Quality of life during active treatment for pediatric acute lymphoblastic leukemia

The objectives of the study were to describe quality of life (QoL), identify predictors of worse QoL and examine QoL during different phases of active therapy for acute lymphoblastic leukemia (ALL). A multiinstitutional cross‐sectional study was performed in children with ALL. We included children at least 2 months from diagnosis who were receiving treatment in first remission. Parents described QoL using the PedsQL 4.0 Generic Core Scales and the PedsQL 3.0 Acute Cancer Module. The 206 children on treatment for ALL had overall [median 62.5, 95% confidence interval (CI) 34.8–94.4], physical (median 62.5, 95% CI 18.8–100.0) and psychosocial (median 65.4, 95% CI 38.3–94.2) summary scores that were one to two standard deviations lower than population norms. In high‐risk ALL, girls and older children had worse QoL. In standard‐risk ALL, those with lower household incomes and unmarried parents had worse QoL. QoL scores were generally constant across phases of ALL therapy. Children on therapy for ALL have lower QoL compared to healthy children. Age and gender predicted QoL in high‐risk ALL, whereas socioeconomics predicted QoL in standard‐risk ALL. Future efforts should focus on longitudinal studies that describe QoL over time within individual patients.     

High expression of Myosin 1g in pediatric acute lymphoblastic leukemia

Acute Lymphoblastic Leukemia (ALL) is the most frequent cancer in pediatric population. Although the treatment has improved and almost 85% of the children are cured about 20% suffer relapse, therefore finding molecules that participate in the pathogenesis of the disease for the identification of relapse and patients at risk is an urgent unmet need. Class I myosins are molecular motors involved in membrane tension, endocytosis, phagocytosis and cell migration and recently they have been shown important for development and aggressiveness of diverse cancer types, however Myo1g an hematopoietic specific myosin has not been studied in cancer so far. We evaluated the expression of Myo1g by qRT-PCR, Immunocytochemistry and Immunofluorescence in a cohort of 133 ALL patients and correlated the expression at diagnosis and after treatment with clinical features and treatment outcomes. We found high expression levels of Myo1g in Peripheral Blood Mononuclear Cells (PBMCs) from patients with ALL at diagnosis and those levels decreased after complete remission; furthermore, we found an increase in Myo1g expression on patients with 9:22 translocation and those who relapse. This study show that Myo1g is over expressed in ALL and that may participate in the pathogenesis of the disease specially in high-risk patients.     

Phase II study of topotecan in combination with dexamethasone, asparaginase, and vincristine in pediatric patients with acute lymphoblastic leukemia in first relapse

BACKGROUND: The authors evaluated the response rate, toxicity, and pharmacokinetics of topotecan given before standard induction therapy for childhood acute lymphoblastic leukemia (ALL) in first relapse. METHODS: Patients received topotecan (2.4 mg/m(2) daily as a 30-minute infusion) for 5 days before induction therapy with dexamethasone, vincristine, and asparaginase (native or pegylated Escherichia coli). The pharmacokinetics of topotecan were measured with the first dose of treatment in 23 patients. RESULTS: Twenty-eight of 31 patients with circulating blast cells were evaluable for response to topotecan. Twenty-five patients (89.3%) had a response (>25% decrease in circulating blast cells). The leukocyte count (P = .0001) and blast cell count (P = .0009) declined significantly during topotecan therapy. The median (range) topotecan lactone area under the concentration-time curve after the first dose was 85.4 L/hour/m(2) (range, 38.7-229.3 L/hour/m(2)). At the end of induction, 23 patients (74.2%) had a complete response, 1 patient (3.2%) had a partial response, 5 patients (16.1%) had no response, and 2 patients had died of infection. Six of the 17 patients who were studied for minimal residual disease (MRD) achieved MRD-negative status at the end of induction. The main toxicities were hematologic, gastrointestinal, and hepatic. The estimated 5-year survival rate, event-free survival rate, and cumulative incidence of second relapse were 24.1% +/- 7.9%, 18.2% +/- 7.4%, and 22.8% +/- 8.7%, respectively, in the 29 patients who had a hematologic first relapse. CONCLUSIONS: A regimen comprising single-agent topotecan given with a standard 3-drug combination was effective in inducing remission in pediatric patients with relapsed ALL and was tolerated well.     

