Practice guidelines in pediatric hematooncology: implementation and survey. A possible way for medical quality assurance

The Hungarian Pediatric Oncology Working Group intended to change the practice of prescribing diagnostic tests as well as to examine the possibility of introducing indicators about the time factors of medical care. A nationwide accepted protocol was established for these tests. The examined time factors were the length of elapsed time from admittance to treatment and the length of hospital stay for different reasons (diagnosis, treatment, complications). Included in to this study are the new cases of 5 common groups of malignancies (acute lymphoblastic leukemia and non-Hodgkin lymphoma, osteosarcoma, soft tissue sarcoma, Wilms tumor, neuroblastoma) for a study period of 1 year. The follow-up data of 152 patients were examined; the length of survey was 1-12 months, depending on when the patients entered the study. As a continuous clinical audit, a system of survey was set up for each follow-up test, using a questionnaire about the conformity of physicians to the protocol, evaluating the principal reasons of deviation from the protocol. Using the data provided by this questionnaire, a renewal of the protocols for each disease was made three times during the whole study period. The principal reasons of nonconformity to the protocol were (1) complications, (2) the nonuse of the protocol, (3) nonacceptance of the protocol, and (4) technical problems. The authors intended to use their time indicators for benchmarking, to make a comparison possible between centers concerning the length of treatment, occurrence of complications, and delays in chemotherapy. However, the examination of the time indicators in the most frequent disease (acute lymphoblastic leukemia, n = 73) showed inverse correlation between the numberof admissions per year per center and the length of time elapsed up to the beginning of treatment. This points to a need for better cooperation in small centers at the initial phase of the diagnosis. The main result of this study is the successful elaboration and implementation of practice guidelines by information linked to performance (the feedback) in daily practice: Compliance during the first 3 months of the study was 28%, and compliance during the last 3 months was 61%.     

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。     

Survival of patients with metastases from Wilms' tumor (SIOP 1, SIOP 2, SIOP 5)

Data of patients with metastases from Wilms' tumor, either at diagnosis or after first treatment, were collected from 25 European centers. Eligible for survival analysis were 293 patients, 142 from SIOP 1, 46 from SIOP 2 and 105 from SIOP 5. There were 134 boys and 159 girls aged between 2 and 216 months with a median of 54 months. The follow-up time for surviving patients was betweeen 6 months and 142 months with a median of 75 months. At the end of the study, 119 patients are alive disease-free and 174 have died, 19 in complications (2 without tumor); one patient died in acute lymphoblastic leukemia. SIOP 2 patients did significantly worse than those from the SIOP 1 and 5 groups. The following variables were significant for the outcome: (a) site, (b) histology, (c) treatment. A possible reason for the low survival in the SIOP 2 patients is discussed.     

Bleeding and thrombosis in children with acute lymphoblastic leukaemia, treated according to the ALL-BFM-90 protocol.

A multi-center retrospective survey was conducted to evaluate the incidence and types of hemostatic complications occurring in children with acute lymphoblastic leukemia (ALL) during treatment according to the ALL-BFM-90 treatment protocol. All of the BFM-treatment centers (n = 77) were approached and a 95% response rate with information on 1100 patients was obtained. Thrombotic or bleeding episodes occurred in 31 patients (2.8%), 19 of whom had thrombosis and 12 bleeding complications, involving the central nervous system (42%), the subclavian vein (29%), the gastro-intestinal tract, skin, lower extremities or pelvis (29%). Recovery was noted in 28 of 31 patients, while 3 died as a result of hemostatic complications. Bleeding or thrombosis occurred in patients receiving prophylactic substitution with plasma or plasma-derived concentrates (n = 16) as well as in those without substitution (n = 13). The majority of hemostatic complications (90%) occurred during the induction therapy of the treatment protocol, in particular during the period which included simultaneous administration of glucocorticoids and E. coli L-asparaginase. The concurrent administration of E. coli L-asparaginase and glucocorticoids may be an additional risk factor for thromboembolic events during therapy according to the ALL-BFM-90 protocol.     

Acute nonlymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We report three cases initially diagnosed as having ALL and showing morphological, cytochemical, and immunophenotypic features of ANLL at relapse (lineage switch). Conversion was observed among 14 patients who developed bone marrow relapse while undergoing intensive treatment with our ALL protocol, which includes teniposide, and that had been administered to 62 patients. The three cases converted at first relapse, with a mean time of 20 months (13–29 months). Clinical and immunologic characteristics of T-cell leukemia were present in one patient. Changes documented in cytogenetic studies are discussed. The underlying mechanisms for the lineage switch remain unclear as does its relation with mixed lineage leukemias, but we believe that drugs employed in our therapy protocol could have had an influence on this conversion.     

