Childhood relapsed acute lymphoblastic leukemia: Biology and recent treatment progress

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. Despite remarkable improvement in the prognosis of childhood ALL over the past few decades, the treatment of relapsed ALL is still challenging. The prognosis of first ALL relapse is associated with time of relapse after initial therapy, sites of relapse, and immunophenotype. More recently, response to treatment, which is evaluated by assessment of minimal residual disease (MRD), has been found to be clinically significant in relapsed ALL as well as in the initially diagnosed disease. Utilizing these factors, risk‐oriented treatment stratification for first ALL relapse has been established. In the standard‐risk group for first ALL relapse, intensification of conventional ALL‐type therapy can provide a cure in approximately 70% of patients. It is important to assess MRD after reinduction therapy to determine the indications for stem cell transplantation in the standard‐risk group. In contrast, no standardized therapy has been established for the high‐risk group, which accounts for more than half of relapsed ALL patients. Recent studies have shed light on the clonal origin of relapsed ALL, which usually exists as a minor subclone at the time of initial diagnosis. Clonal selection and evolution take place during chemotherapy, resulting in distinct genetic and epigenetic characteristics of relapsed ALL, some of which are linked to drug resistance, a common and problematic feature of ALL after relapse. To overcome resistance to standard ALL‐type therapy, and considering the heterogeneous biological background of high‐risk relapsed ALL, innovative therapies using new agents are necessary.     

5‐Azacitidine Monotherapy Followed by Related Haploidentical Hematopoietic Stem Cell Transplantation Achieves Durable Remission in a Pediatric Patient With Acute Undifferentiated Leukemia Refractory to High‐Dose Chemotherapy

Patients with acute leukemias of undifferentiated lineage (AUL) generally have guarded prognosis. Here, we describe the first reported pediatric patient with AUL refractory to high‐dose chemotherapy who achieved clinical remission with ALL maintenance therapy and 5‐azacitidine. His induction remission was followed by consolidation with reduced toxicity haploidentical hematopoietic stem cell transplant (HSCT). At 9 months post‐HSCT, the patient is alive and in remission. This combination therapy of remission induction with ALL maintenance therapy and 5‐azacitidine and consolidation with reduced toxicity haploidentical HSCT is novel and promising for patients who lack conventional donors and are not candidates for myeloablative therapy.     

Venoocclusive disease due to chemotherapy for pediatric acute lymphoblastic leukemia is associated with increased levels of plasminogen‐activator inhibitor‐1

We describe three cases of sinusoidal obstruction syndrome/venoocclusive disease (SOS) in pediatric patients with acute lymphoblastic leukemia (ALL). All three episodes occurred during or just after the induction or reinduction phase of treatment based on prednisone/dexamethasone, vincristine, daunorubicin, and pegylated‐l ‐asparaginase. SOS episodes were categorized as mild/moderate and resolved in 7, 10, and 16 days using supportive measures or defibrotide therapy. In all three episodes, the clinical diagnosis of SOS was associated with a significant increase in plasminogen‐activator inhibitor‐1 (PAI‐1) that reduced with patient clinical improvement. PAI‐1 warrants study as a diagnostic marker for SOS in ALL.     

Optimized treatment of childhood B-lineage acute lymphoblastic leukemia北大核心CSCD

儿童急性淋巴细胞白血病约占整体儿童白血病的75%,其中,急性B淋巴细胞白血病占儿童急性淋巴细胞白血病的80%以上。半个世纪以来,利用新技术不断发现新的分子生物靶标并用于精准的疾病预后分层,儿童急性淋巴细胞白血病的5年总生存率逐年提高。随着对远期生活质量的关注日益增强,儿童急性B淋巴细胞白血病的治疗从诱导治疗到维持治疗强度在不断优化,包括髓外白血病治疗去除放疗也有尝试,并获得成功。优化治疗的实现也得益于免疫学、分子生物学相关新技术的发展、规范化临床队列及与之相应的生物样本库建立。该文对近年来精准分层的实施及急性B淋巴细胞白血病降低强度优化治疗的相关研究进行梳理总结,为临床医生提供参考。     

