Time to platelet recovery predicts outcome of patients with de novo acute lymphoblastic leukaemia who have achieved a complete remission

Survival in acute leukaemia depends on the achievement of complete remission (CR). However, CR is not a clear-cut phenomenon and certain variables of its definition could more accurately characterize the quality of the remission. Because platelet recovery > 100 x 10(9)/l is an essential component of CR in acute leukaemia, we hypothesized that time to platelet recovery (TPR) might be predictive of overall survival (OS) or disease-free survival (DFS) in acute lymphoblastic leukaemia (ALL). We analysed TPR in 249 patients with ALL who entered CR after one course of induction chemotherapy and correlated TPR with DFS and OS. TPR was significantly associated with both DFS and OS if it occurred within a maximum of about 60 d from start of therapy. Furthermore, during that time period, the relative risk of death increased with increasing TPR. Although presence of the Philadelphia chromosome was the single most important adverse feature at diagnosis, the effect of TPR on survival continued to be significant within this patient subgroup. This effect was so pronounced that Philadelphia chromosome-positive patients with a TPR of 12 d had a better outcome than Philadelphia chromosome-negative patients with a TPR of 48 d. Thus, a short TPR seems to be able to override adverse characteristics in the outcome of ALL patients treated with chemotherapy. We conclude that a quicker TPR predicts longer DFS and OS in patients with ALL. As platelet counts are obtained almost daily in patients undergoing chemotherapy, TPR can readily be utilized to assess the prognosis of these patients.     

Clinical utility of marrow cell tissue cultures in acute leukemia of childhood

To determine the clinical value of tissue culture techniques in the study of acute leukemia, marrows from 50 children (40 acute lymphoblastic [ALL], 10 acute myeloblastic [AML]) were cultured by the use of an AML blast colony assay and the CFU-GEMM assay. In the AML assay, AML marrow gave rise to high numbers of blast colonies within 24 to 48 hr; in sharp contrast, 37 of 40 ALL marrows did not yield colonies in this assay. In the CFU-GEMM assay, AML marrow produced excessive numbers of monocyte-macrophage CFU-C colonies, an obvious background of individual macrophages and clusters, and occasional blast colonies. ALL marrow yielded very low numbers of granulocytic CFU-C colonies, no background of macrophage cells, and no blast colonies. These clear-cut differences in cellular growth kinetics in vitro between ALL and AML marrows should allow confirmation of the type of acute leukemia within 24 to 48 hr. The colony assays may also be valuable in differentiating ALL from AML in difficult diagnoses when conventional approaches are nondiagnostic.     

急性淋巴细胞白血病治疗相关的伴骨髓红系明显增生的急性髓系白血病病例报告

<正>2016年更新版《WHO造血和淋巴组织肿瘤分类》中~([1]),将伴有骨髓原始红细胞≥30%,原始髓系20%,既往有放化疗史,定义为治疗相关伴红系明显增生的急性髓系白血病(therapy-related acute myeloid leukemia,T-AML)的范畴。在急性红白血病(acute erythroleukemia,AEL)分类中,相比于2008年的标准~([2]),仅保留了纯红细胞白血病     

Children Diagnosed as Mixed-Phenotype Acute Leukemia Didn’t Benefit from the CCLG-2008 Protocol,Retrospective Analysis from Single Center

Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia with a poor clinical outcome which lacks specific therapy. To evaluate the therapeutic efficiency of CCLG-2008 protocol used for acute lymphoblastic leukemia (ALL) in China on MPAL children who were initially diagnosed as ALL by morphology, we reviewed patients’ database diagnosed as ALL and MPAL according to WHO classification and compared their outcomes from July 2008 to June 2012. Total newly enrolled ALL in this study were 309 cases by morphology, in which ten cases were identified as MPAL mainly by immunophenotyping: B+ myeloid (3/10), T+ myeloid (2/10), B + T (4/10), trilineage (1/10). Two cases were classified as intermediate risk (IR) and 8 cases were high risk (HR) according to the CCLG-2008 criteria. Only one case of IR survived and others died due to primary resistance of chemotherapy and relapse. Compared with MPAL, ALL children in IR and HR had a longer survival (28.1 vs 9.5 months, p < 0.0001) and lower relapse (16.3 vs 85.7 %, p = 0.0002). In a summary, our result indicated that MPAL in children is a poor-risk disease which needs personalized therapy to improve outcome.