Acute nonlymphoblastic leukemia in children treated for acute lymphoblastic leukemia with an intensive regimen including teniposide.

Some cases of conversion from acute lymphoblastic leukemia (ALL) to acute nonlymphoblastic leukemia (ANLL) at relapse have been reported recently. We report three cases initially diagnosed as having ALL and showing morphological, cytochemical, and immunophenotypic features of ANLL at relapse (lineage switch). Conversion was observed among 14 patients who developed bone marrow relapse while undergoing intensive treatment with our ALL protocol, which includes teniposide, and that had been administered to 62 patients. The three cases converted at first relapse, with a mean time of 20 months (13-29 months). Clinical and immunologic characteristics of T-cell leukemia were present in one patient. Changes documented in cytogenetic studies are discussed. The underlying mechanisms for the lineage switch remain unclear as does its relation with mixed lineage leukemias, but we believe that drugs employed in our therapy protocol could have had an influence on this conversion.     

ALL-BFM 95 Treatment in Turkish Children with Acute Lymphoblastic Leukemia—Experience of a Single Center

Little is known about the likelihood of curing children with high-dose chemotherapy regimens for treatment of childhood acute lymphoblastic leukemia (ALL) in Turkey. The authors here report their 13 years’ experience with original ALL-BFM (Berlin-Franfurt-Münster) 95 protocol in a cohort of 140 Turkish children with ALL. Complete remission rate was 97.7% with a relapse rate of 12.9% and death rate 17.9% during a median follow-up of 69 months. The event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) in these patients at 12 years were 75.0%, 87.1%, and 80.6%, respectively. These results show that ALL-BFM 95 protocol is equally applicable in the experienced centers, even in developing countries without substantial treatment-related toxicity. High rate of infection deaths are to be reduced with correct policies.     

ALL-BFM 95 treatment in Turkish children with acute lymphoblastic leukemia-experience of a single center

Little is known about the likelihood of curing children with high-dose chemotherapy regimens for treatment of childhood acute lymphoblastic leukemia (ALL) in Turkey. The authors here report their 13 years' experience with original ALL-BFM (Berlin-Franfurt-Münster) 95 protocol in a cohort of 140 Turkish children with ALL. Complete remission rate was 97.7% with a relapse rate of 12.9% and death rate 17.9% during a median follow-up of 69 months. The event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) in these patients at 12 years were 75.0%, 87.1%, and 80.6%, respectively. These results show that ALL-BFM 95 protocol is equally applicable in the experienced centers, even in developing countries without substantial treatment-related toxicity. High rate of infection deaths are to be reduced with correct policies.     

Treatment of adult acute lymphoblastic leukemia with adriamycin, vincristine, and prednisone

At the present time, it is possible to achieve up to a 95% complete remission in childhood acute lymphoblastic leukemia, using the combination of vincristine and prednisone. Nevertheless, it has not been possible to reproduce these results in the adult. For this reason, a third drug, in this case adriamycin in a low dose, was added to the vincristine-prednisone combination in the treatment of adult acute lymphoblastic leukemia (ALL). Complete remission was achieved in 45 of the 50 patients (90%). The median duration of remission was 23 months and the median survival time in this group was 31 months. The complications were minimal and the tolerance was good. From the point of view of our results and others reported in the literature, we consider that the combination of vincristine, prednisone, and adriamycin is a useful method for induction of remission of adult ALL.     

GZ-ALL-2002方案治疗儿童急性淋巴细胞性白血病临床疗效分析

目的分析研究采用广州地区儿童急性淋巴细胞性白血病协作组方案(GZ-ALL-2002)治疗儿童急性淋巴细胞性白血病的结果。方法对2002年10月1日至2008年4月30日收治的107例初治儿童ALL采用CZ-ALL-2002方案治疗,评价治疗效果、缓解情况、严重感染并发症及治疗相关死亡等。结果107例治疗5周时完全缓解(CR)率100%,除外6例CR后放弃治疗,8例复发(4例中枢神经系统复发、4例骨髓复发),复发率7.92%(8/101),治疗相关死亡1例,本事件生存率(EFS)85.98%(92/107);严重感染发生141例次,包括败血症、严重肺炎和肺脓疡、呼吸衰竭、肺结核空洞、不明病原菌持续高热、严重口腔溃疡等,左旋门冬酰胺酶(L-ASP)相关并发症19例(过敏13例、急性胰腺炎6例其中1例伴休克、L-ASP相关糖尿病3例),无感染相关死亡,未发现股骨头坏死;在标危(SR)组中未出现复发及死亡。结论GZ-ALL-2002方案是目前治疗儿童ALL的先进方案之一。     

