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.     

Allogeneic bone marrow transplantation in acute lymphoblastic leukemia of children. Analysis of prognostic factors. GEGMO (Bone Marrow Study Group) study

Sixty-five children with acute lymphoblastic leukemia (ALL) underwent allogenic bone marrow transplantation (BMT) from an HLA identical donor, following cytoreduction with cyclophosphamide and total body irradiation (TBI): 15 were transplanted in 1st remission, 43 in 2nd and 7 in 3rd or in 4th. The Kaplan Meier estimate of surviving disease free at 4 years post BMT was 49.9% and the probability of continued remission at 4 years was 63.3%. Fourteen patients relapsed between 90 and 690 days (mean: 240 +/- 88) post BMT. The other causes of BMP failure included: graft versus host disease, veno-occlusive disease and sepsis. No interstitial pneumonitis has been reported. Patients who had a relapse while on chemotherapy had a higher probability of relapse than those who had a relapse while off therapy (p less than 0.01). We conclude that allogeneic BMT is the treatment of choice for children with ALL in second hematologic remission, the interval between diagnosis and first relapse being the most significant prognostic factor. Patients with poor prognosis might benefit from a more intensive chemotherapy/total body irradiation schedule or a BMT earlier in the course of their disease.     

Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13.

BACKGROUND: The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) is generally poor and reports from large studies are scarce. We evaluated the efficacy of allogeneic bone marrow transplantation (allo-BMT) for children with this type of leukemia. PROCEDURE: The chemotherapy regimens consisted of an induction phase and very intensive consolidation followed by a reinduction phase and late intensification treatment. The selection of treatment modalities such as chemotherapy, allo-BMT, or autologous transplantation was made by each institute. The principal endpoint was the outcome of children with Ph(+) ALL according to the treatment options. RESULTS: Thirty-two patients (4.3%) were diagnosed as Ph(+) ALL out of the 741 cases of ALL consecutively enrolled in two protocols of the Tokyo Children's Cancer Study Group (TCCSG) from 1989 to 1994. Thirty patients (93.8%) were induced into complete remission (CR). Of these 30 patients, eight children electively received allo-BMT in the first CR. Six of these patients are in continuous remission at a median follow-up of 58 (range 48-105) months after the diagnosis. One patient died following recurrence and another patient died of graft vs. host disease. Three patients treated with autologous BMT or peripheral blood stem cell transplantation in the first CR experienced a subsequent relapse. In the remaining 19 patients, 13 patients were treated with very high-risk chemotherapy alone and all relapsed within 28 months. One patient was excluded from the analysis because he was treated with standard-risk chemotherapy until relapse. The other five patients were also excluded from the analysis because Philadelphia chromosome was not detected until they relapsed. None of the relapsed patients survived in spite of treatment including allo-BMT. In multivariate analysis, only allo-BMT remained as an independent factor for good prognosis. CONCLUSIONS: The only way to cure children with Ph(+) ALL was allo-BMT in this study and its outcome seemed promising.     

Induction of long-term remission of a relapsed childhood B-acute lymphoblastic leukemia with rituximab chimeric anti-CD20 monoclonal antibody and autologous stem cell transplantation

Childhood B-cell neoplasms account for approximately 2% of childhood acute lymphoblastic leukemia (ALL). The short but intensive chemotherapy yields a currently 75% to 85% event-free survival. The prognosis for children with relapsed disease is considered to be dismal.We report a 12-year old boy diagnosed with B-cell ALL with central nervous system (CNS) involvement. He relapsed in the bone marrow immediately after primary chemotherapy. Rituximab as a single agent achieved a complete morphologic remission. After 4 treatments with rituximab an isolated CNS relapse occurred. CNS remission was reinduced with chemotherapy and the patient received an autologous transplant with rituximab for in vivo purging. He is currently in complete clinical and molecular remission for more than 1 year.     

FLAG (fludarabine, high-dose cytarabine, and G-CSF) for refractory and high-risk relapsed acute leukemia in children.