Electronic supplementary material

The online version of this article (doi:10.1007/s12288-014-0372-6) contains supplementary material, which is available to authorized users.     

Molecular and cytogenetic remission in a case of subtype M4E acute myelogenous leukemia with minimal monochemotherapy: high sensitivity or spontaneous remission?

Complete remission was observed in an adult patient with acute myelogenous leukemia after minimal monochemotherapy. Remission occurred after a severe febrile pneumonia and was accompanied by cytogenetic and molecular remission. The hypothesis of spontaneous remission was raised, even if a high sensitivity to low-dose cytostatics cannot be excluded. Such spontaneous complete remissions, often associated with bacterial infections and blood transfusions, are extremely rare, and are usually of short duration. Previous cases are summarized, and the role of etiologic factors is discussed.     

Transformation of myelodysplastic syndrome to acute lymphoblastic leukemia: A case report and review of the literature

Myelodysplastic syndrome (MDS) often transforms into acute leukemia, usually of a myeloid phenotype. However, the transformation of MDS into acute lymphoblastic leukemia (ALL) is extremely rare. We present a case of refractory anemia with excess of blasts (RAEB) that transformed into ALL. MDS (RAEB) was diagnosed in a 68-year-old Japanese woman in August 2001. Two months later, MDS progressed to erythroleukemia (French-American-British [FAB]classification, acute myeloid leukemia [AML]-M6), and in December, 2001, she was treated with combined chemotherapy containing aclarubicin, cytarabine, and granulocyte colony-stimulating factor, which improved her clinical symptoms. However, 1 month after the chemotherapy, she developed ALL. The blasts at that time had a markedly basophilic cytoplasm with multiple cytoplasmic vacuoles, and their morphology mimicked that of ALL-L3. The blasts also expressed CD13, a myeloid marker, in addition to lymphoid markers. Southern-blot analysis revealed rearrangement of the immunoglobulin heavy chain, but no additional chromosomal abnormality characteristic of ALL-L3 was detected. The patient was treated with chemotherapy, but she developed tumor lysis syndrome and died of multiple organ failure. Although the precise mechanism of lymphoid transformation is not yet fully understood, this case clinically supports the nature of MDS as a pluripotent hematopoietic stem cell disorder.     

Successful use of trametinib and dasatinib combined with chemotherapy in the treatment of Ph-positive B-cell acute lymphoblastic leukemia: A case report

Rationale:Relapsed or refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, showing survival rates of less than a year even with the use of novel therapies. In this report, we describe the safe and effective use of trametinib combined with dasatinib in a patient with acute lymphoblastic leukemia (ALL). To the best of our knowledge, this is the first report on the successful use of 2 targeted drugs such as trametinib and dasatinib in a pediatric patient with Ph+ ALL and recurrent pancreatitis.Patient concerns:A 6-year-old boy with ALL and Philadelphia chromosome (Ph+) who had recurrent asparaginase-associated pancreatitis.Diagnosis:The patient was diagnosed with ALL, based on clinical features, laboratory analyses, bone marrow aspiration evaluation in morphology, immunology, cytogenetics, and molecular.Interventions:The patient was treated with dasatinib combined with an intermediate risk-oriented chemotherapy. However, owing to recurrent asparaginase-associated pancreatitis, the patient has to abandon asparaginase in consolidation. Considering the high risk of relapse, we used trametinib and dasatinib combined with chemotherapy as maintenance chemotherapy.Outcomes:After 6 months, there were no obvious side effects or residual disease.Lessons:We suggest that the combination of trametinib and dasatinib may represent a viable option to treat patients with potential relapsed/refractory Ph+ ALL.     

ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia

Background and objectives: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers.

Methods: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27?000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls.

Results: Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and -resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p?=?0.0001) and CDH11 (79% vs. 40%, p?Conclusion: Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further.     

Childhood monosomy 7 syndrome

In recent years, chromosomal aberrations in various hematologic disorders have raised a great deal of interest. In fact, several nonrandom chromosomal abnormalities are now recognized to be responsible for a specific type of dyshemopoiesis while others are closely associated with characteristic hematologic features. Monosomy C, later shown to be monosomy 7 by different banding methods, has been described in children in relation to a peculiar myeloproliferative disorder. Retrospective analysis of early cases published in the literature and a recent observation that we wish to report suggest that the most consistent phenotypic expression of monosomy 7 is an increased susceptibility to bacterial infections related to a preleukemic dyshemopoiesis. Acute nonlymphocytic leukemia is the terminal event of this peculiar preleukemic syndrome, and thus suggests that monosomy 7 involves a stem cell already committed to myeloid differentiation.     

