Search

Background and Objectives: Pegylated-asparaginase (PEG-ASP) has been traditionally used as a second-line preparation in children with acute lymphoblastic leukemia (ALL) presenting with clinical allergy to native asparaginase (ASP) products. The main goal of the present study was to investigate the pharmacological effects of the administration of PEG-ASP given as a first-line product in children with ALL., Design and Methods: PEG-ASP serum enzymatic activity and serum and cerebrospinal fluid (CSF) levels of asparagine were investigated in 20 children with newly diagnosed ALL enrolled in the ongoing AIEOP ALL 2000 protocol and treated with PEG-ASP as a first-line ASP preparation. During induction the drug was administered at the dosage of 1,000 U/m2 i.v. on days 12 and 27. During reinduction the drug was administered only once at the same dosage., Results: Among the 20 patients treated in induction serum PEG-ASP activity equalled or exceeded 100 U/L in 18/18, 11/11 and 15/18 of the samples available on days 22, 25 and 27, respectively, and in 16/16, 12/15 and 5/8 samples available on days 36, 39 and 45, respectively. In the 15 patients treated during reinduction serum PEG-ASP activity > or =100 U/L was observed in 14/15, 11/14, 6/10, and 0/12 samples available on days 11, 15, 18 and 23, respectively, after the administration of the drug. Serum asparagine levels were below the detection limit (< or =0.2 microM) in all patients/samples and at all time points evaluated during induction; during reinduction only one patient had detectable asparagine levels from day 11. CSF asparagine levels were below the detection limit of the method only in a few patients during both induction and reinduction., Interpretation and Conclusions: PEG-ASP given as a first-line ASP product in the context of an intensive chemotherapy protocol for pediatric ALL allowed adequate plasma enzymatic activity and asparagine depletion during both exposures to the drug. However, CSF asparagine depletion was inadequate.

Purpose: Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of high-dose l-asparaginase (HD-l-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy., Patients and Methods: The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-l-ASP (25,000 IU/m2)., Results: The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome., Conclusion: In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-l-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.

Background and Objectives: Treatment of childhood standard-risk (SR) acute lymphoblastic leukemia (ALL) is generally successful. However, intensive chemotherapy regimens may be associated with severe treatment sequelae. Efforts are therefore being made to identify those patients in whom less intensive treatment would be equally successful but cause fewer long-term sequelae. The aim of this study was to evaluate the efficacy of treatment reduction in a subset of children with ALL at minimal risk of failure., Design and Methods: The population of patients with SR ALL included children aged between 1 and 6 years with less than 20,000 WBC/mm3, non-T immunophenotype, DNA index between 1.16 and 1.6, absence of t(9;22) and t(4;11) clonal translocations, no extramedullary leukemia, good response to prednisone and complete remission (CR) at the end of induction therapy. A reduced-intensity, BFM-type treatment schedule (AIEOP-ALL 9501 protocol) was used. Induction therapy was based on vincristine, prednisone, L-asparaginase and intrathecal methotrexate only; high-dose-methotrexate (2 g/m2) was given x4. The BFM Protocol II was given as reinduction therapy; thus the total dose of anthracyclines was 120 mg/m2 and no epipodophyllotoxins or cranial irradiation were employed., Results: Between May 1995 and December 1999, 123 patients were identified as having SR-ALL (7.8% of the ALL-95 population), of whom 102 received the SR protocol. After a median follow-up of 5.9 years, 11 patients in the SR protocol had relapsed, 1 had died in remission, and 1 had developed a second malignant neoplasm. The probabilities (standard errors) of survival and event-free survival (EFS) were, respectively, 97.0% (1.7) and 86.7% (3.5) at 5 years, and 95.3% (2.4) and 86.7% (3.5) at 7 years., Interpretation and Conclusions: Although most of the relapsed patients were rescued, the long-term EFS probability in this small, highly selected group of patients remains inferior to expectation. Thus, alternative selection criteria, such as treatment response measured by minimal residual disease, should be considered to address the issue of treatment reduction.

