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.     

Relapse in childhood acute lymphoblastic leukemia after elective cessation of initial treatment: Failure of subsequent treatment with cyclophosphamide,cytosine arabinoside,vincristine and prednisone (COAP)

Although the majority of children with acute lymphoblastic leukemia (ALL) can electively stop treatment after 21/2–5 years of continuous disease-free remission, 20–25% of those patients relapse after discontinuation of therapy. We treated 15 patients whose disease recurred after stopping treatment. Fourteen of them attained complete remission, but the median duration of disease-free survival was only 11 months. In this population, the site of initial relapse, bone marrow or testicle, did not influence subsequent outcome. Patients who relapsed within six months of stopping initial therapy had shorter second remissions than those who relapsed after six months. We conclude that the combination chemotherapy utilized in this study was inadequte for the control of relapsed ALL. Future programs will have to use different drug combinations or bone marrow transplantation.     

Inevitable and avoidable deaths in childhood ALL

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.     

Concepts in therapy of the first relapse in acute lymphoblastic leukaemia: experience with 28 children (author's transl)]

In 10 out of 15 children with first relapse of ALL complete remission could be achieved by a combination of Adriamycin + Methylprednisolon followed by Asparaginase + Methylprednisolon. Median remission duration was 24 weeks. The results of this regimen proved superior to other regimens tested.     

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.     

Intermediate-dose methotrexate and intravenous 6-mercaptopurine chemotherapy for children with acute lymphoblastic leukemia who did not respond to initial induction therapy

PURPOSE: To determine the complete remission rate of children with acute lymphoblastic leukemia (ALL) who were not induced into remission by initial therapy, when subsequently treated with intermediate-dose methotrexate and intravenous 6-mercaptopurine. PATIENTS AND METHODS: Children with B-precursor ALL who did not achieve initial remission after 4 or 6 weeks of standard three- or four-drug induction chemotherapy were entered on study. Therapy consisted of three doses at weekly intervals of methotrexate 1,000 mg/m2 over 24 hours followed by 6-mercaptopurine 1,000 mg/m2 over 8 hours 20 minutes. Patients achieving a partial remission could receive two additional weekly courses of methotrexate and 6-mercaptopurine. Initially, patients received weekly intrathecal chemotherapy, but the study was amended to include intrathecal therapy only at week 1. RESULTS: Nineteen patients were entered on study. All were evaluable for toxicity and response. There were seven complete remissions, four partial remissions, six patients with no response, and two children with progressive disease, for an overall complete remission rate of 37%. One patient was removed from the study after the second course of methotrexate and 6-mercaptopurine because of renal failure. Two patients had neurologic toxicity resulting in a study amendment. No patients subsequently experienced neurologic toxicity. CONCLUSIONS: Intermediate-dose intravenous methotrexate and intravenous 6-mercaptopurine can induce remission in some patients with ALL who experience initial induction failure. Features predicting complete remission, however, could not be identified.     

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.     

Toxicity and efficacy of intensive chemotherapy for children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary relapse

BACKGROUND: Approximately 25% of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse, with bone marrow being the most common site of recurrence. The ability to achieve a durable second remission is complicated by toxicity and resistant disease. We report a novel combination of chemotherapy for relapsed pediatric ALL. PROCEDURE: Thirty pediatric patients with relapsed medullary (n = 18) and extra-medullary (n = 12) ALL were enrolled at three pediatric institutions. Following receipt of induction and the first Block A and Block B of intensification, each patient was evaluated for toxicity, efficacy in achieving remission, and long-term survival. Additionally, minimal residual disease (MRD) detection by multidimensional flow cytometry (MDF) was performed. RESULTS: During induction, the major non-hematopoeitic toxicities were mucositis (30% of patients) and bacteremia (50% of patients). Two patients (7%) died of toxicity during induction. Toxicity during intensification Block 1A and 1B was markedly reduced. Eight-nine percent of patients with marrow disease achieved a remission following induction and intensification. The event-free survival (EFS) for all patients at 2 and 4 years were 60% (95% CI: 42-78%) and 49% (95% CI: 30-68%), respectively. CONCLUSIONS: This regimen for patients with relapsed ALL was successful in achieving a second remission for the majority of patients with acceptable toxicity.     

