MicroRNA expression and activity in pediatric acute lymphoblastic leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric neoplasia. Highly heterogeneous, ALL includes several genetic subtypes with varying clinical outcome. Although, some features are well established as prognostic predictors, the details of the molecular mechanisms underlying different phenotypes are only beginning to emerge. Recently, microRNAs (miRNAs) have been shown to influence a range of physiological processes and, consequently, alterations in their expression and functions have been associated with the development of many cancers, including leukemia. This article aims to review the current state of knowledge of the role of miRNAs on the biology of childhood ALL, also including relevant findings from the adult leukemia literature.     

培门冬酶治疗儿童初发急性淋巴细胞白血病的远期疗效

目的观察含培门冬酶注射液的VDPAP方案诱导治疗儿童急性淋巴细胞白血病(ALL)的远期疗效。方法选择初发ALL患儿,随机分成两组:试验组采用含国产培门冬酶注射液的VDPAP方案诱导治疗,对照组采用含左旋门冬酰胺酶(L-Asp)的VDLP方案。统计一疗程完全缓解(CR)率,并采用Kaplan-Meier法评估患儿的总生存(OS)率及疾病无进展生存(PFS)率,组间差异用Log-rank检验。结果入组患儿51例,可评估疗效者46例,其中试验组27例,CR率为96%,总有效率为96%;对照组19例,CR率为95%,总有效率为100%,两组间差异无统计学意义。试验组3年预计OS率为(78.8±8.4)%,5年预计OS率为(68.9±11.8)%;对照组3年预计OS率为(88.9±7.4)%,5年预计OS率为(82.1±9.5)%,两组间差异无统计学意义。试验组3年预计PFS率为(74.1±9.1)%,5年预计PFS率为(63.5±12.5)%;对照组3年预计PFS率为(83.3±8.8)%,5年预计PFS率为(77.8±9.8)%,两组间差异无统计学意义。结论含培门冬酶的VDPAP方案与含L-Asp的VDLP方案诱导治疗儿童ALL,其CR率及远期疗效相似,可以作为儿童ALL的一线治疗方案。     

Immunologic classification of acute lymphoblastic leukemia

The study of cell surface antigens in acute lymphoblastic leukemia (ALL) has provided the basic information for classification of ALL into B cell or T cell lineage. Each immunologic type may present at an immature or more mature stage of maturation. This classification has prognostic significance since mature B cell and T cell ALL phenotypes have a worse prognosis, compared to common acute lymphoblastic leukemia-associated antigen (CALLA) positive leukemias that belong to an immature B cell lineage and have the best prognosis. By performing these immunologic studies together with those of molecular biology, it is now possible to establish the precise level of cell differentiation, the point at which the malignant transformation occurred. Further studies may allow correlation of these different maturation stages, thus providing insight into the biologic behavior of lymphoblastic leukemia.     

Recovery of immune function after cessation of maintenance therapy in acute lymphoblastic leukemia (ALL) of childhood

In previously healthy children, serum immunoglobulin levels at diagnosis of acute lymphoblastic leukemia (ALL) were entirely in the normal range. After antileukemic therapy had been given for 26–27 months, serum immunoglobulin levels were low. In 32 children these parameters could be followed for periods up to 3 years after cessation of therapy, the patients remaining in unmaintained remission.At cessation of therapy serum immunoglobulin levels were at the tenth centile of the normal range or slightly below. IgG promptly returned to normal levels and then remained in the normal range. IgA levels were restored much more slowly. Most striking was the slow and incomplete return of serum IgM to normal levels. Even after a follow-up of 3 years the mean was still subnormal. This was not accompanied by clinical signs of disturbed immunity. Our study points out that in assessing the long-term immunosuppressive effects of anticancer therapy the follow-up period must be sufficiently long.     

The Munich study on the treatment of acute lymphoblastic leukemia in childhood (ALL 77-02)