BCL6、KLF5、NCL基因在儿童急性淋巴细胞白血病中异常表达的特点

目的:研究转录因子基因BCL6、KLF5及核仁蛋白基因NCL在急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患儿骨髓细胞中的表达情况及其在不同疾病状态下的表达特点。方法:选取北京儿童医院2004年1月至2005年12月住院ALL患儿100例,另取由于骨骼畸形而在北京儿童医院进行外科手术的5例非ALL患儿作对照;以基因芯片检测ALL患儿骨髓细胞中异常表达基因,GeXP多重基因表达分析系统检测BCL6、KLF5、NCL基因在另外选取的10例配对ALL患儿初诊及缓解期的表达变化。结果:基因芯片筛查发现,在100例各亚型ALL标本中,BCL6和KLF5mRNA表达均下调,NCLmRNA表达均上调。BCL6和KLF5mRNA在10例ALL初诊患儿骨髓细胞中表达较低,完全缓解后表达升高(0.380±0.16vs0.850±0.10,0.074±0.021vs0.228±0.049;均P<0.01);NCLmRNA在ALL初诊患儿骨髓细胞中表达较高,完全缓解后表达降低(0.234±0.054vs0.151±0.055,P<0.01)。在10例配对患者儿中,TEL-AML1阳性及E2A...     

Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV-positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995-2015) for the presence of CMV DNA identifying CMV-positive and CMV-negative cases. We performed a case-only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV-positive and CMV-negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01-1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV-positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06-4.37 and OR: 2.06, 95% CI: 1.17-3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV-positive (OR: 2.12, 95% CI: 1.24-3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV-positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.     

NOTCH1 pathway activating mutations and clonal evolution in pediatric T‐cell acute lymphoblastic leukemia

Molecular mechanisms involved in the relapse of T‐cell acute lymphoblastic leukemia (T‐ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole–exome sequencing in 30 pediatric T‐ALL cases, among which 11 diagnosis‐relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon–based deep sequencing. NOTCH1/FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine–rich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non–relapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P = .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis‐relapse samples, we identified NOTCH1 “switching” characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis‐relapse paired cases analyzed. We found another NOTCH1 “switching” case in a previously reported Berlin‐Frankfurt‐Münster cohort (n = 13), indicating NOTCH1 importance in both the development and progression of T‐ALL. Despite the limitations of having a small sample size and a non–minimal residual disease–based protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T‐ALL.     

Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia

Background

A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsed/refractory (R/R) B-ALL.

Methods

Data from five trials of blinatumomab for R/R B-ALL were pooled for analyses. Patients were placed in one of three groups: group 1, ≥50% bBMBs; group 2, ≥25% to <50% bBMBs; group 3, ≥5% to <25% bBMBs. Response and survival outcomes were compared between groups.

Results

Data from 683 patients (166 pediatric, 517 adult) were analyzed. Collectively, patients in groups 2 and 3 had significantly higher odds of achieving a complete remission (CR) (odds ratio [OR], 3.50 [95% confidence interval (CI), 2.23–5.48] and 3.93 [95% CI, 2.50–6.18], respectively; p < .001) and minimal/measurable residual disease response (OR, 2.61 and 3.37, respectively; p < .001) when compared with group 1 (reference). Groups 2 and 3 had a 37% and 46% reduction in the risk of death (hazard ratio [HR], 0.63 and 0.54, respectively; p < .001) and a 41% and 43% reduction in the risk of an event (relapse or death) (HR, 0.59 and 0.57, respectively; p < .001) compared with group 1. No significant differences in response or survival outcomes were observed between groups 2 and 3. Seven of nine patients whose bBMB% was lowered to <50% with dexamethasone achieved CR with blinatumomab.

