechanisms are still elusive.Here,we demonstrate that phosphoribosyl pyrophosphate synthetase 2(PRPS2)mutations drive ALL relapse through influencing PRPS1/2 hexamer stability.Ultra-deep sequencing was performed to identify PRPS2 mutations in ALL samples.The effects of PRPS2 mutations on cell survival,cell apoptosis,and drug resistance were evaluated.In vitro PRPS2 enzyme activity and ADP/GDP feedback inhibition of PRPS enzyme activity were assessed.Purine metabolites were analyzed by ultra-performance liquid-chromatography tandem mass spectrometry(UPLC–MS/MS).Integrating sequencing data with clinical information,we identified PRPS2 mutations only in relapsed childhood ALL with thiopurine therapy.Functional PRPS2 mutations mediated purine metabolism specifically on thiopurine treatment by influencing PRPS1/2 hexamer stability,leading to reduced nucleotide feedback inhibition of PRPS activity and enhanced thiopurine resistance.The 3-amino acid V103-G104-E105,the key difference between PRPS1 and PRPS2,insertion in PRPS2 caused severe steric clash to the interface of PRPS hexamer,leading to its low enzyme activity.In addition,we demonstrated that PRPS2 P173R increased thiopurine resistance in xenograft models.Our work describes a novel mechanism by which PRPS2 mutants drive childhood ALL relapse and highlights PRPS2 mutations as biomarkers for relapsed childhood ALL.

Re-induction with modified CLAG regimen in relapsed or refractory acute myeloid leukemia in children bridging to allogeneic hematopoietic stem cell transplantation

Background The prognosis for relapsed or refractory acute myeloid leukemia(RR-AML)in children is poor,and the preferred salvage chemotherapy is unclear.One regimen is cladribine,cytarabine,and granulocyte-colony stimulating factor(CLAG),but little is known about its efficacy and safety in children with RR-AML.Methods We enrolled RR-AML patients aged 0-18 years who received modified CLAG regimen for re-induction between July 1,2015 and April 1,2018,or conventional induction between August 1,2011 and April 1,2018.Patients were followed up to March 31,2019.Patients underwent allogeneic stem cell transplantation(allo-SCT)or chemotherapy after the induction of complete remission(CR).The CR rate,survival,and side effects were analyzed.Results The CR rate for induction was 66.7%after one cycle and 75.0%after two cycles of the CLAG regimen in 12 children.The nine children who received conventional chemotherapy had a CR rate of 22.2%after one cycle and 33.3%after two cycles(P=0.087 vs.CLAG).The 3-year event-free survival(EFS)of the CLAG group and the conventional treatment group were 44.4±15.7%and 22.2±13.8%(P=0.112).The 3-year overall survival of the two groups were 59.5±16.2%and 22.2%±13.8%(P=0.057).The 3-year EFS for allo-SCT and chemotherapy after CLAG regimen was 66.7±19.2%and 25.0±21.7%(P=0.015).A single case of chemotherapy-related death was recorded.Conclusion Our data suggest a promising CR rate using CLAG salvage treatment in childhood RR-AML.Allo-SCT after CR may improve the long-term outcome in these patients.

Optimized therapeutic strategy for patients with refractory or relapsed acutemyeloid leukemia:long-term clinical outcomes and health-related quality of life assessment

