Inevitable and Avoidable Deaths in Childhood ALL

ABSTRACT. The causes of 37 deaths among 100 Finnish children with ALL were analyzed after a median follow-up of 5 years. Five children died during primary induction, 9 in complete remission, and 23 in hematological relapse. Infections were responsible for 17 deaths, and four deaths were due to toxicity of chemotherapy. In 16 cases ALL relapse was the major cause of death. Ten of the deaths were defined as "avoidable" because they occurred in potentially curable children, i.e., during induction or primary remission. Critical analysis revealed that 5 out of the 10 "avoidable" deaths might indeed have been prevented by appropriate diagnosis and therapy. We want to emphasize the need for continuous education of all pediatricians involved in the care of ALL patients, as well as the importance of best available clinical expertise and centralization of medical therapy in the efforts to diminish the mortality in childhood ALL.     

Remission death in acute lymphoblastic leukaemia: a changing pattern.

The pattern of remission deaths was examined in 842 children with acute lymphoblastic leukaemia (ALL) treated at a single centre over 18 years. The mortality rate from leukaemia fell significantly during three consecutive time periods during which treatment became progressively more intensive and that during remission induction fell from 3.5% to under 1%, but the rate of death in remission stayed constant at 5-6%. The factors associated with an increased risk of remission death were: young age, a higher leucocyte count, bone marrow transplantation, and Down's syndrome. The pattern of remission deaths changed over the years; measles and herpes viruses decreased while deaths associated with periods of intensification and gut toxicity increased. Four children developed second neoplasms. Treatment of ALL is still associated with a significant risk of death in remission but the pattern of infective deaths has changed. Many should be avoidable by provision of adequate supportive care, close supervision after periods of intensive treatment, and appropriate antibiotic, antifungal, and cytokine therapy.     

Intermittent chemotherapy and BCG in continuation therapy of children with acute lymphocytic leukemia.

Continuation therapy using intermittent chemotherapy and BCG inoculation was commenced in 28 children with acute lymphocytic leukemia (ALL) immediately after remission induction and "CNS prophylaxis." At a median followup time of 17 months, 71% remain in total remission and 86% in bone marrow remission. Complications of the therapy were minimal. Major infections occurred on two occasions and there were no deaths in remission. Neutropenia, "minor" infections and postponement of chemotherapy occurred most often during the first three courses of treatment. There were no local or systemic BCG infections. Tuberculin sensitivity was tested in 25 patients. It was positive in 17 of 18 patients in total remission and all four patients with only CNS relapse, and was negative prior to relapse in three patients who developed bone marrow disease.     

Intermittent chemotherapy and bcg in continuation therapy of children with acute lymphocytic leukemia

Continuation therapy using intermittent chemotherapy and BCG inoculation was commenced in 28 children with acute lymphocytic leukemia (ALL) immediately after remission induction and “CNS prophylaxis.” At a median followup time of 17 months, 71% remain in total remission and 86% in bone marrow remission. Complications of the therapy were minimal. Major infections occurred on two occasions and there were no deaths in remission. Neutropenia, “minor” infections and postponement of chemotherapy occurred most often during the first three courses of treatment. There were no local or systemic BCG infections. Tuberculin sensitivity was tested in 25 patients. It was positive in 17 of 18 patients in total remission and all four patients with only CNS relapse, and was negative prior to relapse in three patients who developed bone marrow disease.     