Conclusion

Any bBMB% <50% was associated with improved efficacy following blinatumomab treatment for R/R B-ALL.     

Plerixafor as a chemosensitizing agent in pediatric acute lymphoblastic leukemia: efficacy and potential mechanisms of resistance to CXCR4 inhibition

In spite of advances in the treatment of pediatric acute lymphoblastic leukemia (ALL), a significant number of children with ALL are not cured of their disease. We and others have shown that signaling from the bone marrow microenvironment confers therapeutic resistance, and that the interaction between CXCR4 and stromal cell-derived factor-1 (SDF-1 or CXCL12) is a key mediator of this effect. We demonstrate that ALL cells that upregulate surface CXCR4 in response to chemotherapy treatment are protected from chemotherapy-induced apoptosis when co-cultured with bone marrow stroma. Treatment with the CXCR4 inhibitor plerixafor diminishes stromal protection and confers chemosensitivity. Using xenograft models of high-risk pediatric ALL, plerixafor plus chemotherapy induces significantly decreased leukemic burden, compared to chemotherapy alone. Further, treatment with plerixafor and chemotherapy influences surface expression of CXCR4, VLA-4, and CXCR7 in surviving ALL blasts. Finally, prolonged exposure of ALL blasts to plerixafor leads to a persistent increase in surface CXCR4 expression, along with modulation of surface expression of additional adhesion molecules, and enhanced SDF-1α-induced chemotaxis, findings that may have implications for therapeutic resistance. Our results suggest that while CXCR4 inhibition may prove useful in ALL, further study is needed to understand the full effects of targeting the leukemic microenvironment.     

MLPA is a powerful tool for detecting lymphoblastic transformation in chronic myeloid leukemia and revealing the clonal origin of relapse in pediatric acute lymphoblastic leukemia

Copy number alterations (CNAs) at 58 different loci have been investigated in 95 bone marrow or peripheral blood samples from patients with chronic myeloid leukemia (CML) or pediatric acute lymphoblastic leukemia (pALL) using multiplex ligation-dependent probe amplification (MLPA). In all but one case, the CNA profile correctly distinguished patients with CML who were in chronic phase from those in lymphoblast crisis. Within the chronic phase group, we could not separate patients resistant to imatinib therapy from those who were good responders. In our investigation of patients with pALL, a panel of MLPA probes broader than ever before was applied. Paired diagnostic and relapse samples from patients with pALL demonstrated clonally related or independent dominant clones, suggesting the presence of a pre-leukemic cell group. Identification of the origin of cell populations dominating at relapse will have a great effect on future treatment strategies. In summary, we have demonstrated the versatility of MLPA by using this cost-effective technique for two new applications.     

Individualized leukemia cell-population profiles in common B-cell acute lymphoblastic leukemia patients

Immunophenotype is critical for diagnosing common B-cell acute lymphoblastic leukemia (common ALL) and detecting minimal residual disease. We developed a protocol to explore the immunophenotypic profiles of common ALL based on the expression levels of the antigens associated with B lymphoid development, including IL-7Rα (CD127), cytoplasmic CD79a (cCD79a), CD19, VpreB (CD179a), and sIgM, which are successive and essential for progression of B cells along their developmental pathway. Analysis of the immunophenotypes of 48 common ALL cases showed that the immunophenotypic patterns were highly heterogeneous, with the leukemic cell population differing from case to case. Through the comprehensive analysis of immunophenotypic patterns, the profiles of patient-specific composite leukemia cell populations could provide detailed information helpful for the diagnosis, therapeutic monitoring, and individualized therapies for common ALL.     

