Reacciones alérgicas por L-asparaginasa en niños con leucemia linfoide aguda / L-asparagibase allergic reactions in children with lymphoblastic acute leukemia

La L-asparaginasa es un medicamento utilizado en distintas fases de todos los protocolos de tratamiento actuales de la leucemia linfoide aguda (LLA). Se describen múltiples manifestaciones secundarias a la L asparaginasa entre las que las reacciones alérgicas son las más frecuente. Se estudiaron 144 niños con diagnóstico de LLA tratados en el Instituto de Hematología e Inmunología, entre 1998 y el 2013. En 30 pacientes (21 por ciento) se presentaron reacciones alérgicas, similar a lo descrito en la literatura. El 76,6 por ciento de ellos habían recibido una dosis acumulativa menor de 80 000 UI (media de 48 757) y el mayor número de las reacciones alérgicas (86,7 por ciento) se reportó entre las dosis 9 y 18 recibidas (media de 11 dosis). Se observó una mayor supervivencia en los enfermos que recibieron más dosis (19 - 26 dosis) (p = 0.003). La sobrevida libre de eventos fue también mayor en este grupo (p= 0.357)(AU)

ABSTRACT L-asparaginase is a medication used in different phases of all current treatment protocols for acute lymphoid leukemia. Multiple secondary manifestations to L- asparaginase are described, and allergic reactions are the most frequent. We studied 144 children with acute lymphoblastic leukemia treated at the Instituto de Hematología e Inmunología between 1998 and 2013. Thirty patients (21 percent) had allergic reactions, similar to what is described in literature; 76.6 percent of them had received a cumulative dose of less than 80 000 IU (average of 48 757); and the highest number of allergic reactions (86.7 percent) was reported between doses 9 and 18 received (mean of 11 doses). A greater global survival was observed in patients who received more doses (19 - 26 doses) (p=0.003). Event free survival was also higher in this group (p= 0.357)(AU)

[Fatal central nervous system hemorrhage during acute lymphoblastic leukemia induction]. / Hémorragie cérébrale fatale en cours d'induction d'une leucémie aiguë lymphoblastique.

Intracerebral hemorrhage (ICH) remains a cause of death in hematologic malignancies. Asparaginase represents a key agent in the treatment of acute lymphoblastic leukemia (ALL). The toxicity of asparaginase includes coagulopathy such as thrombotic or bleeding tendency. We report a case of fatal cerebral hemorrhage in a 12-year-old girl treated for ALL. Cerebral hemorrhage occurred after three injections of L-asparaginase. The patient presented with hypofibrinogenemia (0.36g/L), associated with thrombocytopenia (24,000/mm3). Despite maximal medical and surgical treatment (platelets and fresh-frozen plasma transfusions, red blood cells transfusion, fibrinogen replacement therapy, and craniotomy discharge), the patient died. L-asparaginase is well known for its prothrombotic action. By inhibiting the synthesis of fibrinogen and factors V, VII, VIII, and IX, it causes an increased risk of bleeding, including intracranial bleeding. Predictive scores for ICH onset have been established but there is no consensus on the management of coagulation disorders induced by L-asparaginase. It is recommended to check fibrinogen and antithrombin (AT) blood values in order to substitute them if they drop to < 1 g/L for fibrinogen and < 60% for AT. The management of asparaginase-induced ICH does not differ from that of ICH of other origin. The risk of death is high, and surgical treatment has not proven superior to medical therapy in terms of mortality rates and 6-month survival. Further studies are needed to define consensus guidelines for coagulation disorders induced by asparaginase and also to define the specific management in cases of ICH in childhood hematological malignancies.

Worsening of Seizures After Asparagine Supplementation in a Child with Asparagine Synthetase Deficiency.

OBJECTIVE: Asparagine synthetase deficiency is an autosomal recessive neurometabolic disorder characterized clinically by severe congenital microcephaly, global developmental delay, intractable epilepsy, and motor impairment in the form of spastic quadriparesis. Diagnosis is confirmed by findings of low cerebral spinal fluid or plasma asparagine in addition to a mutation of the subsequently in ASNS gene. There is no documented trial of asparagine as a treatment for this disorder. PATIENT DESCRIPTION: We present a child with asparagine synthetase deficiency whose mental status improved slightly from a vegetative state to a minimally conscious state after starting asparagine supplementation. He subsequently became irritable, developed sleep disturbance, and experienced worsening seizures, requiring discontinuation of the asparagine supplements. CONCLUSIONS: Asparagine supplementation may be not effective in controlling the seizures in asparagine synthetase deficiency, and it is likely to make them worse.

Medication induced diabetes during induction in pediatric acute lymphoblastic leukemia: prevalence, risk factors and characteristics.

INTRODUCTION: Medication induced diabetes (MID) during induction therapy (MIDi) in patients with acute lymphoblastic leukemia (ALL) is not well characterized in children, with recent studies yielding conflicting results. PURPOSE: The purpose of the study was to describe the prevalence of MIDi and risk factors for its development. METHODS: We retrospectively gathered demographic, disease course and treatment data on 363 patients aged 1 to 17.9 years diagnosed with ALL at a pediatric tertiary care hospital between 1998 and 2005. MIDi was defined as blood glucose ≥200 mg/dL (11.1 mmol/L) on at least 2 separate days during induction. RESULTS: Fifty-seven subjects (15.7%) developed MIDi during the study period. Patients ≥10 years were more likely to develop MIDi than those <10 years (odds ratio [OR] 9.6, 95% confidence interval [CI] 5.1-17.8). BMI percentile among those with MIDi (mean ± SD 58.2 ± 31.0) did not differ from those without MIDi (52.2 ± 32.0, P = 0.429). The presence of Trisomy 21 (OR 3.6, 95% CI 1.1-11.4, P = 0.030) and CNS involvement at diagnosis (OR 3.8, 95% CI 1.4-10.1, P = 0.009) were associated with an increased risk of MIDi. After adjustment for potential confounding variables, age ≥10 years and the presence of CNS disease at diagnosis remained significantly associated with MIDi. CONCLUSIONS: Older age and CNS involvement at diagnosis increase the risk of MIDi. In contrast to previous studies, higher BMI was not associated with MIDi in our population.