Induction toxicity of a modified Memorial Sloan-Kettering-New York II protocol in children with relapsed acute lymphoblastic leukemia: A single institution study

Although the chance of cure for children with acute lymphoblastic leukaemia (ALL) is high, their outlook with subsequent relapse is poor. Bone marrow transplantation may be an option for some, but the need for intensive reinduction chemotherapy regimens remains the best hope for effecting cure in the majority of relapsed children. The authors report the experience of using an intensive chemotherapy protocol (Memorial Sloan-Kettering-New York II Protocol, MSK-NY-II) in a series of relapsed children with ALL. Thirty children presenting to the Royal Alexandra Hospital for Children, Sydney, in their first relapse of ALL were treated according to a modification of the original MSK-NY-II protocol. Three children (10%) died during induction therapy, two from overwhelming Gram-negative sepsis, and one from intracerebral haemorrhage. Of 27 children completing induction, two children failed to enter remission; however, both had planned deviations from the protocol. Infectious complications were prominent with a total of 55 admissions for febrile neutropenic episodes. Eight children required the support of the intensive care unit for infectious complications. A total of 36 microbiological isolates were obtained from the patients during induction therapy. Ten bone marrow transplant procedures have been subsequently performed in these children, of whom five are alive and disease free at the time of writing. The MSK-NY-II protocol is an intensive regimen but with encouraging early remission rates in relapsed childhood ALL. Early sepsis in previously immunosuppressed children is an important cause of induction death. © 1996 Wiley-Liss, Inc.     

Serum soluble L-selectin in childhood acute lymphoblastic leukemia

BACKGROUND: Determination of the serum level of soluble (s)L-selectin has been advocated for monitoring patient response to treatment in leukemia. The aim of the present study was to find out whether serum levels of sL-selectin correlated with treatment for acute lymphoblastic leukemia (ALL) in children. METHODS AND RESULTS: Serum samples were obtained from 30 children with ALL, either newly diagnosed during induction therapy, in remission, in maintenance therapy, at the end of treatment or after relapse. Levels of sL-selectin were assayed in the serum of children during the clinical course of ALL using the sandwich enzyme-linked immunoabsorbent assay. Serum sL-selectin concentrations decreased significantly from diagnosis to the end of intensive chemotherapy in children with ALL and increased in the time of relapse. CONCLUSION: These results suggest that monitoring of sL-selectin may be useful for evaluating leukemia activity.     

Combination chemotherapy for bone marrow relapse in childhood lymphoblastic leukaemia (ALL).

Thirty-four children with acute lymphoblastic leukaemia (ALL) in relapse or resistant to initial induction received combination chemotherapy with prednisolone, vincristine, l-asparaginase, and daunorubicin. L-asparaginase was given subcutaneously on alternate days for four weeks and was well tolerated. A complete remission was achieved in 96% of children in relapse and in five out of six children resistant to induction. Remission was achieved without hospitalisation in over 60% of patients. The median duration of subsequent remission was only 13 weeks, but six out of eight children receiving a second course of the drug combination achieved a further remission. We conclude that prolonged l-asparaginase therapy in combination with an anthracycline might well be used in initial or consolidation therapy for childhood ALL.     

Combination chemotherapy for bone marrow relapse in childhood lymphoblastic leukaemia (all)

Thirty-four children with acute lymphoblastic leukaemia (ALL) in relapse or resistant to initial induction received combination chemotherapy with prednisolone, vincristine, 1-asparaginase, and daunorubicin. L-asparaginase was given subcutaneously on alternate days for four weeks and was well tolerated. A complete remission was achieved in 96% of children in relapse and in five out of six children resistant to induction. Remission was achieved without hospitalisation in over 60% of patients. The median duration of subsequent remission was only 13 weeks, but six out of eight children receiving a second course of the drug combination achieved a further remission. We conclude that prolonged 1-asparaginase therapy in combination with an anthracycline might well be used in initial or consolidation therapy for childhood ALL.     

Morphologic changes in blast cells of children with acute lymphoblastic leukemia in relapse

Relapse in children with acute lymphoblastic leukemia (ALL) on therapy may be due to development of a resistant clone of blast cells. Seven children who presented initially with the "common"-type, L1 lymphoblast relapsed with a morphologically different and more undifferentiated blast cell. All were male, with a median age of 12 years at initial presentation. One child who relapsed while off therapy was successfully reinduced and remains in hematologic remission on therapy. The remaining 6 children died within 10 months of relapse. Selection of a resistant clone of lymphoblasts by chemotherapy may be responsible for relapse in children with ALL and should be studied in hopes of controlling the disease.     