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.     

miR-128在急性淋巴细胞白血病中的表达

目的 探讨miR-128在急性淋巴细胞白血病(ALL)中的表达及其意义.方法 采用实时荧光定量聚合酶链反应法对62例ALL患者和20例骨髓正常患者骨髓单个核细胞miR-128的相对表达量进行检测,并与患者的临床资料进行相关性分析.结果 miR-128在ALL患者中的相对表达量高于健康对照组(P＜0.05),但其在急性B淋巴细胞白血病(B-ALL)及急性T淋巴细胞白血病(T-ALL)中的表达水平差异无统计学意义(P＞0.05),miR-128的表达与是否存在bcr-abl融合基因及其mRNA的表达水平均无相关性(均P＞ 0.05).结论 miR-128在ALL患者中表达上调,可作为临床诊断ALL的潜在分子标志物,bcr-abl融合基因的表达对miR-128在ALL中的表达无明显影响.     

Adult acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Although ALL is a success story in pediatric oncology, results in adults lag behind those in children. An expansion of new drugs, more reliable immunologic and molecular techniques for the assessment of minimal residual disease, and efforts at more precise risk stratification are generating new aspects of adult ALL therapy. For this review, the authors summarized pertinent and recent literature on ALL biology and therapy, and they discuss current strategies and potential implications of novel approaches to the management of adult ALL. Cancer 2010. © 2010 American Cancer Society.     

Therapy‐related acute myelogenous leukemia and myelodysplastic syndrome in patients with acute lymphoblastic leukemia treated with the hyperfractionated cyclophosphamide,vincristine, doxorubicin,and dexamethasone regimens

BACKGROUND:

Secondary malignancies including myeloid neoplasms occur infrequently in acute lymphoblastic leukemia (ALL) and to the authors' knowledge have not been as well documented in adults as in children.

METHODS:

A total of 641 patients with de novo ALL who were treated with the hyper‐CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen or its variants were analyzed.

RESULTS:

Sixteen patients (2.49%) developed secondary acute myelogenous leukemia (AML) (6 patients) or myelodysplastic syndrome (MDS) (10 patients). At the time of ALL diagnosis, the median age was 53 years; cytogenetics were normal in 11 patients, pseudo‐diploidy with del(2) in 1 patient, t(9;22) in 1 patient, and unavailable in 3 patients. Frontline therapy included hyper‐CVAD in 7 patients, hyper‐CVAD with rituximab in 8 patients, and hyper‐CVAD with imatinib in 1 patient. Karyotype at time of AML/MDS diagnosis was ?5, ?7 in 9 patients, normal in 1 patient, complex in 1 patient, inv(11) in 1 patient, t(4;11) in 1 patient, del(20) in 1 patient, and unavailable in 2 patients. Secondary AML/MDS developed at a median of 32 months after ALL diagnosis. Cytarabine plus anthracycline–based treatment was given to 12 patients with AML and high‐risk MDS. One patient with MDS received arsenic trioxide, 1 received clofarabine, and 2 received decitabine. Response to treatment was complete remission in 3 patients, partial remission in 6 patients, and no response in 6 patients; 1 patient was untreated. Eight patients (1 with AML and 7 with MDS) underwent allogeneic stem cell transplantation, and all but 2 died at a median of 3 months (range, 0.5–11 months) after transplantation. The median overall survival after a diagnosis of secondary AML and MDS was 9.25 months (range, 1+ to 26+ months).

CONCLUSIONS:

Secondary AML and MDS occur infrequently in adult patients with de novo ALL treated with the hyper‐CVAD regimens, and response to therapy is poor. Cancer 2009. © 2008 American Cancer Society.     

