Immunological Classification of Childhood Acute Lymphoblastic Leukemia

Seven hundred and forty-four newly diagnosed patients with acute leukemias between 1978 and 1990 were classified on the basis of immunological phenotypes. The majority of the patients were enrolled in the Tokyo Children's Cancer Study Group (TCCSG) studies. The incidence of subclassification of acute leukemias in this study was as follows: 522 patients with ALL (70%), 139 patients with ANLL (18%), 29 patients with biphenotypic leukemia, 8 patients with Ph1-positive acute leukemia (Ph^-AL), and 45 patients with infant leukemia. ALLs were classified into common ALL (cALL, 77%), T-ALL (15%), B-ALL (4%), and unclassified ALL (3%). The incidence of ALL subtypes in this study reflected those of TCCSG. Biphenotypic leukemias were categorized into 4 groups as follows; 1) cALL with positive myelomonocytic antigen(s) (N = 11), 2) unclassified ALL with positive myelomonocytic antigen(s) (N = 5), 3) ANLL with positive B-lymphoid antigen(s) (N = 4), and 4) acute leukemia with positive T-lymphoid and myeloid antigen(s). Infant leukemias were classified into ALL type (N = 27) and ANLL type (N = 18). In this present study, clinical features and immunological phenotypes of the acute leukemias with a poor prognosis, i.e. biphenotypic leukemia, Ph^-AL, and infant leukemia are analyzed and discussed.     

COALL-97方案治疗急性淋巴细胞白血病临床及实验室研究

目的　引用德国儿童急性淋巴细胞白血病协作组 (cooperativeALLstudygroup ,COALL)的COALL 97方案治疗急性淋巴细胞白血病 (ALL) ,从临床疗效防治及目前国内外选用有效治疗ALL的药物 ,左旋门冬酰胺酶 (L Asp)的药代动力学方面 ,探讨在我国治疗儿童ALL的最佳方案及L Asp的最佳给药方式。方法　ALL患儿 1 2例自愿接受COALL 97方案在我院完成早期强化治疗后 ,回当地继续口服巯基嘌呤 (6 MP) /硫鸟嘌呤 (6 TG)加甲氨蝶呤 (MTX)持续治疗 ,每隔 3个月、半年来院复查 ,总疗程 1 .5～ 2 .0年。结果　诱导治疗后d1 4做骨髓检查 8例呈缓解骨髓像 ,治疗 2 8d后 1 2例均完全缓解 (CR) ,CR率1 0 0 % ,HR ALL患儿 1例CR后 1 0个月时骨髓复发并重症感染死亡。应用高压液相色谱技术 (HR HPLC)检测 1次注射 40 0 0 0U/m2 L Asp后能使血清和脑脊液 (CSF)中门冬酰胺 (ASN)浓度降低 ,并持续至第 5周后回升。 结论　COALL 97方案可被我国ALL患儿所接受 ;在治疗ALL的临床实践中 ,该方案确有可借鉴之处 ;1次 / 2～ 6周静脉注射 40 0 0 0U/m2 L Asp联合化疗的用药方式不仅作用强、持续时间长 ,耐药性小、不良反应少 ,且避免患儿每天或隔天静脉注射痛苦及患儿家长的经济和精神负担。     

Prognosis after Relapse in Acute Lymphoblastic Leukemia in Childhood

This is a survey of all the 265 relapses occurring in 515 children with ALL diagnosed in Sweden in the years 1973-1980. Two hundred and nineteen relapses occurred on therapy, and 46 after discontinuation of therapy. Bone marrow was involved in the relapse in 71% and 67% of the two groups, respectively. Only 38/265 (14%) children with relapse were still alive at follow-up in January 1985. Of these, 16/219 (7%) had relapsed during therapy (median survival time after relapse 9 months) compared to 22/46 children (48%) with a relapse after cessation of therapy (median 43 months). The prognosis was better if relapse occurred after cessation of therapy and in children with isolated testicular relapse. Thirteen children were bone marrow transplanted, and 6 of these were alive at follow-up. It is concluded that children with ALL relapse have very bad prognosis with cytostatic regimens used today, especially if the bone marrow is involved.     