儿童急性淋巴细胞白血病患儿脑脊液状态与预后的关系

目的 探讨流式细胞学检测儿童急性淋巴细胞白血病（ALL）中枢神经系统浸润阳性（CNSI⁺）患者的临床特征及其与预后的关系。方法 回顾性收集2008年4月至2013年6月CNSI⁺ALL患儿66例临床资料,对不同化疗阶段即诱导期、巩固维持期患儿的临床特征、实验室检查及预后进行比较分析。结果 66例CNSI⁺ALL患儿中,诱导期50例,巩固维持期16例。分子生物学结果显示巩固维持期CNSI⁺患儿预后良好基因比例明显高于诱导期患儿（P < 0.05）,巩固维持期患儿复发率明显高于诱导期患儿（P < 0.05）。21例CNSI⁺ALL患儿复发,其中诱导期10例,巩固维持期11例,巩固维持期复发患儿中枢神经系统合并骨髓的复发比例明显高于诱导期复发患儿（P < 0.05）,巩固维持期复发患儿脑脊液生化阳性率明显高于诱导期复发患儿（P < 0.05）。诱导期患儿无复发生存（RFS）率明显高于巩固维持期（P < 0.001）,两组总体生存（OS）率比较差异无统计学意义（P > 0.05）。结论 ALL患儿CNSI⁺对不同化疗阶段RFS率有影响,但对OS率无明显影响;巩固维持期出现CNSI⁺的患儿复发率高,临床上应引起重视。     

Induction therapy in pediatric kidney transplant recipients discharged with a triple drug immunosuppressive regimen

Sampaio MS, Poommipanit N, Kuo H‐T, Reddy PN, Cho YW, Shah T, Bunnapradist S. Induction therapy in pediatric kidney transplant recipients discharged with a triple drug immunosuppressive regimen.
Pediatr Transplantation 2010: 14:770–778. © 2010 John Wiley & Sons A/S. Abstract: We evaluated the effectiveness of induction therapy on transplant outcomes during 2004–2007 in the United States. We retrospectively reviewed OPTN/UNOS registry and selected kidney pediatric (<21‐yr) recipients that received no induction (NoIND), IL‐2RA, or rabbit anti‐THY and were discharged with a triple drug immunosuppressive maintenance regimen, including steroids. Of 2932 recipients, 20%, 36%, and 43% were in NoIND, THY, and IL‐2RA groups, respectively. The majority received tacrolimus (88%) and MMF (89%) at discharge. There was no association of induction with the risk of acute rejection even after adjusting for known cofounders. Compared to NoIND, IL2‐RA, but not THY, had a modest decrease (3%) in absolute rate of graft loss and was associated with a risk reduction ratio of 0.51 (95% CI, 0.31–0.84) in one‐yr graft loss. At three yr, no induction agent was associated with decreased graft loss. In conclusion, induction agents were used in 80% of pediatric kidney recipients discharged with a triple drug immunosuppressive maintenance regimen between 2004–2007 in the United States. Neither THY nor IL‐2RA was associated with reduced rejection episodes. The use of induction therapy was not associated with improvement in three‐yr graft survival.     

Akute lymphoblastische Leukämien (ALL) im Kindes- und Jugendalter

Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood and adolescence. Nowadays 80–85?% of patients can be cured from the disease with first-line therapy. The development of a relapse risk adapted polychemotherapy, including simultaneous prophylactic treatment of the central nervous system and implementation of the protocols in multicentre therapy optimization trials represent one of the most distinguished stories of success in the whole field of oncology. By using initial laboratory parameters, biological features of the leukemic cells and initial response to therapy, the patient risk for relapse can be predicted very reliably so that in almost all clinical trials most of the prognostic parameters mentioned are used for treatment stratification. Nevertheless, 20?% of patients relapse so that future research aims at developing a more targeted therapy directed towards molecular alterations of the leukemic cells in order to improve therapeutic efficacy and reduce therapy-associated side effects.     

