儿童急性白血病眼底改变的临床分析

摘 要：［目的］ 观察急性白血病儿童的眼底改变。［方法］ 分析确诊的83例急性白血病患者资料。在治疗前及治疗过程观察患者眼底镜表现及其相对特征性。［结果］ 全组83例患者中,有24例患者发生眼底改变。常见眼底损害包括：静脉改变,视乳头改变,网膜出血,视网膜渗出。眼底改变与急性白血病类型、患者性别及年龄无关。中枢神经系统白血病与眼底改变具有相关性（χ2=39.90,P=0.0032）。［结论］ 儿童急性白血病眼底改变有一定的特异性,与疾病的进展过程密切相关。     

Study of Cytogenetic Alterations and Association With Prognostic Factors in Indian Children With B-Lineage Acute Lymphoblastic Leukemia

BackgroundAcute lymphoblastic leukemia (ALL) is a heterogeneous disorder with coexistence of multiple clones. The mortality rate in children with ALL has reduced to 15% to 20% in developed countries. However, it continues to be high in India (25%-35%), which may be attributed to ethnic variation and differences in disease biology. The treatment and outcome in ALL are dependent on risk stratification, which is derived from prognostic factors like leukocyte count, age at diagnosis, immunophenotypic subtypes and, most importantly, cytogenetic alterations. Chromosomal rearrangements are important initiating events in leukemogenesis.Approximately, 75% of children with ALL harbor a recurring chromosomal alteration detectable by karyotyping, fluorescence in situ hybridization, or other molecular techniques. The present study was planned to compare the prevalence of various cytogenetic alterations with western.literature and to see the association of these cytogenetic alterations with other prognostic factors as well as survival outcome.MethodsWe enrolled, 117 children of 1 to 14 years of age with newly diagnosed B-cell ALL from August 2014 to Mar 2016 prospectively. Patients were monitored for response to prednisolone, postinduction complete morphological remission minimal residual disease assessment, and were followed for a minimum 2 years.Results and DiscussionWe observed that poor-risk cytogenetic alterations were more prevalent, whereas good-risk cytogenetic alterations were less frequent in our patient cohort as compared with western studies.ConclusionsWe observed that event-free survival is significantly less in those with poor-risk cytogenetics. We have also highlighted nonrecurrent alterations observed in our study group.     

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Purpose of Review

The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL).

Recent Findings

Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15.

Summary

We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

     

急性淋巴细胞白血病TPMT基因多态性的研究

目的 分析急性淋巴细胞白血病TPMT基因多态性与6-MP不良反应的相关性.方法 收取急性淋巴细胞白血病患儿48例作为研究对象,对其TPMT基因型及6-MP不良反应进行分析.结果 48例患儿中31.25％按照常规6-MP使用剂量完成维持治疗,68.75％患儿出现不耐受后调整为低剂量完成维持治疗.常规剂量组重度不良反应发生率高于低剂量组,但差异无统计学意义(P＞0.05).6-MP所致骨髓抑制及肝功能损害发生率分别为93.75％及83.33％.仅有1例患儿发生杂合型TPMT×3C点突变,突变发生率为2.08％,该患儿同时发生4级骨髓抑制及4级肝功能损害.结论 TPMT×3C基因突变可能与6-MP所致重度不良反应有关,但6-MP所致重度不良反应可能是多种因素共同作用的结果.     

Characteristics and Outcomes of Secondary Acute Myeloid Leukemia and Acute Myeloid Leukemia With Myelodysplasia-Related Changes: Multicenter Study From the Thai Acute Leukemia Study Group

BackgroundSecondary acute myeloid leukemia (sAML) and AML with myelodysplasia-related changes (AML-MRC) both result in dismal outcomes. This retrospective study aimed to determine whether these features are poor prognostic factors independent of older age and adverse cytogenetics, which are commonly associated with a poor prognosis.MethodsThe characteristics and real-world outcomes of sAML and AML-MRC from the Thai AML registry database were investigated.ResultsFrom a total of 992 newly diagnosed AML patients, 315 (31.8%) patients were classified into sAML or AML-MRC subtypes. Older age, low white blood cell (WBC) count, low bone marrow blast, and adverse cytogenetic risk were commonly present in sAML and AML-MRC compared to de novo AML. Complete remission after 7 + 3 induction therapy occurred in 42.3% of patients with sAML or AML-MRC and 62.4% of de novo AML (P < .001). The median overall survival (OS) of sAML, AML-MRC, and de novo AML were 6.9, 7.0, and 12.2 months, respectively (P < .001). The independent prognostic factors for inferior OS were older age, intermediate-risk or adverse-risk cytogenetics, WBC count > 100 × 10⁹/L, poor performance status, and a subgroup of AML-MRC with the morphologic criteria of multilineage dysplasia (AML-MRC-M). In addition, sAML, AML-MRC, and a WBC count > 100 × 10⁹/L were pre-treatment prognostic factors associated with poor relapse-free survival (P = .006, P = .017, and P < .001, respectively).ConclusionBoth sAML and AML-MRC are independently associated with poor outcomes in Thai patients. Our study supports AML-MRC-M as an adverse prognostic factor for OS.     

Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia

BackgroundPatients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) have dismal outcomes. Preclinical studies have suggested that T-ALL cells are sensitive to BCL2 inhibition. The clinical activity of venetoclax, a selective BCL2 inhibitor, in T-ALL is unknown.Patient and MethodsWe retrospectively reviewed the efficacy and safety of venetoclax combined with chemotherapy for patients with R/R T-ALL treated at our institution.ResultsThirteen patients with R/R T-ALL with a median age of 46 years (range, 20-75 years) were treated with venetoclax plus chemotherapy. Five patients (38%) had early T-cell precursor ALL. The patients had received a median of 2 previous lines of therapy (range, 1-11). Venetoclax at a median dose of 200 mg/d for 21 days, generally with a concomitant azole antifungal, was combined with various agents, including hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), asparaginase, nelarabine, decitabine, or other intensive chemotherapy. Of the 10 patients evaluable for bone marrow response, 6 (60%) achieved a remission with bone marrow blasts < 5%, including 3 with complete hematologic recovery. The median overall survival and relapse-free survival were 7.7 and 4.0 months, respectively. No early death or clinically significant tumor lysis syndrome were reported. The median interval to neutrophil recovery and platelet recovery were 15 days and 44 days, respectively, with prolonged cytopenias observed with venetoclax 400 mg/d or when given for > 14 days per cycle.ConclusionCombination therapy with venetoclax showed promising clinical efficacy in R/R T-ALL. Further studies are warranted to evaluate the clinical benefit of BCL2 inhibitors in T-ALL.     

Clinical Experience With Ibrutinib Alone or in Combination With Either Cytarabine or Azacitidine in Patients With Acute Myeloid Leukemia

BackgroundPreclinical studies have suggested a role for Bruton tyrosine kinase (BTK) as a potential therapeutic target in acute myeloid leukemia (AML), and anti-AML activity in vivo has been demonstrated with BTK inhibitors.Patients and MethodsIn this open-label phase 2a study, patients with AML were treated with ibrutinib 560 mg per day alone (cohort 1; n = 7), or ibrutinib in combination with either cytarabine 20 mg administered subcutaneously twice daily for 10 days of a 28-day cycle (cohort 2; n = 21) or azacitidine 75 mg/m² administered intravenously once daily on days 1 to 7 of a 28-day cycle (cohort 3; n = 8). Best overall response (primary end point), overall survival, and safety were summarized.ResultsA total of 36 patients were enrolled and received treatment; median duration of ibrutinib treatment was 5.4 weeks, and median time on study was 16 months. Of 24 patients evaluable for response, 1 partial remission (cohort 3) and 1 complete remission (cohort 2) were observed; the remaining responses were treatment failures. Median overall survival was 4.0 months in cohort 1, 2.2 months in cohort 2, 2.8 months in cohort 3, and 2.4 months for the overall population. No unexpected safety signals were identified. Grade 3 or higher adverse events that occurred in ≥ 10% of patients included AML progression, febrile neutropenia, pneumonia, anemia, thrombocytopenia, fatigue, asthenia, and respiratory failure.ConclusionIbrutinib alone or in combination with cytarabine or azacitidine demonstrated an acceptable safety profile. However, limited efficacy with ibrutinib was observed in patients with AML.     

Molecular Study of Parvovirus B19 Infection in Children with Acute Myeloid Leukemia