Clinical Significance of Lymphokine-Activated Killer Activity in Childhood Acute Lymphoblastic Leukemia

Lymphokine-activated killer (LAK) activity was studied in 29 children with acute lymphoblastic leukemia (ALL). Peripheral blood lymphocytes of the patients and normal volunteers were cultured in the presence of recombinant-interleukin 2 (R-IL2) for five days, and assayed for their LAK activities by ⁵¹ Cr release assay using Raji cells as a target. At the time of onset, LAK activity was 4.3±2.6% (mean±SD, n=6) compared to the normal value. During remission LAK activity improved to 49.6±30.2% (n=16, p<0.01). After cessation of therapy LAK activity further improved to 97.3±21.2% (n=7, p<0.01). The conventional anti-leukemic agents appeared to be suppressive for LAK activity in vitro. Of the patients in remission for more than one year, three with depressed LAK activity relapsed one to four months after the assay. Although it still remains undetermined whether the depression of LAK activity is responsible for the subsequent relapse, the application of adoptive immunotherapy using LAK and R-IL2 is of clinical interest because it can be expected to enhance the activity of LAK. As compared with natural killer cell activity in childhood ALL, LAK activity showed a prompt improvement after remission.     

Cognitive Function in Long Survivors of Childhood Acute Lymphoblastic Leukemia

Thirty long survivors of childhood acute lymphoblastic leukemia were compared with their healthy siblings on cognitive and neuropsychological measures. The subjects were comparable in treatment variables except for type of central nervous system prophylaxis received. Thirteen were given radiotherapy with intrathecal medication, and seventeen received only intrathecal treatment. Patients receiving only intrathecal medication did not differ from controls. Patients receiving radiotherapy scored lower on several measures including Wechsler Full Scale and Performance IQ. Irradiated girls scored lower than boys on most measures. Children whose clinical management has included radiation therapy appear to be at risk for later mild cognitive deficits. No consistent pattern of neuropsychological deficits has emerged and observed deficit patterns may reflect individual vulnerabilities.     

Randomized Multicentric Italian Study on two Treatment Regimens for Marrow Relapse in Childhood Acute Lymphoblastic Leukemia

This paper reports the results of a multicentric randomized clinical trial on the treatment of first hematological relapse in childhood ALL. Induction treatment consisted of vincristine, adriamycin, L-asparaginase, and prednisone. Patients achieving complete remission were randomized to two maintenance regimens (A and B). Regimen A consisted of five different drug associations including VM26 and IDMTX in a sequential schedule; Regimen B was essentially classical Spiers schedule for the first year, followed by a milder treatment. Eighty-four of 102 evaluahle patients (82%) achieved second complete remission. The two maintenance regimens were similar as regards duration of second complete remission (median duration A, 32 weeks; B, 37 weeks) and toxicity. Better results were obtained in patients relapsing after 12 months from suspension of treatment in first complete remission than in those relapsing within the first year off therapy (82.8% vs. 31.4%). In group A fewer CNS relapses were reported. The two regimens produced results similar to those reported by other authors. The good prognosis in patients relapsing at least 1 year after treatment suspension in first complete remission must be emphasized.     