BACKGROUND: The treatment of relapsed and refractory leukemia in children remains a challenge. The morbidity of further chemotherapy is considerable, as most patients have already been exposed to intensive multiagent chemotherapy. The FLAG (fludarabine, high-dose cytarabine, and G-CSF) regimen is as intensive but less cardiotoxic because of the avoidance of anthracyclines. PROCEDURE: Nineteen children were treated in two U.K. centers with the FLAG regimen for relapsed and refractory acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). There were 13 males and 6 females, with an age range of 1.9 to 14.2 years. AML was the diagnosis in 12 children, ALL in 4, biphenotypic leukemia in 3. Eight patients had refractory disease, 11 were in relapse (5 in first relapse, 4 in second, and 2 in third). RESULTS: Complete remission was obtained in 13 patients, partial remission was obtained in 4, and 2 patients were considered nonresponders. There were seven patients alive at 12 months (mean) posttherapy; one of these is awaiting bone marrow transplantation (BMT). All patients experienced grade 4 hematological toxicity; no patient died of infection. Thirteen patients received BMT as consolidation (seven unrelated donor; six sibling allografts). Six of these have died, four due to pneumonitis. CONCLUSIONS: FLAG can be regarded as an effective protocol for inducing remission in a group of heavily pretreated children. Its toxicity is acceptable due to the avoidance of anthracyclines.     

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.     

How to Treat Relapsed Acute Lymphoblastic Leukemia: Transplant vs. Conventional Chemotherapy

Management of relapsed acute lymphoblastic leukemia (ALL) is challenging and far from satisfactory. The treatment approaches are often varied and controversial. The duration of first remission, site of relapse, immunophenotypic and molecular characteristics of relapsed disease and response to therapy influence treatment outcome. There are three main therapeutic options i.e., chemotherapy alone, induction chemotherapy followed by HLA matched allogeneic transplant and palliation. These may be chosen based on the above mentioned factors. The response to therapy may be evaluated morphologically or by minimal residual disease (MRD). Persistence of MRD, as assessed by molecular techniques or through flowcytometry, clearly influences prognosis in children with relapsed ALL. It not only helps in identifying the subset of patients likely to benefit from allogeneic bone marrow transplant (ABMT) but also in determining the timing of transplant. Patients with non-T phenotype, with late relapsing disease and good response to re-induction therapy have been shown to do equally well with chemotherapy alone. On the other hand patients with early relapse and poor initial response are selected for ABMT. With the improvement in supportive care, better selection of HLA match donors and better immunosuppressive therapies, transplant related mortality has decreased considerably. Despite all of these overall salvage rates are still poor and novel agents are being tested in various trials to establish their role in relapsed ALL 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.     

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.     

Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: A 10-year follow-up study

The outcome of 171 children with ALL who relapsed for the first time after elective cessation of therapy (1–86 mo) and followed over 10 years (median 60 mo; range 1–232 mo) has been evaluated. One hundred and three patients relapsed in the bone marrow (BM), 29 in the testis (T), 21 in the central nervous system (CNS), 14 in the BM plus another site and 4 in other sites. Second remission was achieved in 97% of patients (97% BM, 100% T, 90% CNS, respectively) with reinduction schedules including three or more drugs. All but 4 out of 100 patients who relapsed in the BM received cranial reprophylaxis with intrathecal CT alone or CT plus radiotherapy. Seven patients in second CR underwent allogeneic bone marrow transplantation from an HLA matched sibling. The overall survival was 34% and disease-free survival (DFS) probability at 100 years was 22%. A second relapse was observed in 73% of patients. Forty children are alive in second continuous remission and 24 are alive after a second or subsequent relapse. Patients with isolated T relapse showed a significant better outcome than those with BM or CNS involvement. Most patients (62%) with isolated BM relapse showed a further disease recurrence in BM, and DFS was shorter when relapse occurred within 12 months from off-therapy. Eighty-two patients in second CR stopped the treatment a second time and showed a survival and DFS probabilities, respectively, of 69% and 43%. Thus, children with ALL who relapse after cessation of therapy still have a high risk of further late relapses and should be treated with intensive chemotherapy and CNS reprophylaxis. BMT must be considered for all patients relapsing in the BM within 12 months from off-therapy. © 1995 Wiley-Liss, Inc.     

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.     