The results of high risk children's acute lyrnphoblastic leukemia total therapy. A report from the Polish children's leukemia/lymphoma study group

The study evaluates the efficacy of seven drug systemic therapy and three drug intrathecal treatment in children with acute lymphoblastic leukemia (ALL). Three hundred and thirty-five children with ALL treated at six hematological centers in Poland were divided into two groups: standard group and high risk group according to the BFM score method. Ninety-two children estimated as high risk patients diagnosed between 1978 and 1981 were treated according to the Polish Children's Leukemia/Lymphoma Study Group (PCLSG) program adopted from LSA₂L₂ regimen. The patients received prednisone, vincristine, adriamycin and cyclophosphamide as remission induction treatment, followed by cytarabin and 6-thioguanine given as consolidation therapy. The central nervous system prophylaxis consisted of cranial irradiation and intrathecal methotrexate, cytarabin and hydrocortisone. In maintenance phase, three different drug combinations were given as intermittent therapy. The total duration of therapy was 2.5 years. The life table analysis showed a 38% disease free survival and 50% complete continuous remission (CCR) for the total group of patients. A relatively high incidence of CNS relapse was observed. These results indicated that the regimen applied was not satisfactorily effective for the increased risk of ALL. Three of seven evaluated prognostic indices—age, mediastinal mass and cytochemical features—were significantly associated with probability of survival of the patients with protocol applied. Some other therapy proposals are discussed.     

Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia

Approximately 90% of the 2,000 children, adolescents, and young adults enrolled each year in Children's Oncology Group acute lymphoblastic leukemia (ALL) trials will be cured. However, high‐risk subsets with significantly inferior survival remain, including infants, newly diagnosed patients with age ≥10 years, white blood count ≥50,000/µl, poor early response or T‐cell ALL, and relapsed ALL patients. Effective strategies to improve survival include better risk stratification, optimizing standard chemotherapy and combining targeted therapies with cytotoxic chemotherapy, the latter of which is dependent upon identification of key driver mutations present in ALL. Pediatr Blood Cancer 2013; 60: 957–963. © 2012 Wiley Periodicals, Inc.     

儿童急性淋巴细胞白血病化疗后并发脓毒症临床分析

目的探讨儿童急性淋巴细胞白血病(ALL)化疗后并发脓毒症的临床及病原学特点。方法回顾性分析2008年4月至2014年12月诊断为ALL并以CCLG-ALL 2008方案化疗后并发血培养阳性脓毒症患儿的临床及病原学资料。结果 545例诊断ALL并以CCLG-ALL2008方案治疗的患儿中112例(145例次)化疗后并发脓毒症,发生率为20.55%。标危和中危组患儿脓毒症高发于诱导缓解治疗阶段,高危组患儿脓毒症高发于巩固治疗阶段。最常见感染部位是呼吸道。血培养病原菌以革兰阳性菌居多。革兰阳性菌对万古霉素、利奈唑胺、替考拉宁敏感率高,革兰阴性菌对美罗培南、亚胺培南敏感率高。高危型、中心静脉置管、中性粒细胞计数0.1×109/L及中性粒细胞缺乏持续时间7 d者脓毒症发生率显著升高(P0.001)。112例患儿治疗有效率95.17%,脓毒症相关病死率1.28%。结论脓毒症是ALL患儿化疗后的重要并发症及死亡原因之一。     