Assessment of Neuropsychological Late Effects in Survivors of Childhood Leukemia

The neurologic dysfunctions caused by treatment may affect health and quality of life in survivors of childhood leukemia. The objective of this study was to identify the neuropsychological late effects of leukemia treatment to provide an assessment about the degree and incidence of these late effects. Neurological and ophtalmological examination, cranial magnetic resonance imaging (MRI), auditory and neurocognitive tests, and questionnaires of quality of life were performed to 44 acute leukemia survivors at least 5 years after diagnosis. Median time since completion of chemotherapy was 7.5 years (2–18) and median age at the time of the study was 16.4 years (8–31). At least one or more late effects detected by physical examination (PE), neurological tests, or neurocognitive tests encountered in 80% of the patients, and 64% of the patients specified at least one complaint in the quality of life questionnaire. MRI revealed pathological findings in 18% and electroencephalogram (EEG) abnormalities were present in 9% of the patients. Evaluation of total intelligence scores revealed that 30% of patients’ IQ scores were <80 and 70% of the patients’ scores demonstrated neurocognitive dysfunctions. The patients >6 years at the time of diagnosis were found to have more psychological problems and higher rates of smoking and alcohol consumption. The most frequent complaint was headache and the most common problem in school was denoted as difficulty in concentration. Our study demonstrated that most of the survivors of childhood leukemia are at risk of developing neuropsycological late effects.     

Changes in the Eeg Background Activity of Children with Acute Lymphoblastic Leukemia During Cytotoxic Therapy

Thirteen children with acute lymphoblastic leukemia (ALL) were investigated before and during cytotoxic therapy. EEG findings were correlated with the clinical course and the therapy protocol and compared with normal data obtained from 295 healthy children. Frequency analysis of the background activity of the EEG revealed an initial slowing of the background activity prior to therapy and further slowing each time a combination of vincristine (VCR), daunorubicine (DAU) or adriblastine (ADR), prednisone (FRED), and L-asparaginase (L-ASP) was administered. The slowing of the background activity correlated only with the administration of these drugs. DAU, ADR, and FRED are not known to influence the EEG; therefore, VCR and L-ASP remain the primary candidates responsible for the central nervous system alteration.     

急性淋巴细胞白血病并急性呼吸窘迫综合征的治疗

目的探讨小儿急性淋巴细胞白血病(ALL)并急性呼吸窘迫综合征(ARDS)的治疗。方法采用抗感染、甲泼尼龙、盐酸氨溴索、持续呼吸道正压(CPAP)辅助通气为主的综合方法治疗小儿ALL并ARDS7例,对其临床资料进行回顾性分析。结果6例痊愈出院,死亡1例,治愈率85.7%。结论采用综合疗法治疗小儿ALL并ARDS,治愈率高。     

Neurocognitive Outcome and White Matter Anisotropy in Childhood Acute Lymphoblastic Leukemia Survivors Treated with Different Protocols

Neurocognitive outcome affects the quality of life of ALL survivors. This study is aimed to assess the prevalence of neurocognitive dysfunction by psychometric and imaging tools in survivors of childhood ALL, treated with 3 different protocols and the effect of time elapsed since the end of chemotherapy. Sixty-two ALL survivors aged 6–18 years and treated in the period 1997–2007 and 60 healthy age and sex matched controls were subjected to neurocognitive testing using Wechsler Intelligence Scale for Children, Benton visual retention (BVRT) and Trail Making test (TMT), followed by diffusion weighed and diffusion tensor MRI for calculation of fraction anisotropy (FA). Survivors underwent revision of protocol and type of CNS therapy. Three different protocols were used: modified BFM 83, BFM 90, and CCG. Survivors treated with modified CCG protocol showed a significant decrease in all cognitive tests compared to control (p<.05); BFM 90 group had a significant lower IQ and longer TMT compared to both control and BFM 83 group and no significant difference was found in results of cognitive tests between BFM 83 and control group. Frontal FA was lower in CCG treated group compared to control, BFM 90 and BFM 83 groups (p<.05); meanwhile it was significantly lower in BFM 90 and BFM 83 groups compared to control group. We concluded that patients treated with modified CCG protocol showed the worst neurocognitive outcome among three assessed protocols. Frontal lobe FA might be an early marker for predicting the neurotoxicity in childhood ALL survivors.     