149 children with acute lymphocytic leukemia (ALL) were admitted to a prospective therapeutic regime. Remission induction was achieved by vincristine, daunorubicine, L-asparaginase and prednisone. During consolidation the patients received three intermediate dose methotrexate (MTX) infusions over 24 hours combined with intrathecal MTX, followed by L-asparaginase. High-risk patients were treated in addition with high dose cyclophosphamide and ARA-C over 3 weeks. Standard risk patients received cranial irradiation with 18 Gy, high-risk patients with 24 Gy. Maintenance therapy was performed with 6-mercaptopurine and MTX orally. Immunologic phaenotyping revealed: c-ALL 73%, pre-T or T-ALL 15%, c/T-ALL 4% and undifferentiated leukemia (AUL) 8%. Only 1 patient was nonresponder, 7 patients died during induction therapy, 5 patients during continuous complete remission (CCR). 18 relapses occurred, 12 of which were systemic, 8 CNS and 2 testicular relapses. In the total group the 54 months probability of CCR is 0,68 +/- 0,05 (life-table-analysis), for the reduced group 0,75 +/- 0,05. In the reduced group the probability of CCR at 54 months for standard risk patients is 0,86 +/- 0,06; for high-risk patients 0,60 +/- 0,09; for patients with c-ALL 0,73 +/- 0,08; for patients with c/T-ALL 1,0 +/- 0,0; for patients with pre-T or T-ALL 0,58 +/- 0,2 and for patients with AUL 0,45 +/- 0,25. For the reduced group the CCR probability at 54 months in relation to the leukocytes (WBC) at diagnosis is in patients with WBC less than 25 X 10(3)/mm3: 0,80 +/- 0,06; for patients with WBC greater than 25 X 10(3)/mm3: 0,63 +/- 0,11.     

Chemotherapy with cyclophosphamide,vincristine, cytosine arabinoside,and prednisone (COAP) in childhood acute lymphoblastic leukemia (ALL)

Three groups of children with acute lymphoblastic leukemia (ALL) were treated with intermittent cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP). Group A (no prior relapse) and Group B (prior single-agent relapse) received COAP after 12 months on another chemotherapy regimen. Children in Group C (prior relapse on multiagent regimens) received COAP following A-COAP (asparaginase plus COAP) reinduction. Median disease-free survival after beginning COAP was not reached for Group A, but was only 7 months for Groups B and C. As of November 1976, there were 8 of 15 Group A patients, 1 of 12 Group B patients, and 1 of 28 Group C patients who had remained disease-free from 38 to 60 (median 54.5) months and were off chemotherapy. COAP has activity in childhood ALL. However, effectiveness in markedly diminished in patients with prior bone marrow relapse.     

Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95

BACKGROUND: Osteonecrosis (ON) as a complication during treatment of acute lymphoblastic leukemia (ALL) has gained rising attention over the past decade. Corticosteroids, representing an essential element of antileukemic therapy, are known to induce ON, which in turn may cause significant morbidity. Due to spontaneous reporting of affected patients with ON, a group-wide evaluation was performed to determine incidence, risk factors, and morbidity for ON. PROCEDURE: Patients were identified via spontaneous reporting to the study center and via questionnaire, addressing all 64 participating centers. We retrospectively analyzed 1,951 patients below 18 years of age who were treated according to trial ALL-BFM 95 between 01.01.1996 and 30.06.2000. RESULTS: Thirty-one patients (14 male, 17 female) affected by ON were identified. The overall 5-year cumulative incidence for ON is 1.8%. The incidence for patients <10 years is 0.2%, whereas for patients >/=10 years it is 8.9% (P = 0.00) and 16.7% (P = 0.003) for patients >/=15 years. The majority (n = 20) showed ON in two or more joints, and the joints most commonly affected were knees (14 patients, 24 affected knees) and hips (11 patients, 20 affected joints). Thirteen out of 31 patients had to undergo surgery in the course of their disease. CONCLUSIONS: Symptomatic ON is a rare event in patients treated with BFM-type chemotherapy with an overall 5-year cumulative incidence of 1.8%. The age group >/=10 years, and particularly adolescents >/=15 years have a significantly higher risk of developing ON.     

Hemostasis and fibrinolysis in acute lymphoblastic leukemia (ALL) in childhood--analysis of life-threatening bleeding

66 children with ALL, who were admitted to the University Children's Hospital at Münster for treatment according to the BFM protocol 79/81, presented initially with the following abnormal hemostatic parameters: Prolongation of bleeding time (89%), thrombocytopenia (83%), pathological prothrombin time (69%), increased FDP (32%, reduced F XIII (33%), abnormal short PTT (34%). There was a significant discrepancy between immunologically and functionally measured fibrinogen, which is only partially explained by the presence of FDP. Patients with T-cell leukemia (n = 11) had significantly higher WBC, longer prothrombin times, and lower fibrinogen levels than patients with Non-T/non-B ALL. The initial coagulation parameters did not discriminate the 6 patients who presented life threatening bleeding episodes. The two patients with high blast count (350 000 and 548 000/mm3) and T-ALL had intracranial bleeding before therapy started; in one of them vascular infiltration of blast cells was demonstrated at autopsy. Two other patients had bacterial infections, which in one case led to local bleeding into the lungs and in the other case to DIC. Two further children presented intracranial bleeding episodes which could be associated with asparaginase therapy. 5 of the 6 patients with life threatening episodes had a platelet count of more than 35 000/mm3.     