Background:Patients with refractory or relapsed acute myeloid leukemia(AML)have poor survival,necessitating the exploration of optimized therapeutic strategy.Here,we aimed to investigate clinical outcomes and health-related quality of life(HR-QoL)after total therapy,which included allogeneic hematopoietic stem cell transplantation(allo-HSCT),and prophylactic donor lymphocyte infusion(DLI)in the early phase after transplantation,followed bymultiplemeasurable residual disease(MRD)and graft-versus-host disease(GvHD)-guided DLIs.Methods:Consecutive patients who had refractory or relapsed AML and had received non-T-cell-depleted allo-HSCT at Peking University Institute of Hematology were included in the study.If the patients achieved complete remission at 30 days after transplantation and had no evidence of relapse,severe infection,organ failure,and active GvHD at the time of planned DLI,prophylactic DLI was administered at 30 days after transplantation for human leukocyte antigen(HLA)-matched related HSCT or at 45-60 days after transplantation for haploidentical or unrelated HSCT.Subsequently,multiple DLIs were administered based on MRD results and whether they developed GvHD after transplantation.Results:A total of 105 patients were eligible.Eighty-seven patients received prophylactic DLI(group B),while 18 did not receive prophylactic DLI(group A).Among 105 patients,the cumulative incidence of grade 2-4 acute GvHD and chronic GvHDwas 40.6%(95%confidence interval[CI]=30.6%-50.6%)and 73.3%(95%CI=67.4%-79.2%),respectively.The cumulative incidence of relapse(CIR),transplant-related mortality(TRM),and leukemia-free survival(LFS)at 5 years after transplantation were 31.5%(95%CI=21.9%-41.1%),22.1%(95%CI=11.3%-32.9%),and 46.4%(95%CI=36.8%-56.0%),respectively.In group B,the CIR,TRM,and LFS at 5 years after transplantation were 27.6%(95%CI=17.6%-37.6%),21.6%(95%CI=11.2%-32.0%),and 50.8%(95%CI=40.0%-61.6%),respectively.At the end of follow-up,48 patients survived,and more than 90%of survivors had satisfactory recoveries of HR-QoL.Conclusions:Our study indicated that total therapy is not only associated with decreased CIR,comparable TRM,and better long-term LFS,but also with satisfactoryHR-QoL for refractory or relapsed AML,compared with those of standard of care therapy reported previously.Therefore,total therapymay be an optimized therapeutic strategy for refractory or relapsed AML.

Relapse of acute lymphoblastic leukemia in the pancreas after bone marrow transplant

Background:Relapse of acute lymphoblastic leukemia(ALL)in the pancreas is rare.We report a case of a 12-year-old boy who experienced a relapse of ALL in the pancreas after a bone marrow transplant.Methods:Clinical data,including course of illness,laboratory results,and imaging studies are included.The patient presented with acute pancreatitis,suspected to be secondary to gallstones,with ampullary obstruction.Ultrasound and magnetic resonance imaging demonstrated a distended gallbladder and intra-and extra-hepatic biliary dilatation with a cutoff at the pancreatic head,but with no evidence of gallstones.Results:Ultrasound-guided biopsy of the pancreas revealed ALL in the pancreas.Systematic chemotherapy was recommended,but was declined by the parents.The patient died one week later.Conclusion:Relapse of ALL in the pancreas is rare,but when a history of ALL is present,it should be considered in patients with pancreatic enlargement,obstructive jaundice,and pancreatitis.

Breathing adapted radiation therapy for leukemia relapse in the breast: A case report

BACKGROUND Infiltration of the breast by leukemic cells is uncommon but may manifest as an oncological emergency requiring prompt management.Extramedullary relapse of T-cell acute lymphoblastic leukemia(T-ALL)within the breast is exceedingly rare and there is paucity of data in the literature regarding this entity.No consensus exists on management of isolated extramedullary breast relapses of T-ALL.Herein,we report a case of isolated extramedullary breast relapse of T-ALL treated with breathing adapted radiation therapy(BART)using the active breathing control(ABC)system.CASE SUMMARY The patient was a 33-year-old female with diagnosis of T-ALL.She received intensive systemic chemotherapy that resulted in complete remission of her disease,and then underwent allogeneic hematopoietic stem cell transplantation.After a 15 mo period without symptoms and signs of progression,the patient presented with palpable masses in both breasts.She complained from severe pain and swelling of the breasts.Imaging workup showed bilateral breast lesions,and diagnosis of breast infiltration by leukemic cells was confirmed after immunohistopathological evaluation.The patient suffering from severe pain,discomfort,and swelling of both breasts due to leukemic infiltration was referred to the Radiation Oncology Department for symptomatic palliation.Whole breast irradiation was delivered to both breasts of the patient with BART using the ABC system.The patient had complete resolution of her symptoms after treatment with BART.CONCLUSION BART with the ABC system resulted in complete resolution of the patient’s symptoms due to leukemic infiltration of both breasts with T-ALL.This contemporary treatment technique should be preferred for radiotherapeutic management of patients with leukemic infiltration of the breasts to achieve effective symptomatic palliation.