Replication analysis confirms the association of ARID5B with childhood B-cell acute lymphoblastic leukemia

Although childhood acute lymphoblastic leukemia is the most common pediatric cancer, its etiology remains poorly understood. In an attempt to replicate the findings of 2 recent genome-wide association studies in a French-Canadian cohort, we confirmed the association of 5 SNPs [rs7073837 (P=4.2 × 10⁻⁴), rs10994982 (P=3.8 × 10⁻⁴), rs10740055 (P=1.6 × 10⁻⁵), rs10821936 (P=1.7 × 10⁻⁷) and rs7089424 (P=3.6 × 10⁻⁷)] in the ARID5B gene with childhood acute lymphoblastic leukemia. We also confirmed a selective effect for B-cell acute lymphoblastic leukemia with hyperdiploidy and report a putative gender-specific effect of ARID5B SNPs on acute lymphoblastic leukemia risk in males. This study provides a strong rationale for more detailed analysis to identify the causal variants at this locus and to better understand the overall functional contribution of ARID5B to childhood acute lymphoblastic leukemia susceptibility.     

预防性使用左氧氟沙星对降低急性淋巴细胞白血病患儿CAT疗程期间感染风险的效果研究

目的 探讨预防性使用左氧氟沙星对降低急性淋巴细胞白血病(ALL)患儿CAT疗程期间感染风险的效果。方法 回顾性分析2015年1月至2022年8月安徽医科大学第二附属医院收治的324例初诊ALL患儿的临床资料。以诱导治疗期间未服用左氧氟沙星的264例患儿为对照组,接受预防性服用左氧氟沙星的60例患儿为观察组。比较两组CAT疗程期间血流感染(BSI)、中性粒细胞减少症(FN)、临床记录的感染(CDI)等感染事件的发生率,以及炎性指标水平和抗生素使用情况等。结果 观察组BSI、FN、严重感染、发热、CDI的发生率低于对照组,使用抗生素种类数≥3种、使用头孢菌素和大环内酯类药物的人数比例小于对照组,降钙素原(PCT)水平低于对照组,抗生素使用时间、住院时间短于对照组,差异有统计学意义(P<0.05)。logistic回归分析结果显示,经校正危险度分级、性别、年龄,预防性使用左氧氟沙星可有效降低感染的发生(aOR=2.814,P<0.05)。对照组和观察组最常见的感染均为呼吸道感染,但观察组呼吸道感染的发生率较对照组低,差异有统计学意义(P<0.05)。结论 预防性使用左氧氟沙...     

Impact of reinduction regimens for relapsed and refractory acute lymphoblastic leukemia in adults

The clinical outlook for adults with acute lymphoblastic leukemia (ALL) has Improved with the use of intensive chemotherapy. Complete remissions (CR) are achieved in 80% of adults but the majority relapse on maintenance chemotherapy and a few exhibit primary resistance to induction therapy. This report compares the various salvage treatments and provides guidance in selecting a regimen with the optimum clinical outcome. Regimens using high-dose ara-C (HDAC) in combination with mltoxantrone, amsacrine, or idarublcin are superior to HDAC alone or with L-asparaginase. The sequential administration of methotrexate and L-asparaginase Is equally effective. The duration of second CR is short for all chemotherapeutic regimens. © 1994 Wiley-Liss, Inc.     

复发/难治AML患者sorcin基因表达及意义

目的研究复发／难治急性髓细胞白血病（AML）患者骨髓可溶性耐药相关钙结合蛋白（sorcin）基因表达及意义。方法采用逆转录聚合酶链反应（RT—PCR）检测65例AML患者（观察组）,27例非白血病患者和健康人（对照组）sorcin基因表达水平。结果观察组sorcin基因表达水平高于对照组（P〈0．001）,其中复发／难治者高于初诊者和完全缓解（CR）者;AML各亚型sorcin基因过度表达存在差异,以M,阳性表达率最高;观察组临床耐药者sorcin基因表达显著高于非临床耐药者（P〈0．001）,且CR率显著低于非临床耐药者（P〈0．001）。结论sorcin基因过度表达与AML患者临床耐药密切相关,是影响预后的重要因素;sorcin可作为检测AML临床耐药和判断预后的指标之一。     