The clinical and diagnostic findings and the factors influencing the neurologic and radiologic outcome of symptomatic ischemic stroke were evaluated in a group of 2,318 children with acute lymphoblastic leukemia (ALL) treated according to the AIEOP (Italian Association of Pediatric Hematology and Oncology) study protocols. In this multicentric retrospective study, a questionnaire was sent to each of the 43 AIEOP centers participating in the study. The questionnaire was designed to obtain information on the number, type, and time of occurrence of ischemic strokes, biologic and immunologic features of each case, as well as clinical data of the recruited patients. A prevalence of 0.47% was found. All ischemic strokes were sinovenous thrombosis (SVT). The most common neurologic presentations were diffuse neurologic signs and seizures. MRI with or without venography revealed SVT in 100% of cases; superficial SVT was diagnosed in the majority of cases. Antithrombotic drugs, in particular unfractioned heparin and low-molecular-weight heparin, were administered without bleeding complications. This series shows an excellent long-term neurologic outcome in children with SVT. However, a complete radiologic resolution was found in only 54% of cases; the involvement of deep cerebral venous sinuses was associated with an unfavorable imaging outcome.

Background and Objectives: Few data are available on the long-term outcome of children who present with a very late relapse of acute lymphoblastic leukemia, so treatment of these patients remains controversial. The present study was aimed at investigating clinical features and treatment outcome of children with very late relapse, diagnosed and treated in Italy in the last 20 years., Design and Methods: All children diagnosed in Italian centers with a first relapse of acute lymphoblastic leukemia occurring >or= 60 months after attainment of first complete remission were included in this study. These relapses were diagnosed between 1982 and 1997., Results: Ninety-three patients (58 males, 62.4%) had a first very late relapse occurring at a median time of 6.1 years (range 5.8 - 13.7 years) after the initial diagnosis. At a median follow-up time of 9.1 years after relapse, the overall 5-year survival (SE) and event-free-survival (SE) were 55.6% (5.2) and 39.5% (5.1), respectively. In multivariate analysis the site of relapse was the only significant predictor of duration of the second complete remission. Patients with isolated bone marrow relapse fared worse than those with combined or isolated extramedullary relapse [5-year event-free survival (SE) 24.5% (5.9), 51.3% (11.1) and 68.4% (10.7), respectively; (p=0.004)]. All 7 patients who underwent an allogeneic bone marrow transplantation from a matched related donor are alive in second complete remission., Interpretation and Conclusions: In this evaluation patients with a very late relapse isolated to the bone marrow had a poor outcome while re-treatment of extramedullary or combined relapse was associated with better cure rate. Our data suggest that patients with very late isolated bone marrow relapse should be treated intensively; bone marrow transplantation from a matched related donor may be indicated.

We evaluated the incidence of FLT3/internal tandem duplication (ITD) mutation in childhood acute myeloid leukaemia (AML) diagnosed over 15 years. FLT3/ITD was found in 10 of 45 (22.2%) non-acute promyelocytic leukaemia (non-APL) patients. The 5-year event-free survival of non-APL patients was higher in FLT3/ITD-negative versus -positive patients (48.9%, SE 8.9, vs 20.0%, SE 16.1, P = 0.03). In childhood APL, FLT3/ITD incidence was higher than in non-APL, although not statistically significant (10 out of 29 patients, 34.5%, P = 0.29). In APL patients, FLT3/ITD was strongly correlated to a higher white blood cell count at diagnosis and the M3 French-American-British subtype.

One hundred ninety-eight children and adolescents were entered in the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-ALL95 study for high-risk acute lymphoblastic leukemia (ALL). Inclusion criteria were poor response to initial prednisone/intrathecal methotrexate (prednisone-poor response [PPR]), resistance to induction therapy, translocation t(9;22), infants with the t(4;11), or CD10(-) ALL. The event-free survival (EFS) rate at 4 years was 56.5% (SE, 3.9%) for the entire group. The overall EFS rate in the current study was significantly better (P =.002) than that obtained in a comparable group of patients treated in the early 1990s in the AIEOP-ALL91 study. In particular, patients with PPR had a 4-year EFS of 61.1% (SE, 4.4%) versus 42.8% (SE, 5.4%) in the ALL 91 study (P =.008). Among PPR patients, those who were PPR-only (60.1%)-that is, they achieved CR and were negative for t(9;22) and t(4;11) translocations-had the best outcomes with this intensive treatment, even when additional adverse features (hyperleukocytosis, T phenotype) were present (4-year EFS, 70.1%; SE, 4.7%). We attribute this improvement to the replacement of 6 alternating blocks of non-cross-resistant drugs with an 8-drug reinduction regimen (Berlin-Frankfurt-Muenster [BFM] protocol II), repeated twice, in the context of a standard BFM-type intensive chemotherapy for high-risk ALL. This modified therapy may lead to high cure rates for patients defined as at high risk for intrinsic resistance to corticosteroids only.