Intestinal obstruction at the onset of acute lymphoblastic leukemia in a child

Surgical complications need not be fatal in acute leukemia. If these are promptly diagnosed and properly treated, the prognosis will improve. This report deals with a case of acute lymphoblastic leukemia presenting with an acute abdomen following surgery for choledochal cyst. A peripheral blood smear and examination of the bone marrow revealed acute lymphoblastic leukemia. The child received transfusions of blood and platelets. Pretreatment with prednisolone was started as therapy for leukemia, and 2 days later, the patient underwent surgery. Therapy was continued until the general condition allowed a more aggressive form of treatment. Complete remission was achieved, and the patient is still in good health 48 months after diagnosis and 15 months after discontinuation of treatment. The favorable outcome in this child shows that prompt surgery is sometimes an essential step in the treatment of childhood leukemia.     

Duration of adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) recive high doses of glucocorticosteroid as part of their treatment. This may lead to suppression of the hypothalamic-pituitary-adrenal axis, acute adrenal insufficiency, and ultimately to life-threatening conditions. This study explores the adrenal function in 96 children with ALL treated according to common protocols. After cessation of induction glucocorticosteroid therapy, they received hydrocortisone substitution therapy (10 mg/m/24 h) until an adrenocorticotropic hormone test (250 μg tetracosatide) showed a sufficient adrenal response [plasma (p)-cortisol ≥500 nM]. At the first adrenocorticotropic hormone test, 67% of the patients had adrenal insufficiency. When including these patients in a multivariate model, not adjusting for risk factors, the mean elapsed time between end of induction therapy and adrenal sufficiency was 8.5 months (95% confidence interval: 6.3;10.7). Low 0-minute p-cortisol (P=0.02) and low rise in p-cortisol (P<0.0001) at first test caused a longer time of adrenal insufficiency. In addition, patients with B-cell precursor leukemia reached adrenal sufficiency later than those with T-cell leukemia (P=0.067). As adrenal insufficiency is frequent in children treated for ALL and as they often experience infections and other stressors, the adrenal response should be determined and hydrocortisone substitution therapy should be considered during such episodes in patients with adrenal insufficiency.     

Leukemic ophthalmopathy: A report of 21 pediatric cases

A multicentric retrospective study on leukemic ophthalmopathy (LO) is reported. It includes 21 patients, 16 males and 5 females, with acute leukemia (AL) observed in 10 SIOP centers. LO developed in three patients at the time of diagnosis of AL; five patients were in first complete remission (three off therapy); four patients were in second or third remission; and nine were in combined relapse. Most frequent symptoms were blurred vision, photophobia, and ocular pain. Two patients with acute nonlymphoblastic leukemia died before treatment; another underwent bone marrow transplantation; one patient with B-cell acute lymphoblastic leukemia (B-ALL) treated with chemotherapy and radiotherapy died 4 months after LO; the remaining 17 children were treated according to different schedules with (10) or without (7) radiotherapy on the affected eye. Twelve patients achieved ocular remission and four of these had a second ocular relapse. Complete remission after LO treatment lasting for more than 3, 7, 24, 29 months was observed in four patients. The authors conclude that cure is possible in patients who had LO in first complete remission treated with chemotherapy and radiotherapy at high dose on the affected eye. © 1994 Wiley-Liss, Inc.     

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.     

The prognosis and survival of childhood acute lymphoblastic leukemia with central nervous system relapse

Central nervous system (CNS) relapse in childhood acute lymphoblastic leukemia (ALL) has been overcome by sensitive therapeutic approachs. This study was planned to present the development of CNS relapse and survival in newly diagnosed 190 ALL patients whose cases were followed in the authors' unit between March 1991 and May 2002. St. Jude Study XI protocol was given to the patients who applied between March 1991 and March 1997 (group A) (n = 122), and St. Jude Study XIII protocol was given to the patients who applied between March 1997 and May 2002 (group B) (n = 68). The patients having isolated CNS relapse in group A received craniospinal irradiation (CSI) median 3.5 months after CNS relapse (range 2-6 months), a short time after reinduction, and 2 cures of consolidation. In group B, patients having isolated CNS relapse received IT once a month and a high-dose methotrexate treatment once every 8 weeks and 3 or 4, cures later therapy CSI median 7 months after CNS relapse (range 6-8 months) was given. When the overall survival rates of the 2 groups are compared, a statistically significant higher survival rate at 5 years was determined in group B than in group A (respectively, 82.3%, 58.4%) (p < .05). When subgroups of the patients (that is, those with no relapse, isolated CNS or BM relapse, or CNS + BM relapse) were compared in both groups, it was found that survival was much higher for the ones with no relapse and with isolated CNS relapse (respectively, 87.9%, 72.7%) compared to isolated BM or CNS + BM relapse groups (respectively, 10%, 13.3%) (p < .05). In a conclusion, for children with acute lymphoblastic leukemia and an isolated CNS relapse, with delayed definitive craniospinal irradiation allowing more intensive systemic and intrathecal chemotherapy results in better overall survival than has been previously reported.     