中国儿童急性淋巴细胞白血病GATA3基因单核苷酸多态性与预后的相关性研究

目的 研究中国儿童急性淋巴细胞白血病(ALL)患儿GATA3基因单核苷酸多态性(SNP)分布特点及其对预后的影响.方法 利用TaqMan探针荧光定量PCR法检测上海儿童医学中心2009-05～2014-12收治的678例ALL患者GATA3基因rs3781093和rs3824662两个SNP位点,分析其与早期治疗反应、...     

Expression of P-glycoprotein,Cyclin D1 and Ki-67 in Acute Lymphoblastic Leukemia: Relation with Induction Chemotherapy and Overall Survival

Previous studies showed that non-cycling cells have a higher multidrug resistance (MDR) expression, which may be down-regulated by proliferation induction. Triggering these cells into proliferation down-regulates high MDR expression. The aim of this study was to determine the expression of P-glycoprotein (PGP) and cell cycle parameters (cyclin D1 and Ki-67) in acute lymphoblastic leukemia (ALL) at diagnosis, and to evaluate the correlation between the expressions of each marker, and the clinical significance of such expression with response to induction chemotherapy and overall survival. A total of 78 newly diagnosed ALL patients were enrolled in our study. PGP, cyclin D1 and Ki-67 were determined by flow cytometry. PGP expression was encountered in 10/78 (12.8%) of ALL cases. Cyclin D1 and Ki-67 were expressed in 16/77 (20.6%) and 27/76 (34.6%) of ALL cases, respectively. None of the parameters were associated with response to induction chemotherapy and overall survival. Based on the current analysis, we conclude that a joint immunophenotypic evaluation of PGP and cell cycle parameters like that adopted in this study is unlikely to reveal mechanisms of multidrug resistance associated with the clinical outcome.     

High-dose cytosine arabinoside for acute nonlymphocytic leukemia

Eighteen patients with acute nonlymphocytic leukemia (ANLL), aged 17-73 years, were treated with high-dose cytosine arabinoside (HD-Ara-C) using 3 g/m2 IV q 12 hours X 12 doses. Seven patients were treated for relapse and four (57%) obtained a complete remission with a median duration of 19.5 weeks. In nine patients, refractory to conventional chemotherapy, no complete responders were observed. Treatment failure was most commonly due to drug resistance. Two elderly patients with ANLL not previously exposed to chemotherapy died during the initial induction. Recent data on the HD-Ara-C experience in ANLL are presented and compared with this study.     

Soluble l-selectin (sCD62L) in relapsed childhood acute lymphoblastic leukaemia

Soluble l-selectin (sCD62L) plasma concentrations at diagnosis and outcome were investigated in 193 children at first relapse of acute lymphoblastic leukaemia (ALL) after treatment according to the Berlin-Frankfurt-Münster relapsed ALL multicentre trials, ALL-REZ BFM 95 and 96. sCD62L was low (< fifth paediatric reference percentile) in 63 (33%) and high (> 95th percentile) in 36 (19%) children, and was independent of remission duration, sex, BCR-ABL fusion or extramedullary disease. High sCD62L was associated with circulating blasts and T-cell phenotype. More initial adverse events occurred in children with high and low levels of sCD62L (23 out of 99) than in those with normal levels (9 out of 94, P = 0.018). Among 75 worst-prognosis patients (risk groups S3/S4, isolated bone marrow relapse occurring less than 6 months after elective cessation of front-line therapy, or T-cell phenotype with bone marrow involvement), 27 had low sCD62L and decreased event-free survival (EFS) probability (PEFS5 = 0.09 at 5 years) and duration (219 d) compared with normal sCD62L (29 out of 75, PEFS5 = 0.24, 640 d, P = 0.01). Low (44 out of 118), normal (72 out of 118), and high (19 out of 118) sCD62L non-S3/S4 patients fared similarly (average PEFS5 = 0.45, 1369 d; P = 0.5). Low sCD62L may be a marker of malignant blasts replacing normal sCD62L-producing haematopoietic cells. In children with first relapse of ALL and worst prognosis, plasma sCD62L may be useful for risk-adapted stratification.