Survival of childhood leukemia in Singapore

The objective of this study was to evaluate the treatment outcome of children with acute leukemias at a university hospital in Singapore. Between January 1988 and January 1994, 66 children were treated, comprising 13 cases of acute myeloid leukemia (AML) and 53 of acute lymphoblastic leukemia (ALL). The 2-year disease-free survival (DFS) was computed according to the Kaplan-Meier method. The results showed that the survival for AML was poor, with a 2-year DFS of only 30%. The major cause of death for AML was leukemia and leukemia-related complications, such as hemorrhage and severe infections. In contrast, a 62% 2-year DFS was achieved for ALL. It was found that marked hepatosplenomegaly (enlarged liver and/or spleen ≥10 cm below the costal margin) at presentation correlated with a significantly shortened survival in our patients with ALL. The major cause for treatment failure in ALL was recurrence of disease. We conclude that the DFS for our patients with ALL at 2 years was fair. The treatment results for AML were poor, but the numbers are too small to make any definite conclusions. © 1996 Wiley-Liss, Inc.     

ALL-2005方案对儿童急性淋巴细胞白血病髓外白血病防治效果分析

目的总结ALL-2005方案对急性淋巴细胞白血病(ALL)患儿髓外白血病,包括中枢神经系统白血病(CNSL)及睾丸白血病(TL)的防治效果。方法 2005年5月—2008年5月共218例ALL患儿,采用ALL-2005方案进行治疗,总结其临床及治疗情况。结果 218例ALL患儿中,5例初诊时伴CNSL,1例于诱导治疗期间发生CNSL,4例于维持治疗期间发生CNSL;1例初诊时伴TL发生,4例维持治疗期间发生TL。经治疗,2例CNSL患儿骨髓复发,其余8例均缓解至今;TL患儿1例骨髓复发,1例放弃治疗,3例缓解至今。结论 ALL-2005方案疗效良好,有利于提高患儿长期生存质量。[临床儿科杂志,2012,30(5):412-414]     

Initial P-glycoprotein expression in childhood acute lymphoblastic leukemia: no evidence of prognostic impact in follow-up

Treatment results in childhood acute lymphoblastic leukemia (ALL) have improved remarkably during the past 20 years, but still 25% of children cannot be permanently cured. Drug resistance is a major cause of poor outcome. One of the most investigated resistance mechanisms is the P-glycoprotein (P-gp)-mediated multiple-drug resistance (MDR). The authors prospectively analyzed P-gp using flow cytometry with monoclonal antibody JSB1 in a population-based series of 103 children with ALL treated according to intensive Nordic ALL protocols. Increased P-gp expression was detected in 55 patients (53%). With a cutoff value of 1% P-gp-positive blasts in bone marrow, no difference was found in event-free survival (EFS) or overall survival between children with low vs. increased P-gp expression. The 4-year EFS in the whole series was 77%. Patients with T-ALL had higher P-gp levels than the others, 3.6% vs. 1.0% (p = .002). P-gp expression did not correlate with the white blood cell count, age, sex, or cytogenetics. The authors conclude that the level of P-gp expression cannot be used as a tool for treatment stratification in childhood ALL.     

INITIAL P-GLYCOPROTEIN EXPRESSION IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA: NO EVIDENCE OF PROGNOSTIC IMPACT IN FOLLOW-UP

Treatment results in childhood acute lymphoblastic leukemia (ALL) have improved remarkably during the past 20 years, but still 25% of children cannot be permanently cured. Drug resistance is a major cause of poor outcome. One of the most investigated resistance mechanisms is the P-glycoprotein (P-gp)-mediated multiple-drug resistance (MDR). The authors prospectively analyzed P-gp using flow cytometry with monoclonal antibody JSB1 in a population-based series of 103 children with ALL treated according to intensive Nordic ALL protocols. Increased P-gp expression was detected in 55 patients (53%). With a cutoff value of 1% P-gp-positive blasts in bone marrow, no difference was found in event-free survival (EFS) or overall survival between children with low vs. increased P-gp expression. The 4-year EFS in the whole series was 77%. Patients with T-ALL had higher P-gp levels than the others, 3.6% vs. 1.0% (p = .002). P-gp expression did not correlate with the white blood cell count, age, sex, or cytogenetics. The authors conclude that the level of P-gp expression cannot be used as a tool for treatment stratification in childhood ALL.     

儿童急性淋巴细胞白血病骨骼并发症研究进展

ALL是儿童最常见的恶性肿瘤,应用目前的联合化疗方法,5 a生存率超过80%.骨骼并发症可发生于ALL诊断时、治疗过程中和治疗结束后,影响ALL的治疗和生存.骨坏死(ON)是儿童ALL治疗过程中最严重的并发症之一,可影响高达1/3的接受治疗的儿童.ON的危险因素包括糖皮质激素的使用、诊断时年龄及放疗等.双膦酸盐治疗可减轻患者疼痛,减少止痛药用量及改善骨关节功能.间充质干细胞可提高手术治疗的疗效.     