A Marked Decrease of Endogenous and Activated Natural Killer Cell Activities in Childhood Acute Lymphoblastic Leukemia

Natural killer cell activity was studied in 40 children with acute lymphoblastic leukemia by ⁵¹ Cr-release assay using K562 target cells. NK cell activity of ALL at the time of onset or relapse was 9.0 ±4.9% specific lysis (n = 20), being depressed as compared with the normal value of 47.2 ± 5.7% (p < 0.01). The decrease of NK cell activity was also present in the remission phase: % specific lysis was 23.5 ± 9.2% (n = 25). The decrease was still recognized among most of the off-therapy patients. In vitro studies demonstrated that, among the conventional anti-leukemic agents, prednisolone, arabinosylcytosine and daunorubicin depressed NK cell activity. The anti-leukemic agents appear to contribute at least in part to the impaired NK cell activity in ALL. The continuous decrease of NK cell activity even after the cessation of antileukemic therapy, however, cannot be explained by their effects alone, suggesting that the NK cell impairment is one of the characteristic features of ALL. NK cells responded to interferon (IFN) but their activated activity was still below the normal endogenous activity, and they did not respond to an IFN inducer of poly I:C at the time of onset or relapse. In remission phase, NK cells responded to both IFN and poly I:C and their activated activity reached the normal endogenous level. These results certainly demonstrated a marked decrease of NK cell activity in ALL.     

Cranial Computerized Tomography and Cerebrospinal Fluid Procoagulant Activity in Childhood Acute Lymphoblastic Leukemia

Thirty-three children with acute lymphoblastic leukemia (ALL) were studied using serial cranial computerized tomography (CCT) and cerebrospinal fluid procoagulant activity (PCA)for 5 years from the time of diagnosis. PCA was also studied in control children without neurological disease and in those with a variety of neurological disorders. Temporary elevation in the CSF PCA was observed during the phase of prophylactic central nervous system treatment in ALL and there was a late rise at 2-3 years off treatment. PCA also rose in the CSF following CNS disturbance in neurologically abnormal children, which suggests that the elevation observed in ALL is not specific to myelin disturbance.     

Screening Survivors of Childhood Acute Lymphoblastic Leukemia for Obesity,Metabolic Syndrome,and Insulin Resistance

Acute lymphoblastic leukemia (ALL) survivors were screened for risk factors of cardiovascular disease. Forty-four ALL survivors in first remission were enrolled. Twenty-six also received 12–18 Gy cranial radiotherapy (RT). Patients’ body mass indexes (BMIs) at dignosis and during the study were compared. Metabolic syndrome (MS) evaluation was performed in patients, parents, and siblings older than 6 years. Homeostasis Model Assessment (HOMA) index of the survivors was also calculated. In survivors with impaired fasting glucose levels, oral glucose tolerance test (OGTT) was performed. Thyroid functions and IGF-1 and/or IGFBP-3 levels of the survivors who received cranial RT were evaluated. Median age of the survivors was 11.5 years (6–23). At diagnosis, mean BMI percentile was 46.7 (3–95) and mean z-score was ?0.09 ± 1.14; during the study, these values rose to 71.1 ± 25.6 (3–100) and 0.8 ± 0.94, respectively (P < .001). One patient (2.2%) and nine survivors (20%) were obese at diagnosis and during the study, respectively (P = .005). Survivors had significantly higher BMI percentile and BMI z-score compared to their siblings (P = .006 and P = .011, respectively). The study group was small and we could not show a correlation of the patients’ obesity with RT, thyroid functions, IGF-1, and IGFBP-3 levels. In three survivors (6.8%), there was MS. Maternal and paternal MS was not found as a risk factor for MS of the survivors (P = .1, P = .5, respectively). The HOMA index revealed insulin resistance (IR) in 12 (27.2%) of the survivors, whereas OGTT revealed abnormal glucose regulation and/or IR in four. As a conclusion, ALL survivors have high risk for obesity and MS.     