E2A-PBX1融合基因的实时定量检测在小儿急性淋巴细胞白血病微小残留病监测中的应用

目的：实时荧光定量PCR方法检测E2A-PBX1融合基因的表达水平,探讨其在监测急性淋巴细胞白血病（ALL）患儿微小残留病（MRD）及判断预后中的临床价值。方法：采用实时荧光定量RT-PCR方法,动态检测11例E2A-PBX1融合基因阳性的ALL患儿在初治期（11例）、完全缓解期（11例）、复发期（3例）和10例同期骨髓细胞形态学正常的非血液及肿瘤疾病对照组患儿的E2A-PBX1融合基因表达水平。结果：11例ALL患儿初治期和复发期的E2A-PBX1基因表达水平均显著高于缓解期及对照组（P<0.01）。与诱导缓解治疗第33天E2A-PBX1水平表达阴性的患儿比较,表达阳性的患儿3年的复发率增高,无病生存率降低（均P<0.05）。结论：实时荧光定量RT-PCR检测E2A-PBX1融合基因的表达水平是监测MRD、预测复发、指导个体化治疗的良好指标,诱导缓解第33天E2A-PBX1融合基因水平可用于判断预后。     

Treatment of childhood acute lymphoblastic leukemia with intermediate-dose cytosine arabinoside and adriamycin

Eight pediatric patients with acute lymphoblastic leukemia (ALL) were treated with intermediate-dose cytosine arabinoside (ID-AraC, 1 g/m2) in combination with adriamycin except one patient. Of the eight patients, four refractory to the initial induction therapy and one in bone marrow relapse gained complete remission with two to three cycles of this therapy. Four of the five patients have been in continuous remission for 4 to 24 months with the maintenance therapy of monthly administration of ID-AraC. One patient in central nervous system (CNS) relapse has continued in remission from CNS leukemia after two cycles of the therapy. Side effects of ID-AraC and adriamycin were generally mild to moderate and tolerable in all children. These results suggest that the use of ID-AraC and adriamycin might prove effective in the treatment of ALL refractory to other regimens.     

Hematopoietic stem cell transplantation after first marrow relapse of non-T, non-B acute lymphoblastic leukemia: a pediatric oncology group pilot feasibility study

BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) in children is associated with a poor outcome, especially for those patients whose relapse occurs during the first 36 months after diagnosis. The best therapy for these patients is not known. This study was designed to evaluate the feasibility of enrolling children with recurrent ALL in a standardized treatment protocol that included receipt of a hematopoietic stem cell transplant (HSCT). PROCEDURE: Eligible patients with a bone marrow relapse of non-T, non-B ALL underwent a common induction and consolidation followed by receipt of either an allogeneic HSCT from a human leukocyte antigen (HLA)-identical sibling or an autologous HSCT purged with B-4 blocked ricin. A common conditioning regimen was used for all patients. RESULTS: Twenty-eight patients from eight institutions were enrolled. Fourteen patients did not receive a transplant during the study, because of toxicity (4), relapse (1), inadequate purging (1), and parental or physician preference for an alternative donor transplant (8). Six patients received allogeneic HSCTs. Five of them have remained in remission for a median of 78 months. Eight patients received autologous HSCTs purged with B4-blocked ricin. Four have remained in remission for a median of 94 months. Of the nine patients who received alternative donor transplants, only two remain in remission. CONCLUSION: We conclude that well designed and controlled prospective studies are necessary to define the role of HSCTs in children with recurrent ALL. In order to be successful, such studies must have the full support of participating centers. Autologous HSC transplantation may have a role in the treatment of relapsed ALL, but further studies are needed.     