ADEP方案双诱导加HAD方案治疗儿童急性粒细胞和急性粒单核细胞性白血病临床疗效分析

目的　分析初治急性粒细胞性白血病 (急粒 )和急性粒单核细胞性白血病 (M4)患儿用ADEP(阿糖胞苷、柔红霉素和依托泊苷 )方案双诱导加HAD(大剂量阿糖胞苷和柔红霉素 )方案的疗效。方法　总结 1991年 7月至 1999年 12月北京大学人民医院 2 6例急粒和 10例M4其中男 2 1例 ,女 15例 ,EFS(长期无病生存 ) 3年以上 ,停药 2年以上 ,中位EFS 7年 ,随访时间至 2 0 0 2年 12月。结果　 (1)用ADEP诱导治疗一个疗程完全缓解率 (CR)91% ,粒细胞白血病EFS率 5 0 % ,M4EFS率 5 7% ,中位生存时间 7年。 10例复发患儿 83%在 6～ 10个月内复发。(2 )大剂量阿糖胞苷 1g/m2 每日 2次持续 3d或 4d加蒽环类方案两者EFS率和复发率无差别 ,但在疗程中 16例用Idr(去甲氧柔红霉素 )的患儿长期存活 11例 (6 8 75 % ) ,6例不用Idr的患儿长期存活 1例 (16 7% ) ,差异有显著性。结论　 (1)用ADEP双诱导方案加HAD方案 ,在疗程中用Idr,有高的CR率和较高的EFS率。 (2 )对 10例复发病例分析 ,9例有高危因素存在 ,复发时间 80 %在CR后 6～ 10个月内 ,因此有高危因素的患儿 ,最好在CR 4～ 6个月期间行造血干细胞移植治疗     

Acute myelogenous leukemia in children: a preliminary report of combination chemotherapy.

Twenty-four children (2 to 21 years) diagnosed as having AML from 1969 to 1972 were randomized to receive either a single combination (COMP or PRAVD) or sequential combination chemotherapy (alternating POMP and PRAVD). Seventeen achieved complete remission. Patients who received POMP alone had the longest median duration of remission (1,400 days) compared to PRAVD (395 days) or POMP-PRAVD (270 days); interpretation of this difference is uncertain, since the numbers in each group are small. Fifteen patients have relapsed, four initially with CNS involvement. Successful reinduction was achieved almost exclusively for patients who had initially received POMP. Survival after first relapse was short. Patients less than 16 years had a median survival of 632 days, compared to 285 days for patiens greater than 16 (p less than 0.05). The high initial induction rate in these patients is encouraging, but the duration remission is inferior to that seen in childhood ALL. Moreover, the slope of the relapse curve is continuous over a five-year period with no definite plateau where it might appear that patients are no longer at risk of relapse. Improved methods for the treatment of childhood ALL and adult AML suggest possible new approaches to AML in children, with prophylactic treatment of central nervous system, late intensification, and immunotherapy.     

Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia

In 1971, Cancer and Leukemia Group B (CALGB) mounted a study of acute lymphocytic leukemia (ALL) that compared the effects of the two steroid hormones dexa-methasome and prednisone. Six-hundred-forty-six children and adolescents with ALL were randomized to receive either prednisone or dexamethasone as part of their remission induction therapy. The 493 evaluable patients who achieved complete remission received the same steroid as pulses throughout remission. Specific central nervous system (CNS) therapy was randomized to either six injections of intrathecal methotrexate (IT MTX) alone or to six injections of IT MTX with cranial radiation (2,400 cGy). Both cranial radiation and dexamethasone offered increased protection against CNS relapse as the first site of failure over IT MTX alone. There were 30 CNS relapses among 238 patients (12.6%) receiving cranial radiation plus IT MTX, whereas there were 70 CNS relapses among 225 (P < 0.001) (22.5%) in those who received IT MTX alone. Similarly, there were 33 CNS relapses among 231 (14.3%) children treated with dexamethasone, whereas there were 67 CNS relapses among 262 (25.6%) treated with prednisone (P = 0.017). Both steroids appeared equal in protecting the bone marrow. Recent national studies have shown significant improvements in preventing CNS relapse over the results in the present report. However, this finding warrants further investigation and, with further documentation, could lead to the substitution of prednisone by dexamethasone to aid further in preventing CNS relapse. This may be particularly important in patients at higher risk for CNS relapse.     

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.     

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.     

Testicular relapse in childhood acute lymphoblastic leukaemia in Malaysia, 1967–82

From 1967–82,9 children with testicular relapse (TR) of acute lymphoblastic leukaemia (ALL) were diagnosed out of 99 boys treated, an incidence of 9.1%. The median time from the onset of ALL until diagnosis was 28 months (range 3–41 months). All were asymptomatic; six were detected on routine examination while three were diagnosed only on biopsy. Routine biopsy prior to stopping chemotherapy is useful in detecting occult TR. Biopsies should be done on both the testes regardless of the clinical findings. The age, leucocyte count and hepatosplenomegaly at diagnosis of ALL were not found to be significant factors in influencing relapse. Eight-children were in bone marrow remission at the time of TR, but three had preceding or concurrent meningeal leukaemia while in the other five the testis was the first and only site of relapse. Radiotherapy was effective in local disease control but failed to prevent bone marrow relapse in all except two patients despite continuation of chemotherapy. The median time from onset of TR until bone marrow relapse was 7 months (range 3–13 months) and the median time until death, was 11 months (range 6–18 months). The frequency of testicular relapse may be related to the intensity of either the initial induction therapy or the consolidation chemotherapy. Further studies are required to determine whether the incidence of testicular relapse will decline with more intensive early treatment.     

Neutrophil chemotaxis and random migration in acute lymphoblastic leukaemia of childhood. Cellular and humoral aspects.