Purpose: To assess in a randomized study the therapeutic effect of the addition of high-dose L-asparaginase (HD ASP) in the context of a Berlin-Frankfurt-Münster (BFM)-based chemotherapy regimen for intermediate risk (IR) childhood acute lymphoblastic leukemia (ALL)., Patients and Methods: From March 1991 to April 1995, a total of 705 patients, with 59% of the cohort of patients fewer than 15 years old, with newly diagnosed non-B ALL, enrolled onto the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-91 study, were assigned to the IR group. Patients in remission at the beginning of the reinduction phase were randomized either to the standard treatment (SD ASP arm) or the experimental treatment (HD ASP arm; weekly intramuscular administration of HD ASP 25,000 IU/m(2) repeated for a total of 20 weeks). Most of the patients (90%) were treated with Erwinia chrysanthemi L-asparaginase product., Results: Among the 610 patients randomized to the SD ASP arm (n = 322) or to the HD ASP arm (n = 288), relapse occurred at a median time of 24 months after randomization in 76 (24%) and in 64 children (22%), respectively. Most of the relapses occurred in the marrow (100 isolated, 21 combined). There was no significant difference between the disease-free survival in the two treatment arms (P =.64), with estimated values at 7 years from randomization of 72.4% (SE 3.1) v 75.7% (SE 2.6) in the SD ASP and HD ASP arms, respectively., Conclusion: No advantage was observed for IR ALL children treated with BFM-based intensive chemotherapy who received protracted E chrysanthemi HD ASP during reinduction and the early continuation phase.

Purpose: The present study was aimed at investigating L-asparaginase (L-ASE) activity (in plasma) and L-asparagine (L-ASN) depletion (in plasma and CSF) in children with newly diagnosed acute lymphoblastic leukemia (ALL) exposed for the first time to different L-ASE products., Patients and Methods: During the induction treatment of the AIEOP ALL 95 study, 62 patients were treated with either Erwinase (n = 15), or E. coli medac (n = 47) L-ASE products, given either i.m. or i.v., at the standard dosage of 10,000 IU/m2, q 3 days x 8 (first exposure)., Results: Plasma and CSF L-ASN trough levels were undetectable in all cases, including those with L-ASE trough activity < 50 mU/ml. L-ASE trough activity during the administration of medac was however significantly higher when compared with that of Erwinase., Conclusions: L-ASN depletion after a first exposure to standard doses of Erwinase or medac is obtained in virtually all patients. No differences are seen between the I.M. or I.V. administration routes but the medac product is associated with a significantly higher enzyme activity in respect of Erwinase. L-ASN levels may be undetectable also in patients with L-ASE trough activity levels < 50 mU/ml, challenging the current opinion that an activity level of 100 mU/ml is needed to obtain L-ASN depletion.

Background and Objective: Since 1988 the AIEOP has used BFM-based chemotherapy for childhood ALL. Current organization and results and role of cranial irradiation in the AIEOP-ALL 91 study are reported., Design and Methods: From 1991 to 1995, 1194 children (< 15 years) with non-B ALL, were enrolled and assigned to the standard risk [SR: age > 1 year, non-T-ALL, BFM risk factor (RF) < 0.8], intermediate risk (IR: RF > or = 0.8 but < 1.7, or with RF < 0.8 and age < 1 year, or T-ALL), or high risk [HR: RF > or = 1.7, or t(9;22), or t(4;11) or prednisone poor response or late response or CNS involvement] groups. All patients received initially protocol Ia. Thereafter SR patients received HD-MTX 2 g/m2, a modified protocol II, and continuation therapy with triple intrathecal chemotherapy (TIT); IR patients received protocol Ib, HD-MTX 5 g/m2, protocol II and continuation therapy with TIT; HR patients received 9 polychemotherapy blocks, cranial irradiation and continuation therapy. Duration of treatment was 24 months. A randomized study was conducted to evaluate the impact of high-dose asparaginase in non high risk patients: the results of this study cannot be disclosed yet., Results: One thousand one hundred and fifty-two (96.5%) patients achieved CR. Overall EFS (SE) at 5-years was 71.0% (1.4), with a survival of 80.3% (1.3). Relapse occurred in 262 children (21.9%), either in the marrow (n = 192 isolated and 32 with other sites, 18.7%), in the CNS (n = 18, 1.5%), or elsewhere (n = 20, 1.7%). 5-year EFS (SE) was 83.3% (2.4) in SR, 74.7% (1.8) in IR, and 39.7% (3.5) in HR groups, respectively., Interpretation and Conclusions: Overall cure rate was higher than in the previous AIEOP-ALL 88 study. Treatment intensification with polychemotherapy blocks did not improve results in HR. Cranial irradiation can be safely omitted in over 80% of children treated with BFM based chemotherapy.