急性淋巴细胞白血病初诊患儿诱导缓解阶段总医疗费用的影响因素分析

背景：儿童急性淋巴细胞白血病（ALL）所致家庭经济负担沉重。 目的：探索影响ALL患儿医疗费用的影响因素，为合理控制费用提供依据。 设计：横断面研究。 方法：回顾性纳入重庆医科大学附属儿童医院血液肿瘤专科收治的初诊ALL患儿，分析诱导缓解治疗过程的总医疗费用，并采用秩相关分析和广义线性模型统计分析影响医疗负担的因素。 主要结局指标：ALL患儿诱导缓解阶段住院总费用。 结果：1 081例初诊ALL患儿纳入本文分析，男622例（57.5%），女459例；平均年龄（70.5±44.5）月龄。诱导缓解阶段平均总诊疗费用（59 860±25 989）元，日均住院费用（1 244±581）元，平均血液制品输注费用（7 106±5 391）元。单因素秩相关分析显示，按患儿年龄，疾病免疫分型，初诊危险度分层，是否发生院感、真菌感染以及败血症，是否非血液专科入院，是否入住PICU治疗，住院时长，血液制品输注费用分组，诱导缓解阶段总医疗费用组间差异有统计学意义。广义线性模型构建结果提示，是否转入PICU、是否非血液专科入院、是否发生院感、免疫分型、是否发生真菌感染、住院时长和输血治疗费用为影响诱导缓解阶段总医疗费用的独立风险因素。 结论：儿童ALL医疗费用受到疾病严重程度、并发症严重程度以及院感、专科入院等医疗管理相关因素的影响。     

Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X

The benefits of achieving a long term event free survival of 60-70% by using increasingly intense treatment regimens must be weighed against the increased risk of treatment toxicity. From 1985 to 1990, 1612 children with childhood acute lymphoblastic leukaemia (ALL) in the UK were treated on MRC UKALL X with intensive induction therapy, central nervous system directed therapy (cranial irradiation and intrathecal methotrexate), and continuing treatment for two years. There was a randomisation to receive blocks of additional intensification treatment at five weeks, 20 weeks, not at all, or both. The five year disease free survival was 71% for children randomised to two blocks of intensification, a 14% improvement on children randomised to no intensification treatment. Treatment related mortality in this national multicentre study has been analysed for induction and first remission (including those after intensification treatment). There were 38 induction deaths, 2.3% and 53 deaths in first remission, 3.3% (including those from a second malignancy). Thirty one (84%) of the induction deaths followed an infection: bacterial in 22 and fungal in nine. Thirty seven infective remission deaths occurred: bacterial in 11, viral in 16, fungal in seven, and three caused by Pneumocystis carinii pneumonia. Ten of these deaths followed a block of intensification treatment. The majority of noninfective remission deaths followed the development of a second tumour. Risk analysis for an induction death showed girls and children with Down's syndrome to be at greater risk. For deaths in first remission analysis showed an increased risk for bone marrow transplant (BMT) patients and children with Down's syndrome. There was no effect of age and leucocyte count for either group. Most significantly when BMT patients were excluded from the analysis, intensification treatment did not increase the risk of remission death.     

A phase II study of diaziquone in childhood leukemia: a report from the Children's Cancer Study Group

Diaziquone (aziridinylbenzoquinone, AZQ) was given by 30-min infusion at 25 mg/m2/day on a daily x 5 schedule to 16 children with acute lymphoblastic leukemia (ALL) in bone marrow relapse, 16 children with acute nonlymphocytic leukemia (ANLL) in bone marrow relapse, and 1 child with chronic myelocytic leukemia in blast crisis. None of the children achieved bone marrow remission. Five children (four with ALL and one with ANLL) were also evaluable for the response of central nervous system leukemia; all had a significant reduction in the cerebrospinal fluid blast count. Mild transient transaminase elevation was commonly seen. Grade 3 and 4 hyperbilirubinemia was seen in association with sepsis. AZQ was ineffective for induction of bone marrow remission as utilized in this study.     