The cellular and humoral components of the neutrophil chemotactic response were studied in 65 children with acute lymphoblastic leukaemia (ALL). An abnormality in both components was found during relapse. In remission the cellular component only was affected. Although less obvious than during relapse the abnormality persisted while all cytotoxic therapy was given, returning to normal several weeks after treatment had been stopped. The absence of significant infection in relapse in this series could be due to the fact that a remisison was achieved within 3 weeks in all patients. However, a positive correlation between the migration index and incidence of bacterial infection during remission stressed the importance of impaired neutrophil chemotaxis in ALL.     

Initial response to therapy as an important prognostic factor in acute lymphoblastic leukemia in childhood. COALL study group

Prognostic factors to estimate the risk of relapse are crucial for risk-adapted therapy in acute lymphoblastic leukemia (ALL). In a cooperative multicenter treatment study for childhood ALL (COALL-03-85) the prognostic relevance of the bone marrow (BM) blast count at day 28 was evaluated. Treatment was adjusted to the initial risk factors; patients with high risk (white blood count (WBC) greater than or equal to 25/nl, age greater than or equal to 10 years, T- or NULL-ALL) received intensified therapy consisting of rotation of 6 non cross-resistant drug combinations with 12 different agents. After 4 weeks 289/305 (94.8%) children were in complete remission (CR); one child died of infection, and 15 (14 high-risk patients) still had more than 5% blasts in the BM. Twelve of these 15 patients were in remission after 2 to 4 weeks additional treatment. Poor responders often had a high initial WBC, age above 10 years of T- or NULL-ALL. In spite of continuation of intensive therapy all children with more than 10% blasts in the BM on day 28 suffered an early relapse except 2 who were transplanted in first remission. Event-free survival for the poor responders is 0.15 compared to 0.71 (p = 0.0001) for the good responders (median observation time 48 months). In multivariate analysis remission status on day 28 was the only significant prognostic factor in high-risk patients above one year of age; traditional risk factors as initial WBC, age above 10 years, hepatosplenomegaly, and immunological subtype were of no prognostic significance in this study. (ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

MRI diagnosis of bone marrow relapse in children with ALL

Background Diffuse marrow replacement in acute leukemia is well known, but there are few reports describing the MRI features of pediatric leukemic relapse. Objective Our purpose was to describe the MRI appearance of pediatric leukemic relapse. Materials and methods A total of 53 consecutive children with a history of ALL were referred for musculoskeletal MRI from 1 January 1998 to 28 February 2007 at one center, and from 1 January 2000 to 2 May 2007 at a second center. From this group, 14 children seen at initial diagnosis of leukemia and 2 children who underwent MRI after therapy for relapse were excluded. The remaining 37 children, 8 with relapse and 29 in remission, were studied. Images of patients with relapse and in remission were reviewed for type and configuration of marrow infiltration; coexisting marrow alterations including osteonecrosis or stress reaction were also reviewed. Results All eight children with relapse demonstrated nodular lesions with well-defined margins. Coexisting osteonecrosis was present in three children (38%) and pathologic fracture in one. Among the 29 children in remission, 9 showed stress reaction/fracture, 14 showed osteonecrosis and 9 showed ill-defined nodules, and in 5 the marrow was completely normal. Conclusion Well-defined nodules in all patients with leukemic relapse suggest that this appearance is characteristic and distinct from the published findings of diffuse marrow replacement in acute leukemia.     

RQ-PCR检测Ig/TCR基因重排监测急性淋巴细胞白血病患儿治疗过程微小残留白血病

目的 研究RQ-PCR检测急性淋巴细胞白血病（ALL）患儿Ig/TCR基因重排在微小残留白血病（MRD）监测中的作用。方法 以2009年3月至2011年3月在广州市妇女儿童医疗中心血液肿瘤科确诊和治疗的ALL患儿为研究对象,PCR检测初诊ALL患儿的Ig/TCR基因重排;基因扫描分析初诊患儿Ig/TCR基因重排的克隆特性;对ALL患儿的单克隆性Ig/TCR基因重排进行测序,RQ-PCR检测不同治疗阶段Ig/TCR基因重排的表达量。结果 86例ALL患儿进入分析,男52例,女34例;年龄1~13（4.3±3.0）岁,随访时间1~26（14.3±7.0）个月。①83例（96.5%）检出1种或以上Ig/TCR基因重排,共检出209个Ig/TCR基因重排;②91.8%（56/61例）检出1种或以上单克隆性Ig/TCR基因重排;61例172个Ig/TCR基因重排中,单克隆性、寡克隆性和多克隆性Ig/TCR基因重排的检出率分别为58.1%（100个）、30.8%（52个）和11.0%（19个）,差异有统计学意义（P=0.000）;③26例完成连续3次随访,其中22例持续完全缓解患儿的Ig/TCR基因重排平均相对表达量持续下降,在维持治疗前均为MRD阴性（≤1.0×10-4）;4例复发患儿在诱导缓解治疗后至复发前各检测时点Ig/TCR基因重排表达量均＞1.0×10-4,并在复发前已有回升,从开始回升至临床复发的平均时间为3.75（2～8）个月。结论 Ig/TCR基因重排相对表达量可反映MRD水平,可作为判断预后、监测复发和指导治疗的有效手段。