Isolated extramedullary ocular relapse of acute lymphoblastic leukemia after peripheral blood stem cell transplantation

Isolated extramedullary ocular relapse of acute lymphoblastic leukemia （ALL） after allogeneic peripheral blood-stem cell transplantation （allo-P-BSCT） without concomitant involvement of the bone marrow is very rare,while the common sites of extramedullary relapse are the central nervous system, skin, bone, and breasts.^1 This is the report of isolated ocular relapse without any extra- ocular involvement of ALL after allo-PBSCT confirmed by histopathology.

CD19 CAR-T细胞治疗难治/复发急性B淋巴细胞白血病儿童及青少年患者的疗效及安全性

目的探讨CD19嵌合抗原受体T细胞(CAR-T)治疗对于儿童及青少年难治/复发急性B淋巴细胞白血病(B-ALL)的疗效及安全性。方法回顾性分析2017年6月至2021年3月接受CD19 CAR-T治疗的<25岁难治/复发B-ALL患者的临床资料,评估该疗法的疗效及安全性。结果共纳入64例难治/复发B-ALL患者,男35例、女29例,中位年龄8.5(1.0~17.0)岁。CD 19 CAR-T回输后1个月进行短期疗效评估,64例患者均获得完全缓解(CR)/完全缓解兼部分血细胞计数缓解(CRi),其中有62例患者达骨髓微小残留病灶(MRD)阴性。细胞因子释放综合征(CRS)及免疫效应细胞相关神经毒性综合征(ICANS)发生率分别为78.1%及23.4%。共22例患者复发,中位复发时间10.1个月,4年总生存(OS)率为(66.0±6.0)%,4年无白血病生存(LFS)率为(63.0±6.0)%。长期随访结果显示桥接异基因造血干细胞移植(allo-HSCT)患者的LFS和OS率均优于未桥接移植患者(4年LFS率:81.8%±6.2%对24.0%±9.8%,4年OS率:81.4%±5.9%对44.4%±11.2%;均P<0.01)。结论CD 19 CAR-T可有效治疗难治/复发B-ALL,输注后桥接allo-HSCT能进一步改善患者的长期生存情况。

Efficacy and safety analysis of the combination of cladribine,cytarabine,granulocyte colony stimulating factor( CLAG ) regime in patients with refractory or relapsed acute myeloid leukemia

Objective To analyze efficacy and safety of CLAG regimen in patients with refractory or relapsed acute myeloid leukemia(AML).Methods Efficacy and adverse events of patients with refractory or relapsed AML who were treated with one course of CLAG from April 1st,2014 through December 9th,2015 in our hospital were retrospectively reviewed.Results Thirty-three