High-dose methotrexate for the remission induction of refractory adult acute lymphocytic leukemia.

Six adults with refractory acute lymphocytic leukemia (ALL) were treated with high-dose methotrexate, citrovorum factor, and vincristine. All patients had previously received extensive treatment with standard therapeutic agents, including vincristine, and all but one had received prior methotrexate. Two patients achieved complete remission and one achieved partial remission. Responses were seen at 3--6 gm/m2 of methotrexate. The durations of remission were 7--10 weeks. High-dose methotrexate with citrovorum factor is effective in the treatment of advanced ALL and should be considered for inclusion in initial combination chemotherapeutic regimens for adult ALL.     

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.     

Extramedullary Relapse in Childhood Leukemia

As long-term survival of children with leukemia is increasing, the prophylaxis of extramedullary leukemia has become a more important part of treatment. We studied the pattern of occurrence of extramedullary leukemia in a retrospective review. This review included a total of 2317 childhood leukemia patients aged 15 years or less who had been treated at 38 institutes in Japan between 1976 and 1985. Extramedullary leukemia developed in 386 of 1,724 ALL patients (22.4%) and 63 of 544 patients with ANLL (163%). Among the ALL patients, CNS-L was the most common form and was observed in 315 cases (81.6%), followed by testicular leukemia in 89 (23.0%). In the case of ANLL, the most common form of extramedullary leukemia was CNS-L (45 cases, 71.4%), followed by cutaneous leukemia in 10 cases (15.9%). In addition, leukemia of the lymph nodes, ovaries, bones, kidneys and eyes was observed in 7, 5, 5, 4 and 4 cases, respectively. The survival rate of ALL patients with CNS-L was 40.1% for isolated relapse and 2.7% for bone marrow relapse, and no more deaths occurred after 6 years from relapse. The survival rate of patients with testicular leukemia was 40.1% for isolated relapse and 5.9% for complicating bone marrow relapse, and no deaths occurred after 7 years from relapse. Cutaneous leukemia tended to occur late in older children with ALL and early in infants with ANLL, and all these patients died. Infiltration into the kidney was observed in 4 patients, all of whom died. More than 75% of patients died after isolated relapse of leukemia of the bones, ovaries, lymph nodes and eyes. Prophylactic extramedullary leukemia therapy, of CNS-L in particular, has played an important role in the treatment of childhood leukemia. Careful development of more effective therapy and close observation of late effects are required when monitoring affected children who are still growing.     

Mucoepidermoid Carcinoma of the Parotid Gland in Childhood Survivor of Acute Lymphoblastic Leukemia With Need of Radiotherapy for Treatment and Review of the Literature

Diagnosis of secondary malignancies began with the increasing survival in childhood cancer. Children treated for acute lymphoblastic leukemia (ALL) have an increased risk for developing mucoepidermoid carcinoma (MEC) of the parotid gland. The latent period ranges from 5 to 16 years. A 2 6/12-year-old girl was treated for pro-B ALL. Treatment included multidrug chemotherapy, prophylactic intrathecal methotrexate, and cranial radiotherapy. MEC of the left parotid gland was diagnosed at the age of 8 years, 3 years after completing treatment. She was treated with multiple surgery and radiotherapy. The authors aimed to emphasize the need for concern about second cancers of the parotid gland in children treated for ALL.     

Mucoepidermoid carcinoma of the parotid gland in childhood survivor of acute lymphoblastic leukemia with need of radiotherapy for treatment and review of the literature

Diagnosis of secondary malignancies began with the increasing survival in childhood cancer. Children treated for acute lymphoblastic leukemia (ALL) have an increased risk for developing mucoepidermoid carcinoma (MEC) of the parotid gland. The latent period ranges from 5 to 16 years. A 2 6/12-year-old girl was treated for pro-B ALL. Treatment included multidrug chemotherapy, prophylactic intrathecal methotrexate, and cranial radiotherapy. MEC of the left parotid gland was diagnosed at the age of 8 years, 3 years after completing treatment. She was treated with multiple surgery and radiotherapy. The authors aimed to emphasize the need for concern about second cancers of the parotid gland in children treated for ALL.     