The early toxicity, incidence of graft-versus-host disease (GVHD) and long-term follow-up were evaluated in two children with Down syndrome (DS) treated for acute lymphoblastic leukemia (ALL) in second complete remission by HLA-matched sibling allogeneic bone marrow transplantation (BMT). Preparative conditioning therapy consisted of cytosine arabinoside (Ara-C) and fractionated total body irradiation (F-TBI) and GVHD prophylaxis of cyclosporin A. The conditioning regimen was well tolerated, the only acute complication being mild mucositis. Engraftment (polymorphonuclear cells >500/microliter) was documented by day +17 in both patients. One child remains in continuous complete remission, without medical problems, 60 months after BMT. The second patient died from complications associated with chronic GVHD 21 months following BMT. Ara-C and F-TBI is a well-tolerated preparative regimen for children with DS undergoing allogeneic BMT.

In a 7-month period we studied 38 Hickman central venous catheters (CVCs) positioned in children with hematologic malignancies with the aim of evaluating the incidence and clinical impact of CVC clots. Clots were found in 74% of the CVCs. Three methods of catheter care were developed for flushing the clotted CVCs: (a) use of a heparinized solution (400 IU/mL) on alternate days, (b) use of a heparinized solution (400 IU/mL) and saline solution containing urokinase (10,000 IU/mL) on alternate days, and (c) use of a saline solution containing urokinase (10,000 IU/mL) daily. Only method b decreased clot formation (33% success rate). There were no major mechanical complications in any of the CVCs with clots. Eighteen percent of patients with clots in their CVCs presented with CVC-related infections while no infective complications were observed in the patients without clots in their CVCs. In conclusion, CVC clots may predispose the patient to infections, which must be correctly treated.

In order to assess the prognostic value of nephromegaly (kidney enlargement > or = 2 SD from mean for age) in children at diagnosis of acute lymphoblastic leukemia (ALL), kidney size was investigated by intravenous pyelogram (IP), according to the method of Ekl of and Ringertz, in 101 children diagnosed with ALL in the period of 1975-1983. In the same period 103 additional patients with ALL were not investigated with IP for logistical reasons. Characteristics at the diagnosis of ALL in the patients of the investigated and non-investigated (with IP) groups were quite similar and event-free-survival (EFS) curves superimposable. Eighty-nine (50 males and 39 females, median age 61 months) out of 101 patients underwent IP before starting any therapy and were evaluated in the study; 27 (30.3%) presented with nephromegaly (bilateral in 13 cases and unilateral in 14). With a median follow-up time of 14.4 years (range 11-19 years), the EFS at 15 years from diagnosis was 18.5% (SE 9.5) in the nephromegalic group and 48.4% (SE 6.4) in the non-nephromegalic group. The association of poorer EFS with nephromegaly was confirmed when the comparison was adjusted by white blood cell count and age at diagnosis in a Cox regression model. Nephromegaly at diagnosis of childhood ALL may have an independent prognostic value in patients treated with 'not intensive' protocols; however, this finding should be confirmed in patients treated uniformly with contemporary intensive protocols.