贝林妥欧单抗联合化疗治疗难治复发ALL患者的疗效及其对血清IL-6、IL-17水平的影响

目的探讨贝林妥欧单抗联合化疗治疗难治复发急性淋巴细胞白血病(ALL)患者的疗效及其对血清白细胞介素(IL)-6、IL-17水平的影响。方法回顾性选取2017年1月至2024年1月在该院接受治疗的78例难治复发ALL患者作为研究对象,根据治疗方案不同将难治复发ALL患者分为研究组和对照组,每组39例。研究组采用HyperCVAD方案+贝林妥欧单抗治疗,费城染色体阳性(PH+)患者加用达沙替尼治疗,对照组采用HyperCVAD方案治疗,PH+患者加用达沙替尼治疗,两组均治疗1个疗程。治疗1个疗程后评估患者临床疗效;比较两组治疗前、治疗1个疗程后血常规指标[白细胞计数(WBC)、血小板计数(PLT)和血红蛋白(Hb)]及血清IL-6、IL-17水平;采用Kendall′s tau相关分析血清IL-6、IL-7水平与难治复发ALL患者疗效的相关性;比较两组不良反应发生情况。结果研究组总有效率高于对照组,差异有统计学意义(P<0.05);研究组治疗后WBC及血清IL-6、IL-17水平均低于对照组,PLT、Hb水平均高于对照组,差异均有统计学意义(P<0.05)。完全缓解患者血清IL-6、IL-17水平最低,其次为完全缓解伴血液学不完全恢复和难治性疾病患者,疾病进展患者最高,差异均有统计学意义(P<0.05)。Kendall′s tau相关分析结果显示,血清IL-6、IL-17水平与难治复发ALL患者疗效均呈负相关(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论贝林妥欧单抗联合达沙替尼能够有效改善难治复发ALL患者血常规指标水平,减轻机体炎症反应,提升患者临床疗效,并且血清IL-6、IL-17水平与患者疗效密切相关。

维奈克拉方案治疗复发/难治性急性髓系白血病的临床研究

目的:评价维奈克拉(venetoclax,VEN)快速剂量递增、最长治疗时间为14天,联合低剂量阿糖胞苷(low-dose cytarabine,LDAC)方案挽救治疗复发/难治性急性髓系白血病(relapsed/refractory acute myeloid leukemia,R/RAML)的安全性和有效性。方法:回顾性分析2018年10月至2023年11月于江苏大学附属医院接受VEN+LDAC方案挽救治疗的16例R/R AML患者,所有患者既往均未接受过含VEN方案治疗。该方案VEN的剂量第1天为200 mg,其后均为400 mg固定剂量;LDAC 20 mg/m^(2)/d皮下注射。患者在治疗第8天复查骨髓,根据骨髓增生情况决定总疗程为10天还是14天。所有患者均不给予VEN单药治疗。有治疗反应的患者采用相同方案维持直到疾病进展或移植。结果:本研究纳入的R/R AML患者,中位随诊时间为27.5个月。治疗期间未发生有临床表现的肿瘤溶解综合症(tumor lysis syndrome,TLS)。治疗后总反应率(overall response rate,ORR)为68.75%,其中4例达完全缓解(complete response,CR),1例达血液学未恢复的完全缓解(CR with incomplete hematologic recovery,CRi),6例达部分缓解(partial response,PR)。达最佳疗效的治疗周期中位数为1个周期。中位总生存期(overall survival,OS)为5.8(0.5~47.2)个月,中位无进展生存期(progression-free survival,PFS)为22.2(7.3~42.9)个月。发生的不良反应主要为3~4级的血液学不良事件和感染。结论:本研究根据治疗第8天骨髓复查结果调整用药天数的VEN+LDAC方案,对于既往没有接受过含VEN方案治疗的R/R AML患者有较好的安全性和有效率。即使14天的VEN+LDAC治疗也是安全的。

Advances in the development of chimeric antigen receptor-T-cell therapy in B-cell acute lymphoblastic leukemia

CD19-targeted chimeric antigen receptor T-cell(CAR-T)therapy is effective in refractory/relapsed(R/R)B-cell acute lymphoblastic leukemia(B-ALL).This review focuses on achievements,current obstacles,and future directions in CAR-T research.A high complete remission rate of 68%to 93%could be achieved after anti-CD19 CAR-T treatment for B-ALL.Cytokine release syndrome and CAR-T-related neurotoxicity could be managed.In view of difficulties collecting autologous lymphocytes,universal CAR-T is a direction to explore.Regarding the high relapse rate after anti-CD19 CAR-T therapy,the main solutions have been developing new targets including CD22 CAR-T,or CD19/CD22 dual CAR-T.Additionally,some studies showed that bridging into transplant post-CAR-T could improve leukemia-free survival.Some patients who did not respond to CAR-T therapy were found to have an abnormal conformation of the CD19 exon or trogocytosis.Anti-CD19 CAR-T therapy for R/R B-ALL is effective.From individual to universal CAR-T,from one target to multi-targets,CAR-T-cell has a chance to be off the shelf in the future.