Transient hyperglycemia in Hispanic children with acute lymphoblastic leukemia

BACKGROUND: Transient hyperglycemia occurs commonly during the treatment for childhood acute lymphoblastic leukemia (ALL). The purpose of this study was to examine the incidence of and risk factors for transient hyperglycemia during induction chemotherapy in Hispanic pediatric patients diagnosed with B-Precursor ALL. PROCEDURE: The study cohort consisted of 155 Hispanic pediatric patients diagnosed with ALL and treated at one of two South Texas pediatric oncology centers between 1993 and 2002. Hyperglycemia was defined as > or = 2 glucose determinations of > or = 200 mg/dl during the first 28 days of induction chemotherapy. RESULTS: Overall, 11.0% of the study cohort developed transient hyperglycemia during induction chemotherapy. Age and body mass index (BMI) were both positively associated with the risk of hyperglycemia. Females exhibited a substantially higher risk of hyperglycemia than males, but this association did not reach statistical significance after adjusting for other covariates. Among patients who developed hyperglycemia, 100% of those who required insulin were in the 13-18-year age group and reported a family history of diabetes. Hyperglycemic patients classified as obese (BMI > or = 95 centile) were more than twice as likely to have required insulin therapy compared to overweight patients (BMI 85-<95 centile) and three times as likely to have required insulin compared to normal weight (BMI < 85 centile) patients. CONCLUSIONS: The incidence of chemotherapy-induced transient hyperglycemia in the present study cohort is comparable to that reported in previous pediatric ALL patients. This finding is interesting in view of the elevated prevalence of obesity and the underlying dietary behaviors in this Hispanic study cohort.     

Children's Oncology Group's 2013 blueprint for research: Renal tumors

Renal malignancies are among the most prevalent pediatric cancers. The most common is favorable histology Wilms tumor (FHWT), which has 5‐year overall survival exceeding 90%. Other pediatric renal malignancies, including anaplastic Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor, and renal cell carcinoma, have less favorable outcomes. Recent clinical trials have identified gain of chromosome 1q as a prognostic marker for FHWT. Upcoming studies will evaluate therapy adjustments based on this and other novel biomarkers. For high‐risk renal tumors, new treatment regimens will incorporate biological therapies. A research blueprint, viewed from the perspective of the Children's Oncology Group, is presented. Pediatr Blood Cancer 2013; 60: 994–1000. © 2012 Wiley Periodicals, Inc.     

Impact of pretransplant minimal residual disease on the post‐transplant outcome of pediatric acute lymphoblastic leukemia

There are few reports on the clinical significance of MRD before HSCT in pediatric ALL. We retrospectively analyzed the clinical significance of FCM‐based detection of MRD (FCM‐MRD) before allogeneic HSCT in pediatric ALL. Of 38 pediatric patients who underwent allogeneic HSCT for the first time between 1998 and 2014, 33 patients were in CR and five patients were in non‐CR. The CR group was further divided into two groups based on the pretransplant FCM‐MRD level: the MRD^neg (<0.01%; 30 patients) group and the MRD^pos (≥0.01%; three patients) group. There were significant differences in the three‐yr event‐free survival rates between the CR and non‐CR group, and between the MRD^neg and MRD^pos group. The three‐yr cumulative RI in the MRD^neg group were 27.3% ± 8.8%, whereas two of the three patients in the MRD^pos group relapsed within one yr after HSCT. The clinical outcome of the MRD^pos group was as poor as that of the non‐CR group in pediatric ALL. Therefore, an improvement in pretransplant treatment that aims to achieve a more profound remission would contribute to reducing the risk of relapse.     

Biology and treatment of acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL), the most common type of cancer in children, is a heterogeneous disease in which many genetic lesions result in the development of multiple biologic subtypes. Today, with intensive multiagent chemotherapy, most children who have ALL are cured. The many national or institutional ALL therapy protocols in use tend to stratify patients in a multitude of different ways to tailor treatment to the rate of relapse. This article discusses the factors used in risk stratification and the treatment of pediatric ALL.     

Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia

1 Background

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.

2 Procedure

In this retrospective population‐based study, we described the causes of death and estimated the risk for treatment‐related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL‐92 and ALL‐2000 trials.

3 Results

Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment‐related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment‐related mortality were as follows: high‐risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3–3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3–9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17–9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment‐related causes.

4 Conclusions

Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.     