Background: Parvovirus B19 is a common viral infection in children. Nearby evidences are present about itsassociation with acute leukemia, especially acute lymphoblast leukemia. Nevertheless, scanty reports have discussedany role in acute myeloid leukemia (AML). Purpose: To evaluate the frequency of virological markers of B19 infectionincluding its DNA along with specific immunoglobulins G (IgG) and M (IgM) among children with newly diagnosedAML. Besides, describing the clinical importance of Parvovirus B19 infection in those patients. Patients and methods:A case-control retrospective study was conducted on 48 children recently diagnosed with AML before and duringchemotherapy induction and 60 healthy control. Specific serum IgM and IgG levels were determined by enzyme linkedimmunosorbant assay (ELISA) and DNA detection by polymerase chain reaction (PCR). Results: Parvovirus DNA wasdetected in 20 patients with AML. IgM was found in sera of four patients and one case had positive DNA and IgG (5%).Patients with recent parvovirus B19 infection had a significantly reduced hemoglobin levels, RBCs counts, plateletcounts, neutrophil counts and absolute lymphocytosis (p=0.01, p=0.0001, p=0.01, p=0.02, p=0.0003, respectively).There were no clinical findings with statistically significant association to recent infection. Half of the patients withAML had positive PCR and/or IgM for parvovirus B19. Among children with AML under chemotherapy, there werereduced hemoglobin levels (P=0.03), reduced platelet counts (P=0.0001) and absolute neutropenia (mean±SD, 1.200±1.00) in those with parvovirus B19 infection. More than half of patients with parvovirus B19 (72.2%) had positive PCRand/or IgM and 36.4% of them had positive IgG. Conclusion: This study highlights that parvovirus B19 is commonin children with AML either at diagnosis or under chemotherapy. There are no clinical manifestations that can be usedas markers for its presence, but hematological laboratory findings can provide evidence for infection in the presenceof anemia and neutropenia. Detection of parvovirus B19 by combined molecular and serological markers is requiredin such patients for accurate diagnosis.     

急性白血病并发侵袭性肺曲霉病的临床分析

[目的]探讨急性白血病（AL）并发侵袭性肺曲霉病（IPA）的临床特点、诊断及治疗。[方法]回顾性分析7例AL并发IPA病例的临床资料。[结果]7例AL患者强烈化疗后第8.6d（4～11d）出现中性粒细胞（ANC）缺乏（ANC〈0.5×10^9/L）,粒细胞缺乏持续时间达15d（6～20d）,并在此期间出现持续发热、咳嗽、少痰、痰中带血、胸痛等症状;在发热后6d（3～10d）行CT检查均发现胸膜下结节或肺内多发结节影,呈晕征改变,2例伴有类圆形空洞病灶;4例行痰培养发现烟曲霉菌。4例患者予两性霉素B治疗,2例好转,1例疗效欠佳改用卡泊芬净后好转,1例因并发肾功能衰竭死亡;另外3例患者予伏立康唑治疗后好转。6例好转者随访中位时间18个月未见复发。[结论]粒细胞缺乏是IPA发病的高危因素,CT检查有助于IPA的早期诊断。伏立康唑是治疗IPA的首选药物,其有效性及安全性均优于两性霉素B。     

Month-of-Birth and Incidence of Acute Lymphoblastic Leukemia in Children

As a means of examining the virus-relatedness of acute lymphoblastic leukemia (ALL) in children, we investigated the association between month-of-birth and the occurrence of ALL in 1487 children aged 0-15 years at the time of diagnosis. Our hypothesis being that evidence of seasonal variation in births of ALL cases would suggest exposure to a transmissible etiologic agent during the perinatal period. The data were obtained Surveillance, Epidemiology, and End Results (SEER) Program and consisted of children diagnosed during the years 1973-1986. Aggregate monthly incidence rates of ALL stratified by month-of-birth, for each SEER site, all sites combined, and for broad geographic regions were calculated. No evidence for an association between month-of-birth and childhood ALL was found.     

Preliminary Phase II Study of Aclacinomycin A in Patients With Adult Acute Leukemia

Seventeen patients with adult acute leukemia in relapse weretreated with aclacinomycin A in 5-day courses given at a doseof 90 to 210 mg/m²/5 days as a daily bolus injection. Completeremission was achieved in patients treated with 130 or moremg/m²/5 days. Three out of seven patients with acute nonlymphocyticleukemia achieved complete remission lasting 15 mo, 14+ mo,and 2 mo. Of seven patients with acute lymphocytic leukemia,one achieved complete remission which lasted more than 11 mo.One patient with refractory anemia with an excess of blast cellsalso achieved complete remission. Neutropenia and thrombocytopeniaoccurred in all patients. The dose-limiting factors were gastrointestinalsymptoms and stomatitis, the latter occurring in three of theseven patients who received 200–210 mg/m²/5 days. Hyperbilirubinemiaassociated with antibiotic therapy was seen in four patients.Since aclacinomycin A has significant activity in acute nonlymphocyticleukemia, consideration should be given to exploring its usein combination with other active drugs.     