改良CLAG方案治疗儿童复发/难治急性髓系白血病的疗效和安全性

目的探讨减低化疗剂量的改良CLAG方案(克拉屈滨、阿糖胞苷、粒细胞集落刺激因子)治疗复发/难治急性髓系白血病(R/R-AML)儿童的疗效及安全性。方法回顾性分析2016年6月至2023年4月接受改良CLAG方案治疗的R/R-AML患儿的临床资料,计算总体反应率(ORR)、不良反应发生率、总生存(OS)率和无事件生存(EFS)率。结果26例患儿中复发17例,其中1例为睾丸白血病复发,3例为骨髓2次复发,余均为骨髓首次复发,难治9例。所有患儿均完成1疗程改良CLAG方案化疗,1例未评估治疗反应桥接造血干细胞移植,余25例患儿ORR为84.0%(21/25)。复发患儿的ORR为81.3%(13/16),难治患儿的ORR为88.9%(8/9)。细胞遗传学分层为低危的患儿ORR为76.9%(10/13),中高危患儿ORR为91.7%(11/12)。所有患儿64个月的OS率和EFS率分别为69.7%和63.3%,15例治疗有反应并顺利桥接异基因造血干细胞移植的患儿64个月OS率和EFS率均为92.3%。最常见的不良反应为骨髓抑制(100%)和胃肠道反应(100%),其次为感染(57.7%)、转氨酶升高(34.6%)、出血(19.2%),1例患儿因4级颅内出血放弃,其他不良反应均经对症治疗后好转。结论减低化疗剂量的改良CLAG方案是儿童R/R-AML的一种有效、安全的治疗选择。

高通量药敏检测技术在儿童复发难治性急性白血病中的应用

目的探究高通量药敏(high-throughput drug sensitivity,HDS)检测技术在儿童复发难治性急性白血病(relapsed and refractory acute 1eukermia,RR-AL)的应用现状及分析挽救治疗方案的可行性。方法回顾性收集2021年11月—2023年10月郑州大学第一附属医院儿童血液与肿瘤科行HDS检测的RR-AL患儿的临床资料,并对药敏结果及治疗结局进行分析。结果17例RR-AL患儿接受HDS检测,复发难治性急性髓系白血病7例(41%),复发难治性急性淋巴细胞白血病10例(59%)。高度敏感化疗药物/方案的检出率为53%(9/17),中度敏感化疗药物/方案的检出率为100%(17/17)。17例RR-AL患儿高度敏感度和中度敏感度化疗药物及方案中,MOACD方案(米托蒽醌+长春新碱+阿糖胞苷+环磷酰胺+地塞米松)占比100%,单药米托蒽醌抑制率最高(94%,16/17),靶向药抑制率最高为硼替佐米(94%,16/17)。9例患儿根据HDS结果调整化疗,行造血干细胞移植4例;无病生存4例,死亡5例。8例经验化疗,行造血干细胞移植2例;无病生存4例,死亡4例。结论HDS检测技术可为儿童RR-AL筛选出高度敏感药物/方案,提高再次缓解率,为后续进行造血干细胞移植创造条件。