Relapses after termination of therapy of acute lymphoblastic leukemia in children

In the past 16 years, 2004 children with acute lymphoblastic leukemia (ALL) have been treated in the Polish Pediatric Group centers. Eight hundred and eighty-seven (44.3%) of these patients discontinued treatment after the first remission. Acute lymphoblastic leukemia relapse occurred in 180 patients (20.3%). This group was analyzed for the method of treatment and its influence on long-term survival, the time between cessation of treatment and relapse, the character and localization of relapse and later follow-up. It was shown that the patients with the best chance of a second remission are those with late testicular relapse. The most frequent and prognostically poor are bone marrow (BM) relapses which warrant intensive chemotherapy with BM transplantation. Patients with ALL relapse still have the possibility of a second remission and long-term survival.     

High-dose methotrexate for the remission induction of refractory adult acute lymphocytic leukemia

Six adults with refractory acute lymphocytic leukemia (ALL) were treated with high-dose methotrexate, citrovorum factor, and vincristine. All patients had previously received extensive treatment with standard therapeutic agents, including vincristine, and all but one had received prior methotrexate. Two patients achieved complete remission and one achieved partial remission. Responses were seen at 3–6 gm/m² of methotrexate. The durations of remission were 7–10 weeks. High-dose methotrexate with citrovorum factor is effective in the treatment of advanced ALL and should be considered for inclusion in initial combination chemotherapeutic regimens for adult ALL.     

Features and outcome of neonatal leukemia in Japan: experience of the Japan infant leukemia study group

BACKGROUND: Neonatal leukemia characterized by early stem cell origin and extramedullary infiltration in the first 4 weeks of life is rare. We analyzed the features and outcome of neonatal leukemia in Japan to establish an appropriate treatment strategy for this rare disorder. PROCEDURE: Patients with infant leukemia registered and treated in the Japan Infant Leukemia Study between 1996 and 2001 were analyzed. RESULTS: Among 162 infant leukemia patients, 11 exhibited neonatal leukemia; frequencies for all infant leukemias were 6.9% (8/116) for acute lymphoblastic leukemia (ALL) and 7.3% (3/41) for acute myeloid leukemia (AML). Positive MLL gene rearrangement was observed in all eight patients with ALL; a single patient with AML displayed germline configuration. Acute monoblastic leukemia was apparent in all three patients with AML (M5a in the FAB classification). Most of the patients demonstrated hepatoplenomegaly and hyperleukocytosis at diagnosis. Cutaneous and central nervous system involvement were detected in half of the patients. Four patients (one with AML, and three with ALL) have survived following stem cell transplantation (SCT); however, growth impairment related to SCT was observed in these patients. CONCLUSIONS: These results suggest an improvement attributable to treatment of neonatal leukemia. International-based collaborative studies are necessary to investigate the biology of this condition and to establish appropriate therapeutic strategies.     

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。     

FLAG-liposomal doxorubicin (Myocet) regimen for refractory or relapsed acute leukemia pediatric patients

Despite the success in treating the majority of children with newly diagnosed acute leukemia, children with relapsed or refractory disease are an exceptionally difficult group of patients to cure. We assessed the combination of fludarabine with cytarabine and granulocyte colony-stimulating factor (FLAG) and nonpegylated liposomal doxorubicin (Myocet) in children with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) refractory to first-line therapy or who had relapsed after risk-tailored chemotherapy. We treated 35 patients with FLAG-Myocet. The median age at treatment was 9 years and 7 months (range, 1 to 18 y). The 94% of ALL patients (16/17) and the 61% AML patients (11/18) achieved complete remission after FLAG-Myocet. A partial response was observed in the 17% of AML patients (3/18). Twenty-eight of 35 (80%) patients received hematopoetic stem cell transplantation in remission induced by FLAG-Myocet regimen. The ALL and AML overall survival at 3 years after FLAG-Myocet is 33% and 38%, respectively. The probability of ALL and AML event-free survival at 3 years after FLAG-Myocet is 33% and 40%, respectively. The probability of ALL and AML disease-free survival at 3 years after hematopoietic stem cell transplantation is 19% and 58%, respectively. Nonhematological toxicity was remarkably low, while almost all patients showed severe hematological toxicity. FLAG-Myocet is an efficient and a well-tolerated regimen that allows nearly all patients to undergo hematopoetic stem cell transplantation. FLAG-Myocet proved to be safe in terms of acute cardiac toxicity although particular care must be taken to reduce infectious complications due to severe myelosuppression. The promising results shown in our study need to be confirmed by larger and possibly randomized trials.     