儿童急性淋巴细胞白血病VDLP方案中应用音乐疗法的疗效观察

目的探讨儿童急性淋巴细胞白血病(ALL)VDLP方案中应用音乐疗法的疗效及对神经元特异性烯醇化酶(NSE)和25羟维生素D(25(OH)D)水平的影响。方法将88例ALL患儿随机分为对照组44例和观察组44例。对照组采取VDLP诱导缓解方案。观察组在对照组基础上加用音乐疗法。比较两组患儿的生存率、近期疗效及不良反应发生率。检测两组儿童ALL血清中NSE和25(OH)D的水平。结果对照组患儿的6个月和1年生存率分别为90.91%和84.09%,观察组为97.73%和93.18%,观察组低于对照组,但两组比较无统计学意义(P>0.05)。观察组近期总缓解率为84.09%,明显高于对照组为(63.64%)(P<0.05)。观察组患儿的肝功能损害、骨髓抑制、皮肤损害、口腔粘膜损害及胃肠道反应发生率低于对照组,其中胃肠道反应的发生率明显低于对照组(P<0.05)。观察组治疗后患儿血清中NSE水平明显低于对照组,25(OH)D明显高于对照组(P<0.01)。结论儿童急性淋巴细胞白血病VDLP方案中应用音乐疗法的疗效明显,且可降低血清中NSE水平和提高25(OH)D水平。     

白血病患儿血中β_2－MG和中分子物质水平的研究

本研究同时检测儿童白血病患者血中β２－微球蛋白和中分子物质的含变化，并动态观察它们与疗效转好的关系，结果发现，无论是急淋还是急非淋白血病血中β２－ＭＧ和ＭＭＳ均显著升高（β２－ＭＧ在急淋组为３．１９ｎｇ／Ｌ±０．５４ｎｇ／Ｌ，急非淋组为４．３ｌｎｇ／Ｌ±１．０５ｎｇ／Ｌ，正常对照为１．７０ｎｇ／Ｌ±０．２６ｎｇ／Ｌ，ＭＭＳ在急淋组为４８．４ｕ／Ｌ±１８．８ｕ／Ｌ，急非淋组为３６．０ｕ／Ｌ±７．８ｕ／Ｌ，正常对照为２２．０ｕ／Ｌ±３．０ｕ／Ｌ，急性白血病患儿得到有效治疗获得完全缓解时，它们则显著下降，趋向正常水平（β２－ＭＧ为１·９７ｎｇ／Ｌ±０．３５ｎｇ／Ｌ，ＭＭＳ为２９．０ｕ／Ｌ±８．９ｕ／Ｌ），反之，治疗无效者则居高不下（β２－ＭＧ为２．６７ｎｇ／Ｌ±０．４５ｎｇ／Ｌ，ＭＭＳ为４０．４ｕ／Ｌ±９．３ｕ／Ｌ）。研究结果提示，血清β２－ＭＧ和ＭＭＳ检测对急性白血病的实验诊断有重大意义，并可供治疗和预后参考。     

地西他滨联合参麦注射液治疗儿童急性髓系白血病的临床研究

目的 探讨地西他滨联合参麦注射液治疗儿童急性髓系白血病的疗效、安全性.方法 将急性髓系白血病患儿80例随机分为对照组40例和治疗组40例.对照组给予地西他滨和减量FLAG联合方案.治疗组在对照组基础上予参麦注射液20 mL,1次/天,连续21 d.比较2组中医证候积分、不良反应情况、临床疗效及死亡率等.结果 治疗后,治疗组患儿的发热、口干和乏力积分明显少于对照组(P＜0.01).治疗组患儿的不良反应发生率均少于对照组,其中中性粒细胞减少和肝损伤明显少于对照组(P＜0.05).治疗组的总有效率为77.5％,显著高于对照组为55.0％(P＜0.05).治疗组患儿的复发率和死亡率分别为22.5％和17.5％,均明显少于对照组的47.5％和40.0％ (P ＜0.01).结论 地西他滨联合参麦注射液治疗儿童急性髓系白血病具有增效减毒的作用,且可降低死亡率,值得临床借鉴.     

Clinical Significance of Serum Ferritin at Diagnosis in Patients With Acute Myeloid Leukemia: A YACHT Multicenter Retrospective Study

Purpose

A multicenter retrospective analysis was performed to evaluate the clinical significance of serum ferritin at diagnosis in patients with acute myeloid leukemia (AML).