CD19/CD22 CAR-T细胞治疗MLL基因重排阳性难治/复发儿童急性B系淋巴细胞白血病临床分析

目的 分析双靶点CD19/CD22嵌合抗原受体T(CAR-T)细胞治疗混合谱系白血病基因重排(MLL-r)阳性难治/复发急性B系淋巴细胞白血病(R/R B-ALL)患儿的有效性及安全性。方法 回顾性分析2019年10月至2021年11月接受双靶点CD19/CD22 CAR-T治疗的MLL-r阳性R/R B-ALL患儿的临床资料。结果 共纳入37例MLL-r阳性R/R B-ALL患儿,男24例、女13例,诊断时中位年龄1.2(0.5~2.6)岁,其中17例(45.9%)为婴儿白血病。CAR-T细胞输注后中位时间9(7~13)天,37例患儿的完全缓解率达100%。中位随访时间28.2(11.3~30.9)个月,3年总体生存(OS)率为67.6%(95%CI:52.5%~82.7%),3年无事件生存率为59.5%(95%CI:43.6%~75.4%)。75.7%(28/37)的患者在CAR-T细胞治疗后接受过异基因造血干细胞移植,移植距离CAR-T细胞输注的中位时间为83(61~92)天。接受巩固性移植与未接受患儿的2年OS分别为75.0%(95%CI:58.9~91.1%)与44.4%(95%CI:11.9%~76.9%),差异无统计学意义(P=0.068)。35.1%(13/37)的患儿复发,中位复发时间为156(86~202)天,其中4例为CD19、CD22双阳性复发,2例CD19、CD22双阴性复发,4例单纯CD19阴性复发,1例淋系向髓系转化,另2例不明确。97.3%(36/37)患儿发生了细胞因子释放综合征,11例(29.7%)达到了3~4级,5例(13.5%)患儿出现了免疫效应细胞相关神经毒性综合征;无CAR-T细胞治疗合并症导致的死亡。结论 CD19/CD22 CAR-T细胞治疗可有效诱导MLL-r阳性儿童R/R B-ALL获得快速缓解,且不良反应可耐受。

儿童急性淋巴细胞白血病的治疗失败相关因素分析———福建省多中心真实世界数据分析

目的:分析真实世界中儿童急性淋巴细胞白血病(ALL)的治疗失败相关因素。方法:回顾性分析2011年4月至2020年12月福建省5家医院收治的1414例初诊ALL患儿的临床资料。治疗失败定义为复发、非复发相关死亡和第二肿瘤。结果:中位随访时间为49.7(0.1-136.9)个月,共有269例(19.0%)治疗失败,其中140例(52.0%)为复发,129例(48.0%)为非复发死亡,0例第二肿瘤。Cox单因素及多因素分析结果显示,初诊白细胞计数≥50×10^(9)/L、T-ALL、BCR-ABL1、KMT2A基因重排、早期治疗反应不佳是导致治疗失败的独立危险因素(均HR>1.000,P<0.05)。140例复发ALL患儿的5年OS率仅为23.8%,其中极早期复发(复发时间在诊断18个月内)预后更差。129例非复发死亡患儿中,包括71例(26.4%)治疗相关死亡,56例(20.8%)因放弃治疗死亡,2例(0.7%)疾病进展死亡;其中治疗相关死亡与化疗强度显著相关,而放弃治疗主要与经济因素相关。结论:福建省儿童ALL的治疗失败率仍较高,复发为治疗失败的最主要原因,而治疗相关死亡、经济因素放弃导致死亡则是无复发死亡的主要原因。

Pharmacogenetics of asparaginase in acute lymphoblastic leukemia

Asparaginase is a key component in leukemias and lymphomas treatment protocols and is suggested as a treatment for other malignancies in which an amino acid depletion strategy is indicated.Asparaginase intolerance is subject to inter-individual variability and can manifest as hypersensitivity reactions,pancreatitis,thrombosis,as well as metabolic abnormalities,and may affect treatment outcome.Pharmacogenetics aims at enhancing treatment efficacy and safety by better understanding the genetic basis of variability and its effect on the pharmacological responses.Many groups tried to tackle the pharmacogenetics of asparaginase but the potential implementation of such findings remains debatable.In this review,we highlight the most important findings reported in studies of the pharmacogenetics of asparaginase related complications and treatment outcome in acute lymphoblastic leukemia.