10岁以上儿童及青少年急性淋巴细胞性白血病的临床总结

目的总结64例年龄为10~17岁急性淋巴细胞性白血病(以下简称急淋)的临床疗效。方法64例患儿中男44例,女20例均接受99-XH-ALL方案治疗,随访1~116个月,平均随访时间为43个月,并应用SPSS 11.0软件进行无事件生存期和总生存期的分析。结果64例患儿中24例(37.5%)无不良临床特征,早期治疗反应良好,40例(62.5%)有不良临床特征及早期治疗反应不佳,64例患儿中58例达到CR,其中55例一疗程达到CR(85.94%),总CR率为90.63%,平均CR时间为38.45(25~56)天;13例复发(22.41%),平均复发时间为CR后15.77(2~58)个月;9例死亡(14.06%),其中4例死于感染,5例死于复发;随访中有21例失访,其中7例为复发后,10例为CR后,4例为未CR者,3例患儿接受移植,其中2例存活,1例死于移植后疾病复发,4例患儿出现并发症,占11.76%,其中1例乙肝(50个月),3例股骨头坏死(25、32、60个月),1例女孩4个月时发生第二肿瘤恶性葡萄胎,治愈存活至今。64例病人7年EFS:(37.31±7.23%),7年OS:(54.40±6.51%)。结论10岁以上儿童及青少年的急淋预后不良,长期生存率低。     

Successful treatment of ICE-rituximab chemotherapy and subsequent bone marrow transplantation in a patient with early-relapse Burkitt leukemia and inverted duplication of 1q

Although childhood acute lymphoblastic leukemias are of good prognosis than leukemias of adulthood, some chromosomal abnormalities may have negative effects on their prognosis. Inverted duplication (1q) is a chromosomal abnormality with negative effect on outcome of Burkitt leukemia and lymphomas. We report a case of CD20 Burkitt leukemia with inverted duplication (1q) mutation, who had an early relapse during NHL-BFM 95 treatment. Two courses of ICE-rituximab treatment were administered after relapse and a successful HLA-full match bone marrow transplantation was carried out. He is in follow-up for 18 months without any problem after the bone marrow transplantation. We suggest the usage of ICE protocol combined with rituximab in childhood CD20 Burkitt leukemia with poor prognostic criteria such as inverted duplication (1q) mutation.     

Polycythemia vera in a child following treatment for acute lymphoblastic leukemia

Polycythemia vera (PV), a hematologic stem cell disorder characterized by predominant erythroid proliferation, is extremely rare in childhood. Some PV patients develop acute leukemia, especially acute myelogenous leukemia, but cases of PV occurring after treatment of acute leukemia are rare. The authors describe a girl with an atrioventricular canal who was diagnosed with acute lymphoblastic leukemia (ALL) at 23 months of age, was cured with chemotherapy, and developed PV 7 years later. She went on to develop hepatic complications of PV that culminated in death from liver disease at 20 years of age, without recurrence of ALL.     

Infectious complications of the treatment of acute lymphoblastic leukemia in children

The authors report the infectious complications observed during the treatment of acute lymphoblastic leukemia in 70 children, followed by a same team, with the same protocole, for a period of 6 years (mean follow-up: 42.3 months). The complications were mainly bacterial during induction phase, mainly staphylococcic the microbiological follow-up and a rapid empiric antibiotic therapy allowed to control more than 80% of the febrile episodes. There was one death from fulminant pyocyanic infection.     

SERIAL DETERMINATIONS OF SERUM FERRITIN IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA Evaluation of its Usefulness as a Prognostic Index

Abstract. Thirty children with acute lymphoblastic leukemia were monitored with serial serum ferritin determinations for up to 17 months. In children with acute lymphoblastic leukemia before initiation of therapy, or in relapse, the mean serum ferritin concentration was 636 μg/l. In children who went into primary remission, the mean serum ferritin concentration fell from 265 μg/l prior to start of treatment, to 161 μg/l after 3 months of treatment. Five patients relapsed. Their serum ferritin levels prior to the relapses ranged from 7 to 135 μg/l. At the time of relapse a further increase in serum ferritin was found in only 2 of the children. Thus, whereas high serum ferritin levels may signal disease activity in acute lymphoblastic leukemia, a normal serum ferritin level does not exclude disease activity or impending relapse.