Chromosomal Abnormalities in Pakistani Children with Acute Lymphoblastic Leukemia

Background: Cytogenetic abnormalities have important implications in diagnosis and prognosis of acuteleukemia and are now considered an important part of the diagnostic workup at presentation. Karyotype, ifknown at the time of diagnosis, guides physicians to plan appropriate management strategies for their patients.Aim and Objectives: To determine the cytogenetic profile of acute lymphoblastic leukemia (ALL) in Pakistanichildren in order to have insights regarding behavior of the disease. Materials and Methods: A retrospectiveanalysis of all the cases of ALL (<15years old) diagnosed at Aga Khan University from January 2006 to June2011 was performed. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique.Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN)criteria. Results: A total of 153 patients were diagnosed as ALL during the study period, of which 127 samplessuccessfully yielded metaphase chromosomes. The male to female ratio was 1.8:1. A normal karyotype waspresent in 51.2% (n=65) of the cases whereas 48.8% (n=62) had an abnormal karyotype. Most of the abnormalcases showed hyperdiploidy(13.4%) followed by t(9;22)(q34;q11.2) (7.08%). Conclusions: This study revealeda relative lack of good prognostic cytogenetic aberrations in Pakistani children with ALL.     

Clinical Outcomes of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia in a County Hospital System

BackgroundMajor advances in the treatment of acute lymphoblastic leukemia (ALL) over the past decade have resulted in 5-year overall survival (OS) rates of 80% in mature B cell ALL, 50% in precursor B cell ALL, 50% to 60% in T cell ALL, and 60% to 70% in Philadelphia chromosome–positive (Ph+) ALL, as reported in studies from large, specialized centers. However, many patients treated in the community have limited access to novel therapies and stem cell transplantation (HSCT).Patients and MethodsThe purpose of this retrospective cohort analysis was to evaluate the clinical outcomes of patients ≥ 16 years with newly diagnosed ALL treated from October 2007 to June 2019 in the Harris County Health System, Houston, TX.ResultsOne hundred forty-six patients were included, with newly diagnosed pre-B-ALL (n = 127), T-ALL (n = 18), and chronic myeloid leukemia and/or lymphoid blast crisis (n = 1). Median age was 35 years (16-82) at diagnosis, and 81(55%) were male. The majority of patients with pre-B ALL identified as Hispanic (n = 118, or 92%). Ninety-eight (67%) of patients were uninsured or indigent, receiving care under the county's financial assistance programs. Hyper-CVAD-based induction chemotherapy was administered in 134 (92%) of patients, while 9 (6%) were treated on different protocols, and 3 (2%) were not treated due to early death, or patient refusal. Imatinib was the most common TKI used in 17 of 30 or 57% of patients with Ph+ disease. Out of 137 evaluable for response patients, 117 (85%) achieved complete remission (CR + CRi), 19 (14%) had refractory disease, and 1 (1%) died within 4 weeks of diagnosis. Median follow-up time was 50 months (1.5-135). For the entire study cohort, the median duration of CR/CRi was 15.4 months. Out of 62 patients who were eligible for consolidative HSCT at first CR, 52 (89%) did not receive it, with lack of insurance being the most common reason (n = 29, or 56%). Barriers to utilization of novel therapies such as blinatumomab or CAR-T were also observed. Patient-caused delays in administration of chemotherapy and treatment interruptions of at least 30 days were seen in 31(23%) patients. At 1, 2, and 5 years, relapse rates were 37%, 56%, and 70%. Recurrent and/or refractory disease was the cause of death in most patients (n = 69 [85%]). Five-year EFS and OS rates were 22% and 38% for patients with pre-B ALL, 24% and 44% for patients with T ALL, and 13% and 27% for patients with Ph+ ALL. Median OS was significantly increased (not reached [NR] vs. 24 months; P = .00088) in patients with an indication for HSCT in first CR due to high-risk features who underwent HSCT, versus those who did not.ConclusionAddressing barriers raised by socioeconomic disparities, increasing access to effective therapies, and including patients with ALL treated in the community in clinical trials may improve survival for underserved populations.     

Livin蛋白在儿童急性白血病中的表达及临床意义

目的 探讨Livin蛋白在儿童急性白血病(AL)中的表达及临床意义.方法 采用免疫组织化学S-P方法检测Livin蛋白在65例AL患儿骨髓细胞中的表达,其中初治35例,缓解30例;对照组10例为非恶性血液病.结果 AL初治患儿Livin蛋白阳性表达率(65.71%)高于缓解患儿(16.67%)和对照组(10.00%)(P<0.01),初治ALL患儿Livin蛋白阳性表达率(64.00%)与初治AML(60.00%)比较差异无统计学意义(P>0.05).结论 Livin蛋白在AL初治患儿中表达上调,提示其可能参与了儿童AL的发生、发展,为儿童AL的基因治疗提供了新思路.