The results of high risk children's acute lyrnphoblastic leukemia total therapy. A report from the Polish children's leukemia/lymphoma study group

The study evaluates the efficacy of seven drug systemic therapy and three drug intrathecal treatment in children with acute lymphoblastic leukemia (ALL). Three hundred and thirty-five children with ALL treated at six hematological centers in Poland were divided into two groups: standard group and high risk group according to the BFM score method. Ninety-two children estimated as high risk patients diagnosed between 1978 and 1981 were treated according to the Polish Children's Leukemia/Lymphoma Study Group (PCLSG) program adopted from LSA₂L₂ regimen. The patients received prednisone, vincristine, adriamycin and cyclophosphamide as remission induction treatment, followed by cytarabin and 6-thioguanine given as consolidation therapy. The central nervous system prophylaxis consisted of cranial irradiation and intrathecal methotrexate, cytarabin and hydrocortisone. In maintenance phase, three different drug combinations were given as intermittent therapy. The total duration of therapy was 2.5 years. The life table analysis showed a 38% disease free survival and 50% complete continuous remission (CCR) for the total group of patients. A relatively high incidence of CNS relapse was observed. These results indicated that the regimen applied was not satisfactorily effective for the increased risk of ALL. Three of seven evaluated prognostic indices—age, mediastinal mass and cytochemical features—were significantly associated with probability of survival of the patients with protocol applied. Some other therapy proposals are discussed.     

Intermittent combined chemotherapy with doxorubicin in recurrent childhood acute lymphoblastic leukemia

A series of 14 children with bone marrow or testicular recurrence of acute lymphoblastic leukemia (ALL) and treated with pulsed combined chemotherapy incorporating doxorubicin is reviewed. All had been previously adequately treated according to established leukemia protocols. Median disease-free survival for the series is 46 weeks, overall survival 62 weeks, and the toxicity of the therapy relatively low. This compares favorably with other reports of treatment of relapsed ALL and supports the formulation of prospective trials to evaluate anthracyclines in initial induction and consolidation phases of treatment of childhood ALL.     

Five-year single-center study of asparaginase therapy within the ALL-BFM 2000 trial

Background

Therapeutic drug monitoring (TDM) of asparaginase (ASNase), a fundamental element of acute lymphoblastic leukemia treatment, was integrated in the ALL‐BFM 2000 protocol on a voluntary basis.

Methods

Over a 5‐year period, 127 patients (1,355 samples) were monitored for asparaginase activity in a single‐center setting. We report monitoring data from throughout the ASNase containing treatment elements. Additional information obtained on risk stratification, minimal residual disease (MRD), steroid randomization and relapse is discussed in relation to ASNase activity.

Results

At completion of the induction phase 93% (115/124) of patients showed sufficient ASNase activity (5,000 U/m² Escherichia coli ASNase), 77 of 86 (90%) monitored patients finished the first re‐intensification element without requiring Erwinia ASNase. MRD, risk stratification and steroid randomization were not associated with significant differences in ASNase activity. Of patients who relapsed, only 25% (3/12) were able to maintain sufficient ASNase activity after E. coli ASNase.

Conclusion

This single‐center data set gives a true and unbiased insight into clinical reality of ASNase therapy. It shows no significant relationship between MRD positivity or risk stratification and ASNase treatment intensity. Overall, within the ALL‐BFM 2000 trial, 90% of patients completed first re‐intensification without requiring third‐line Erwinia ASNase. Pediatr Blood Cancer 2011; 57: 378–384. © 2011 Wiley‐Liss, Inc.     

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials

Children with Down syndrome have a 150‐fold increased risk of developing acute myeloid leukemia (AML) and 20‐fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non‐Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non‐Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow‐up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed‐lineage leukemia.     

Association of clinical trial enrollment and survival using contemporary therapy for pediatric acute lymphoblastic leukemia

While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event‐free survival (EFS) in pediatric B‐cell acute lymphoblastic leukemia (B‐ALL). In a retrospective cohort of 274 children (1–21 years) treated for B‐ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three‐year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5–94.5] versus 86.5% [95% CI, 77.7–92.0]). Clinical trial enrollment did not affect pediatric B‐ALL survival, albeit in a limited‐size cohort treated at a single academic institution.