Immunological aspects of acute lymphoblastic leukemia (ALL) in children (author's transl)]

The prognostic significance of the immunological classification of ALL in children is described. While the prognosis of patients with the most frequent O- or common-ALL (frequency 70-85%) is comparatively good, prognosis of patients with T-ALL, which is most probably identical with acid phosphatase positive ALL,and with the rare B-ALL is worse. The therapeutic implications of the immunological classification is discussed.     

Prognostic value of chromosome aberrations in childhood acute lymphoid leukemia (ALL)

Cytogenetic analyses were performed on 43 children with acute lymphoblastic leukemia (ALL) before starting the therapy. Evaluable metaphases were obtained in 26 cases (60.46 %). The prognostic value of the initial chromosome picture and that of the different non-cytogenetic prognostic features was studied. In 14 out of 26 children (53.85 %) clonal chromosomal aberrations were found. The prognosis in the normal and normal/abnormal groups was significantly better than in patients with only abnormal cells. They found the remission rate of the diploid and hyperdiploid groups to be better and the survival duration significantly longer than in the pseudodiploid patients. Studying the correlation between the cytogenetic and non-cytogenetic findings the diploidy and hyperdiploidy seems to associate with low risk factors, while pseudodiploidy with high risk factors. When opposite cytogenetic and non-cytogenetic prognostic parameters were associated, the outcome of disease was determined by the cytogenetic picture. In eight patients out of the 14 children with abnormal karyotype various specific aberrations were found. While patients with specific translocations had a poor prognosis, the prognosis of the patients with 6q- was relatively good. The findings support the necessity of chromosome examination in all the children with ALL at diagnosis in order to distinguish the poor risk patients from the good ones.     

儿童急性淋巴细胞白血病南方ALL99方案临床疗效分析

目的对82例儿童急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)治疗结果进行分析,探讨如何提高儿童ALL无病生存率。方法应用南方ALL99方案治疗82例ALL患儿。该方案引进德国BFM95和香港-新加坡ALL97方案,作了少许改动,形成南方ALL99方案。改动方面包括将三联鞘注中的氢化可的松换成地塞米松,将外院不规则化疗过的标危患者按中危治疗,将每一疗程开始时的中性粒细胞和血小板的标准提高到中性粒细胞≥1×109/L,血小板≥100×109/L。采用SPSS软件进行寿命表法分析。结果对1999年4月至2003年9月收治的82例ALL患儿按南方ALL99方案进行治疗,78例获完全缓解(completeremission,CR),CR率为95%;13例患者因经济困难或其他原因失访。其中按南方ALL99方案坚持治疗的69例,预期2年无病生存率91%,预期5年以上无病生存率75%;因感染死亡3例(死亡率为4%),复发死亡6例。结论引进德国BFM95和香港-新加坡ALL97方案而成的南方ALL99方案治疗儿童ALL疗效好,化疗相关死亡率低,该方案对中国人耐受性好,值得推广应用。     

Chemotherapy with cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP) in childhood acute lymphoblastic leukemia (ALL).

Three groups of children with acute lymphoblastic leukemia (ALL) were treated with intermittent cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP). Group A (no prior relapse) and Group B (prior single-agent relapse) received COAP after 12 months on another chemotherapy regimen. Children in Group C (prior relapse on multiagent regimens) received COAP following A-COAP (asparaginase plus COAP) reinduction. Median disease-free survival after beginning COAP was not reached for Group A, but was only 7 months for Groups B and C. As of November 1976, there were 8 of 15 Group A patients, 1 of 12 Group B patients, and 1 of 28 Group C patients who had remained disease-free from 38 to 60 (median 54.5) months and were off chemotherapy. COAP has activity in childhood ALL. However, effectiveness is markedly diminished in patients with prior bone marrow relapse.     

Ikaros基因与儿童急性淋巴细胞白血病预后的关系

Ikaros是淋巴细胞发育和增殖所必需的转录因子,在部分儿童急性淋巴细胞白血病(ALL)中表现为不同的缺失状态,其中以Ik6显性负相亚型过表达多见.Ikaros缺失是B祖细胞型ALL患者预后不良的一个独立危险因素.国外学者最近还确立了ALL的一种新亚型BCR/ABL1-like ALL,同样以Ikaros缺失、预后不良为主要特征.由此推测,Ikaros对儿童ALL的诊断和治疗可能起着关键的作用.