Treatment of recurrence of acute myeloid leukemia in childhood. A retrospective analysis of recurrence in the AML-BFM-83 study]

Complete remission (CR) rates of 80% are achieved with the AML-BFM protocols but one third of patients relapse within the first three years. There are few reports of treatment of relapsed childhood AML, and these deal with the evaluation of new drugs for frontline therapy. We performed a retrospective analysis to investigate how patients previously treated with the AML-BFM-83 protocol were treated after relapse and how many long term remissions were achieved. 48 of 139 patients relapsed after having achieved complete remission with the AML-BFM-83 protocol which consists of continous infusion of ARA-C 100 mg/m2 day 1-2, ARA-C 200 mg/m2 day 3-8, Daunorubicin 60 mg/m2 day 3, 4, and 5, and VP-16 150 mg/m2 day 6, 7, and 8, and an 8 week consolidation therapy consisting of Prednisolone, Thioguanine, Vincristine, ADR, ARA-C, Cyclophosphamide, intrathecal ARA-C and cranial irradiation followed by maintenance therapy. Duration of first remission ranged from 1.5 months to 66.3 months. Excluding 5 children with either isolated or combined extramedullary relapses and another 4 patients for missing data, 39 children were evaluable. 20 children received no therapy or palliative therapy while 16 patients received chemotherapy and another 3 children were transplanted in relapse. Although 9 different intensive chemotherapy regimens were used for reinduction, a high number (12 of 16 = 75%) of second complete remissions was achieved. Several therapeutic options were used to maintain a second remission: regular maintenance therapy (7 patients), allogeneous bone marrow transplantation (BMT) (2 patients), autologous BMT (3 patients).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Bone marrow necrosis and thrombotic complications in childhood acute lymphoblastic leukemia

Two children with bone marrow necrosis at diagnosis or at relapse of acute lymphoblastic leukemia (ALL) had thrombotic complications 15 and 17 days after starting remission induction therapy including prednisone, vincristine, and L-asparaginase. The close temporal relationship of these two relatively rare events suggests that bone marrow necrosis is a predisposing factor to the development of thrombosis.     

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.     

Bone marrow necrosis and thrombotic complications in childhood acute lymphoblastic leukemia.

Two children with bone marrow necrosis at diagnosis or at relapse of acute lymphoblastic leukemia (ALL) had thrombotic complications 15 and 17 days after starting remission induction therapy including prednisone, vincristine, and L-asparaginase. The close temporal relationship of these two relatively rare events suggests that bone marrow necrosis is a predisposing factor to the development of thrombosis.     

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.     

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。     

Ex vivo chemopurging of autologous bone marrow with 4-hydroperoxycyclophosphamide to eliminate occult leukemic cells. Laboratory and clinical observations

The application of autologous bone marrow transplantation (ABMT) in treating acute leukemias in children has been limited by the presence of residual occult viable leukemic cells in the marrow cell suspension. One approach to this problem is the ex vivo treatment ("purging") of the autograft to eradicate these tumor cells yet spare the normal lymphohematopoietic stem cells. Initial studies of acute myeloid leukemia (AML) in a rodent model demonstrated that incubation with 4-hydroperoxycyclophosphamide (4HC), a congener of cyclophosphamide and an active alkylating agent in aqueous solution, could effectively eliminate viable AML cells from marrow cell suspensions without apparent toxicity to normal stem cells. We have conducted clinical trials of ABMT with 4HC-treated marrow in children with acute leukemia in remission; marrow was collected, treated ex vivo with 4HC (100 micrograms/ml), and cryopreserved in liquid nitrogen until reinfusion. Children received pre-ABMT conditioning with either high-dose cyclophosphamide and total body irradiation (CY-TBI) for acute lymphocytic leukemia (ALL) or high-dose busulfan and cyclophosphamide (BU-CY) for AML. Of nine children who underwent ABMT with 4HC-treated marrow for ALL in second complete remission (CR2), all relapsed (eight in the marrow, one in the central nervous system) at a median of 5 months (range, 2-17) after ABMT and all have died with relapsed ALL or as a consequence of its treatment. Twenty-nine children with AML (five in CR1, 24 in CR2) received autografts with chemopurged marrow at a median remission duration of 3 months (range, 2-15). Three patients died from sepsis during aplasia; 10 children (one in CR1 and nine in CR2) relapsed with AML at a median of 7 months (range, 2-23) after ABMT, for an actuarial relapse rate of 47%. Sixteen patients with AML (four in CR1, 12 in CR2) are in unmaintained remission at a median of 16 months (range, 6-102) after ABMT, for an actuarial disease-free survival of 49%. Although ABMT with 4HC-treated marrow appears to have a limited role in the treatment of children with ALL who lack a suitable related donor, the results in AML are encouraging and compare favorably with both syngeneic and allogeneic BMT in similar groups of patients.     

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.