Role of CXCL12, TP53 and CYP1A1 gene polymorphisms in susceptibility to pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukemia and represents one third of all pediatric malignancies. Epidemiological studies have shown that various genetic factors play a crucial role in leukemogenesis. Recent genetic association studies on cancer risk have focused on the effects of single-nucleotide polymorphisms (SNPs) in genes that regulate inflammation and tumor suppression, such as chemokines, TP53 and cytochrome P450s (CYPs). Genetic polymorphisms in the 3′ untranslated region of the C-X-C motif chemokine ligand 12 (CXCL12; rs1801157) and TP53 (rs1042522) genes have been suggested to influence the risk of ALL in children, while other studies have indicated an association between the CYP1 subfamily A member 1 (CYP1A1)*2C (rs1048943) allele and leukemia risk. The aim of the present study was to investigate the possible association of rs1801157 (CXCL12), rs1042522 (TP53) and rs1048943 (CYP1A1*2C) SNPs with an increased susceptibility of developing ALL. These SNPs were analyzed in 86 children or adolescent patients with ALL and 125 control subjects by PCR-restriction fragment length polymorphism and allelic-specific chain reaction techniques. A higher frequency of CYP1A1*2C heterozygotes and TP53 rare homozygotes, which include the proline (Pro)/Pro genotype, was observed among children with ALL and control subjects, whereas no significant differences were observed for the CXCL12 SNP. Furthermore, the analysis of various allelic combinations of the aforementioned gene polymorphisms demonstrated a markedly increased risk of developing ALL in children. In conclusion, the present study demonstrated that there was a strong association between CYP1A1*2C heterozygotes, as well as the TP53 Pro/Pro genotype, and an increased susceptibility for pediatric ALL in Caucasians.     

New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia

Significant advances have been made in the last decade toward a better understanding of the disease pathogenesis and the development of novel therapies that target specific subsets of adult acute lymphoblastic leukemia (ALL). Risk‐adapted strategies are transforming the disease treatment and prognosis. With current treatment regimens, long‐term survival is achieved by approximately 50% of patients with B‐cell ALL, 50% to 60% of patients with Philadelphia chromosome–positive ALL, and approximately 80% of patients with Burkitt's leukemia. Genomic profiling in ALL has identified new prognostic markers, new therapeutic targets, and novel ALL subtypes. These may be amenable to future targeted therapies that can further improve outcomes. The early recognition of early precursor T‐cell ALL, a distinct pathobiological entity with a poor prognosis, is essential for the development of an effective clinical management strategy. The role of monoclonal antibodies and cytotoxic T‐cell therapies continues to be defined. Many of the approaches are currently being evaluated for ALL salvage. Their incorporation into frontline adult ALL therapy, in concomitant or sequential strategies, may increase the cure rates to levels achieved in pediatric ALL and may reduce the need for prolonged intensive and maintenance chemotherapy. Cancer 2015;121:2517–2528 . © 2015 American Cancer Society.     

microRNA与急性淋巴细胞性白血病关系的研究进展

microRNA是一类长度为19～25个核苷酸的内源性非编码小分子RNA,通过抑制靶基因的表达参与包括细胞增殖、分化、凋亡、炎症调节、干细胞发育等几乎所有重要的生物学过程,许多microRNA在肿瘤细胞中异常表达,提示可能与肿瘤的发生发展有关。急性淋巴细胞性白血病（ALL）是最常见的儿童肿瘤,临床表现、形态学、免疫表型及遗传学特征极具异质性。现已发现若干microRNA在ALL 中异常表达,且与其生物学特性以及临床特征、预后和治疗相关。对microRNA的了解有助于帮助人们更深入地认识ALL 的发病机理,有助于在寻找合适的诊断、判定预后的分子标志物以及潜在的治疗靶点方面取得新突破。      

Treatment of acute leukemia in children: recent advances and future challenges

Recently advances have been made in the treatment of acute leukemia in children, it is now possible to cure more than 70% of children with acute lymphoblastic leukemia. With the introduction of more intensive chemotherapy regimens in patients at higher risk of relapse and the identification of cases that could be less intensely treated to diminish long-term toxicity, it could be possible to improve these excellent results. In contrast, pediatric acute myeloid leukaemia seems to be a more heterogeneous disease and its response to conventional chemotherapy is not as uniform. Introduction of new and more efficacious therapies is necessary to improve the poor outcome, especially among patients with high-risk features.