The incidence of bone lesions at diagnosis of childhood acute lymphoblastic leukemia (ALL) is relatively high. However, no cases of severe osteoporosis with multiple vertebral collapses secondary to treatment in children with ALL have been reported. We report the case of a 9-year-old-boy with B-ALL, with no bone lesions at the diagnosis that, following the 4th block of aggressive chemotherapy (protocol B-ALL BFM 86), presented severe back pain and functional impairment with diffuse osteoporosis and vertebral collapses. He was treated with calcitonin, vitamin D, calcium, physical therapy and orthopedic corset. Osteoporosis progressed slowly during the following 2 months of chemotherapy and the boy developed dorsal kyphosis. After discontinuing antiblastic treatment progressive clinical improvement was observed, with complete resolution of kyphosis in about 6 months. An almost complete bone recovery was seen on X-ray survey at 26-months follow-up.

The association of cystic fibrosis (CF) and acute lymphoblastic leukaemia (ALL) is extremely rare. Only three cases have been reported in the literature and all of them had a fatal outcome. In this paper we describe the case of a little girl who was diagnosed with CF (mild course) when she was five months old, and who presented at the age of five years with ALL (intermediate risk). Complete Remission (CR) was rapidly obtained with standard chemotherapy for ALL.; treatment was continued for two years without major complications and with no apparent influence on the course of CF. The patient remains alive and well and in continuous CR four years after discontinuing treatment, and six years after the diagnosis of ALL.

In a 61-month period, 135 single-lumen central venous catheters (CVCs) were positioned in 125 children with mainly hematological malignancies. We retrospectively investigated the different role of home and hospital CVC management in development of CVC-related infections (CI) during different hematological conditions (presence or absence of neutropenia). Forty-nine percent of the children presented at least one CI, for a total of 109 episodes, during the 20,558 days a CVC remained in situ. CVC hospital management was safer and more reliable than CVC home management in both neutropenic and nonneutropenic patients. None of the CI was life threatening and only in 11% of the cases was it necessary to remove the catheter. Analysis of the microorganisms involved showed that they were mainly gram-positive with CVC home management and gram-negative with CVC hospital management. Careful evaluation of our retrospective survey study suggests that a better training of parents in the care of the CVC and more careful measures of asepsis in hospital could further decrease the incidence of CI, thus improving patients' quality of life.

We studied infectious and mechanical complications occurring with 55 central venous catheters (CVCs) managed in hospital and at home, in 53 children with hematological malignancies who underwent bone marrow transplantation (BMT). The total catheter life span was 6906 days (median 111), 2359 days (median 40) in hospital and 4547 days (median 78.5) at home. Duration of neutropenia was 1241 days (median 20), mostly in hospital. We observed 21 CVC-related infections from 17/55 CVCs (31%): 0.30 episodes/100 days of CVC use with 0.55/100 days in hospital vs 0.17/100 days at home. Antibiotic treatment resolved 72% of infections without CVC removal, which was required in six instances. There were 14 mechanical complications (0.20 episodes/100 days of CVC use) in 6/55 CVCs (11%), with three removals. Interventions to resolve mechanical problems included catheter declotting by urokinase, repair and replacement. We conclude that CVC is an essential component of care of children with cancer undergoing BMT and that it has a relatively low complication rate. Most complications can be resolved by an appropriate CVC handling and by a multidisciplinary intervention in the critical post-BMT phase.

Visual-evoked potentials (VEPs) were studied in 55 asymptomatic children with leukemia or solid tumors in remission in order to detect subclinical demyelination of the optic pathway after CNS prophylaxis. In group I (11 patients with ALL studied prospectively), VEP latency was increased in ten after cranial radiation (CR) as compared with previous values. Group II (18 patients with ALL in maintenance) and group III (16 patients with ALL off therapy) were studied retrospectively and VEP latency was found above normal limits in 33 and 31%, respectively. In group IV (four patients with solid tumors and six with leukemia, all of whom received no CR), VEP latency was normal despite periodical intrathecal methotrexate administrations to five of them. We conclude that CR determines a slowing of conduction on VEP test, probably due to demyelination of the optic pathway, in a high proportion of patients. The future clinical significance of these findings must be established throughout a prolonged follow-up period.

The authors report a case of fatal Daunorubicin cardiotoxicity on initial phase of therapy for Acute Myeloblastic Leukemia at cumulative doses (225 mg/mq) considered still safe from the current literature. Despite the interruption of therapy and the interventions performed in support of cardiac functionality the patient came to exitus for heart failure 24 hours after the symptoms onset. This example represents a further confirmation of the utility of a steady monitoring with specific tests for the patients undergoing Daunorubicin therapy.