Second induction in pediatric patients with recurrent acute lymphoid leukemia using DFCI-ALL protocols

Between 15% and 30% of children with acute lymphoblastic leukemia (ALL) experience disease recurrence. With the possible exception of patients presenting with late isolated extramedullary relapse, induction of second complete remission (CR) is employed as a stepping stone to allogeneic hematopoietic stem cell transplantation (HSCT). The authors report their institutional experience in the management of children with recurrent ALL using the Dana Farber Cancer Institute (DFCI) ALL protocol in patients treated initially with that same protocol. Successful reinduction was followed by allogeneic HSCT when possible. Between April 1986 and May 2003, 34 patients with recurrent ALL, treated at initial diagnosis with DFCI-ALL protocol therapy, were given the same protocol as repeat induction chemotherapy. The median age was 4.6 years at diagnosis and 7.1 years at recurrence. Median duration of CR1 was 30.3 months. Second CR was obtained in 29 (85%) patients. Twenty went on to allogeneic HSCT; 10 of them currently remain in CR. Two additional patients treated with chemotherapy without HSCT are also in continuous CR2. Overall, 13 (38%) of the 34 patients are alive with a median follow-up of 105 months. There were no toxic deaths due to the reinduction therapy. One child died of cardiac failure after autologous HSCT. The treatment of children with recurrent ALL using the DFCI-ALL protocol induction regimen after initial use of the same protocol is associated with a high rate of second CR with no excess toxicity. However, the overall prognosis in these patients remains unsatisfactory and needs to be improved.     

Delayed craniospinal irradiation for a first isolated central nervous relapse of acute lymphoblastic leukemia: report on 14 cases

BACKGROUND: Children developing an isolated central nervous system (CNS) relapse as first recurrence of their acute lymphoblastic leukemia (ALL) are considered to have a systemic relapse as well. They are mostly treated with intensive chemotherapy and craniospinal irradiation. In most treatment schedules, irradiation is given early after induction treatment. Because craniospinal irradiation affects a large portion of hematopoietic bone marrow systemically, treatment is often delayed owing to aplasias. Also, dose reductions are frequently needed. Children receiving simultaneously irradiation and chemotherapy are prone to (often severe) neurotoxicity. This study reports on children with a first isolated CNS relapse of their ALL receiving chemotherapy for 40 weeks. Treatment ends with the administration of irradiation given after cessation of chemotherapy. PROCEDURE: Fourteen children, with blasts and >5 cells/mm(3) in two consecutive samples of cerebrospinal fluid and a blast percentage <5% in their bone marrow were treated according to an intensive systemic and site-specific chemotherapy. Craniospinal irradiation was administered after cessation chemotherapy. RESULTS: Event-free-survival was 57% (confidence interval 35-89%), freedom from relapse was 61.5%; follow-up ranges from 2.0 to 15.1 years (median 11.7 years). One child died from septicemia during induction. Five children experienced a second relapse and died from their malignancy. Two children [with a t(9;22) or a rearranged MLL gene] relapsed prior to radiotherapy. Outcome was related to duration of first remission, age at relapse, and identification as a high-risk patient at initial diagnosis. No neurologic complications were noted during and after treatment. CONCLUSIONS: Delayed irradiation for isolated CNS relapse in children with ALL gives favorable survival rates, without significant toxicity. Neurotoxicity was absent.     

Prognosis improvements in children with acute myelocytic leucemia after more intensive induction therapy (author's transl)]