Physical Activity and Late Effects in Childhood Acute Lymphoblastic Leukemia Long-Term Survivors

In the present study the authors evaluated therapy-related long-term adverse effects and physical activity in a cohort of long-term survivors of childhood acute lymphoblastic leukemia (ALL), diagnosed in their center between March 1991 and August 2000, treated according to the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) ALL 91 or 95 study protocol and regularly seen in the authors’ long-term follow-up unit. The authors analyzed the long-term sequelae of major body systems in this cohort of subjects and administered an “ad hoc” questionnaire concerning sport. The authors found that 70 patients out of 102 (68.5%) showed no late effects, 10% presented only instrumental or neuropsychological test abnormalities, and 21.5% had 1 or more clinical late sequelae. None of the evidenced late effects represented a contraindication to do physical activity. Sixty-one percent of survivors do physical activity, most of them regularly. Sixty-one percent of males and 18.5% of females (P < .005) do competitive sport (sports rates are similar to those of the general age-matched population). Nearly all subjects spontaneously choose to do sport and think physical exercise is an important and useful resource for their health. The authors conclude that the more recent therapy regimens for leukemia treatment, excluding bone marrow transplantation, do not seem to cause such late effects as to prevent survivors from doing sport. Therefore, in the care of ALL survivors, physical activity is not only not contraindicated, but should also be promoted as much as possible. The development of specific educational programs is warranted as part of the care of cancer survivors.     

急性淋巴细胞白血病患儿血清瘦素及铁蛋白检测的意义

目的研究急性淋巴细胞白血病(ALL)患儿血清瘦素(leptin)和铁蛋白(SF)水平变化,探讨血清瘦素及SF与ALL的关系。方法采用酶联免疫分析法分别检测22例初治、26例缓解期ALL患儿及25例健康儿童血清瘦素水平,同时采用双抗体夹心酶联免疫分析法检测血清SF水平。结果ALL初治组血清瘦素水平显著低于正常对照组(P<0.01),经化疗缓解半年后,其血清瘦素浓度上升至正常水平;ALL初治组血清SF水平显著高于正常对照组(P<0.01),缓解后其血清瘦素浓度降至正常水平。结论血清瘦素和SF可作为判断ALL治疗效果的有效指标之一。     

Relationship Between Modified CT Severity Index and Clinical Features of L-Asparaginase-Associated Pancreatitis in Pediatric Acute Lymphoblastic Leukemia

Purpose: To describe clinical and CT features of L-asparaginase-associated pancreatitis (L-AP) and to correlate CT grades with clinical parameters. Methods: A total of 16 children (M:F = 9:7; mean age, 8.1 years) who developed L-AP after L-asparaginase (L-asp) treatment and underwent abdominal CT scan were included. We retrospectively reviewed clinical data (age, sex, signs, and symptoms related to pancreatic toxicity and its complications, the number of L-asp doses receiving before L-AP); laboratory test results (serum amylase, lipase, C-reactive protein (CRP), calcium, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), glucose, and serum albumin); and clinical course (the number of days of hospitalization, number of NPO days, use of nasogastric tube, intravenous (IV) narcotics, total parenteral nutrition (TPN) or any surgical intervention). We also reviewed CT images and modified CT severity index (MCSI) for grading the severity of AP and classified to three groups (mild, moderate, and severe) or two groups (low and high score) according to MCSI. Results: L-AP typically occurred early in the course of therapy. Use of IV narcotics (P = .014) and peak amylase (P = .009) showed a significant difference between mild and severe L-AP groups according to MCSI. Between the low and high score groups, Use of IV narcotics (P = .046), BUN (P = .039), and peak amylase level (P = .013) was significantly different. However, the L-asp dose, hospital day, and other clinical date associated with prognosis did not show any significant difference. Conclusion: In L-AP with pediatric ALL patients, MCSI may correlate with usage of IV narcotics, BUN, and peak amylase levels.