Serial Ultrasound Monitoring for Early Recognition of Asparaginase Associated Pancreatitis in Children With Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and L-asparaginase is an essential component of the treatment. Cessation of L-asparaginase decreases event free survival. Acute pancreatitis is the toxicity that most commonly results in cessation of L-asparaginase. We tested whether serial ultrasound examinations could predict asparaginase-associated pancreatitis (AAP). Methods: Children (aged 1.0–17.9 years) with childhood ALL treated at the University Hospital Rigshopitalet, Copenhagen, according to the standard or intermediate risk arms of the NOPHO ALL2008 protocol, with PEG-asparaginase of 2 or 6 week intervals, for 30 weeks had their pancreas monitored using serial ultrasound in order to detect early signs of inflammation. Results: Nineteen of 31 eligible patients were included. Three of the included patients developed AAP. None of the patients, including the three patients that developed AAP, had signs of inflammatory edema or pancreas enzymes above three times the upper normal limit prior to AAP. Conclusion: We found no signs of inflammatory edema within the pancreas on ultrasound during treatment with PEG-asparginase in our cohort prior to development of AAP or in patients that did not develop AAP.     

Radiation-induced meningioma following prophylactic radiotherapy for acute lymphoblastic leukemia in childhood

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although it was considered to be a poor prognostic disease, modern treatment protocols (aggressive chemotherapy and prophylactic cranial irradiation) have resulted in dramatically improved survival rates. In a group of low-risk ALL patients, the 5-year survival rate is estimated to be 85%. However, ALL patients who undergo this treatment are at risk of developing secondary neoplasms related to treatment, which has become an increasingly recognized problem. CASE DESCRIPTION: A 3-year-old boy with ALL was successfully treated with chemotherapy (vincristine, prednisolone, mercaptopurine and methotrexate) and prophylactic cranial irradiation (total 18 Gy). At the age of 23, he was admitted to our hospital for weakness in the right leg. Computed tomography and magnetic resonance imaging revealed a parasagittal tumor of the left frontoparietal lobe with perifocal edema. The tumor was completely removed surgically and pathohistologically diagnosed as atypical meningioma. CONCLUSION: Long-term survivors who received radiotherapy for ALL in childhood are at risk for late complications, including radiation-induced meningioma. Therefore, careful follow-up neurological examinations, for example magnetic resonance imaging, are indicated in these patients. In addition, late complications should be taken into account during the initial planning of prophylactic radiotheraphy dosage, which has implications for informed consent of the patient.     

Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement

Blinatumomab is a bispecific T‐cell engaging αCD19 antibody used in refractory or relapsed B‐cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again. During this treatment, the leukemia lost CD19 expression as well as nearly all other B‐cell markers, while still harboring the initial minimal residual disease marker, and switched to a myeloid phenotype.     

A population-based study of children with standard risk acute lymphoblastic leukemia in the five Nordic countries. A follow-up of 230 patients

Two hundred and thirty children with standard risk acute lymphoblastic leukemia (ALL) were diagnosed during a period of 3 years from July 1, 1981 to June 30, 1984 in the five Nordic countries. Criteria for standard risk ALL were age above 2.0 and below 10 years, WBC less than or equal to 20 x 10(9)/l, no evidence of CNS-involvement, mediastinal mass or T- or B-cell leukemia. The children were treated without prophylactic CNS irradiation, the majority (200 patients) according to two treatment programs. Follow-up of the entire group after a minimum of 30 months showed 64% of the children living in complete continuous remission with a probability of event-free survival of 0.60. The treatment results are not entirely satisfactory and intensification of therapy is required. A subgroup of patients with WBC between 10 and 20 x 10(9)/l and with adverse prognosis was identified, justifying a change of the present criteria for risk grouping.     

98-方案诊治儿童急性淋巴细胞白血病疗效和预后因素分析

目的探讨98-方案诊治儿童急性淋巴细胞白血病(ALL)的疗效和预后因素,以便进一步提高儿童ALL无事生存率(EFS)。方法回顾性分析1998年10月—2003年7月83例初诊儿童ALL临床资料,采用Kaplan Meier法评估各因素对患儿5年无事生存率(5-year EFS)的影响,组间患儿5-year EFS差异比较采用Log-Rank检验,COX比例风险回归模型分析各变量的独立预后价值。结果83例儿童ALL完全缓解(CR)率为96.4%,总体5-year EFS为(62.0±6.0)%。多因素分析表明泼尼松诱导试验不良是预后不良的独立因素,其相对危险度(RR)为1.577;而治疗顺从是预后良好的独立因素,其RR为0.443。泼尼松诱导试验高度敏感对预后不良预测的敏感度和特异度分别为67.9%和76.7%,泼尼松诱导试验高度敏感+敏感对预后不良预测的敏感度和特异度分别为94.3%和33.3%。结论采用98-方案治疗儿童ALL疗效满意,泼尼松诱导试验不良是预后不良的独立因素,泼尼松诱导试验高度敏感对预后不良预测的敏感度和特异度都比较高,治疗顺从是预后良好的重要因素。