Between October 1974 and October 1978 23 children with acute myelocytic leucemia (AML) received intensive therapy in the Univ.-Kinderklinik Münster: 4 children were treated according to the ALGB-protocol consisting of 5-7 day courses of ARA-C-infusion and 3 DNR-injections. 19 patients received the West-Berlin-protocol: The first 7 the original ALL protocol, 11 the modified form of AML, which will be presented here as AML-therapy-study BFM 78. 4 of the 23 patients died with early acute cerebral bleeding. 2 patients were nonresponders. 17 children went into remission. One girl died in remission of septicemic aspergillosis. 4 children had a relapse. In November 1978 there were still 12 patients in continuous complete remission, 3 of them already without therapy. 13 of the 19 patients, who were treated with the West-Berlin-protocol went into remission. 1 had a relapse. At present there are 11 patients in continuous complete remission. The above results and those found in the literature could signify that the long term prognosis of children with AML will be improved. To coordinate efforts toward this goal a cooperative AML-therapy-study in the "Deutsche Arbeitsgemeinschaft für Leuk?mieforschung" (BFM-group) using the here presented therapy protocol was formed in November 1978.     

Low relapse rate in children with acute lymphoblastic leukemia after risk-directed therapy

PURPOSE: Even though acute lymphoblastic leukemia (ALL) responds well to chemotherapy, relapse remains the major problem. This study documents relapse and survival rates in 85 consecutive children (33 at good risk, 52 at high risk) with ALL diagnosed in 1991 to 1996. PATIENTS AND METHODS: Until 1993, the New York II protocol for the high-risk group and a combination of UKALL XI (induction) and R blocks of ALL-REZ BFM-87 (intensification) regimens for patients at good risk were used. To reduce toxicity, the protocols were subsequently modified. Consolidation treatment was the same for both groups, consisting of a lower cytarabine dose and methotrexate removal, whereas intensification was changed only for the high-risk group using the BB block of the NHL-BFM-90 protocol. The bone marrow clearance of leukemia was assessed on day 22, and minimal residual disease was detected using polymerase chain reaction analysis of Ig heavy-chain gene rearrangements. RESULTS: Seventy patients had common precursor B lineage ALL, six had pre-B-ALL, eight had T-ALL, and one had B-ALL. Two patients never achieved remission and died. Six patients died of consolidation-related complications. Four more patients died, two during induction and two during maintenance therapy. Two other children had relapse (2.3%), both of whom were treated with the earlier protocols and then underwent bone marrow transplantation. Four more children with morphologically complete remission showed minimal residual disease (which reached the levels of 1 leukemic cell among 10(2)-10(4) normal cells) with the use of clone-specific probes at several points of the study intervals, but never had relapse. The 5-year overall and event-free survival rates were 86% and 83%, respectively. The 5-year overall survival rates for good-risk and high-risk groups were 94% and 81%; the corresponding event-free rates were 91% and 78%. The 5-year event-free survival rate in the patients at high risk was significantly higher after the protocol change (90% vs. 65%, P = 0.04). CONCLUSIONS: The modification proved to be effective in diminishing the therapeutic toxicity and improving the efficacy, mainly for the high-risk group.     

Acute lymphoblastic leukemia in children. Results of a protocol including bone marrow transplantation during the first remission in high-risk forms for relapse

Ninety-two previously untreated children with ALL were admitted to the same institution between November 1984 and November 1988. According to early prognostic factors, patients were divided into 3 groups: group 1 at "low risk" for relapse (n = 18), group 2 at "intermediate risk" (n = 62) and group 3 at "high risk" (n = 12). Every patient received an 8 week-long induction chemotherapy; after CNS prophylaxis, groups 1 and 2 children received a consolidation chemotherapy and then a classical maintenance treatment. Group 3 patients were selected to receive a bone-marrow transplantation during their first remission because of the presence, at diagnosis, of at least one of the following criteria: hyperleukocytosis greater than 100,000 (7 cases), translocation t(1;19) and t(4;11) (2 cases), adolescents (2 cases), no remission at day 30 (2 cases). Ninety-one of 92 children achieved a complete remission and none died during induction therapy. Probability of leukemia-free survival at 4 years is 73 +/- 7% for the whole patient population and 95%, 71% and 60% for patients of groups 1, 2, and 3 respectively. Persistence or disappearance of leukaemic cells in bone marrow after the initial 15 days of chemotherapy appears to influence the probability of a leukemia-free survival.