[Therapeutic alternatives to native L-asparaginase in the treatment of adult acute lymphoblastic leukemia]. / Alternatives thérapeutiques à la L-asparaginase native dans le traitement de la leucémie aiguë lymphoblastique de l'adulte.

L-asparaginase is an effective antineoplastic agent, which is an integral part of combination chemotherapy protocols for adult acute lymphoblastic leukemia. Its antitumor effect results from the depletion of asparagine, an amino acid essential to leukemia cells, and subsequent inhibition of protein synthesis leading to cytotoxicity. However, its use has been limited by a high rate of hypersensitivity reactions and development of neutrolizing anti-asparaginase antibodies, and by the need of frequent administration. To overcome these limitations modified versions of L-asparaginase (such as asparaginase from other sources, pegylated formulations, and asparaginase loaded into erythrocytes) have been recently proposed. Advantages of these therapeutic alternatives to native L-asparaginase and their results as part of preliminary clinical trials in adults have been outlined in this review.

Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia.

L-asparaginase (L-ASNase) has been an essential component of multiagent chemotherapy for acute lymphoblastic leukemia in childhood for over 3 decades. There are currently 2 Food and Drug Administration (FDA)-approved formulations of L-ASNase derived from Escherichia coli and 1 non-FDA approved formulation derived from Erwinia chrysanthemi. Modifications in L-ASNase have included pegylation, which decreases drug immunogenicity and increases the half-life, allowing less frequent administration. Although L-ASNase is well-tolerated in most patients and causes little myelosuppression, significant toxicities occur in up to 30% of patients. Hypersensitivity is the most common toxicity of L-ASNase therapy and limits the further use of the drug. Other significant toxicities relate to a reduction in protein synthesis and include pancreatitis, thrombosis, central nervous system complications, and liver dysfunction. The spectrum of common toxicities and the efficacy of different formulations of L-ASNase are presented in this review.

Hiperlipidemia transitoria secundaria al tratamiento con asparraginasa y prednisona / Transient hyperlipidemia secondary to treatment with asparaginase and prednisone

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Efficacy and safety of ritonavir-boosted dual protease inhibitor therapy in antiretroviral-naive HIV-1-infected patients: the 2IP ANRS 127 study.

OBJECTIVES: We evaluate the efficacy and tolerability of ritonavir-boosted dual protease inhibitor as a nucleoside reverse transcriptase inhibitor-sparing regimen in a prospective open-label randomized pilot trial in antiretroviral-naive patients. METHODS: Thirty patients received fosamprenavir/atazanavir/ritonavir (Group 1) and 31 patients received saquinavir/atazanavir/ritonavir (Group 2). The primary endpoint for efficacy was the rate of early virological success, defined as plasma viral load <50 copies/mL at week 16. The study is registered with ClinicalTrials.gov (NCT00122603). RESULTS: At baseline, median (range) viral load was 4.8 log(10) copies/mL (4.0-5.7) and the median CD4 cell count was 271/mm(3) (197-740). Viral load was <50 copies/mL in 12/30 patients [40%, 95% confidence interval (CI) 23%-58%] and 13/31 patients (42%, 95% CI 25%-59%) at week 16 in Groups 1 and 2, respectively. Patients with failing regimens (viral load >or=400 copies/mL at week 16 or >or=50 copies/mL at week 24) were switched to a standard antiretroviral regimen. At week 48, by an intention-to-treat analysis, 23/30 patients (77%) and 26/31 patients (84%) had plasma HIV-1 RNA <50 copies/mL in Groups 1 and 2, respectively. Four patients discontinued treatment for adverse events, all before week 4. No major changes in the protease gene were detected at treatment failure relative to baseline. Baseline viral load <50 000 copies/mL was the only predictor of virological success at week 16. CONCLUSIONS: Ritonavir-boosted dual protease inhibitor regimens targeting only one step of viral replication were insufficient to rapidly suppress plasma HIV RNA to <50 copies/mL in antiretroviral-naive patients with high viral load at baseline.

Epidural spinal lipomatosis with acute onset of paraplegia in an HIV-positive patient treated with corticosteroids and protease inhibitor: case report.

STUDY DESIGN: Case report. OBJECTIVE: To report a case of HIV-related lipodystrophy with a rapid onset of symptoms from epidural lipomatosis in the wake of protease inhibitor and steroid treatment. SUMMARY OF BACKGROUND DATA: Symptomatic spinal epidural lipomatosis is considered to be a rare condition usually presenting with slowly progressive cord or nerve root compression. Only 2 cases of spinal lipomatosis in HIV-related lipodystrophy have been reported. METHODS: We describe the case of a 41-year-old male with HIV who received protease inhibitor medication and had neurologic deficits rapidly develop. RESULTS: The patient had complete paraplegia develop within 12 hours from admission following a 1-day history of unsteady gait and a 3-day history of leg numbness. After diagnosis of epidural lipomatosis on magnetic resonance imaging, the patient underwent decompressive thoraco-laminectomy. He recovered well and was able to walk by postoperative day 4. CONCLUSION: It is important to maintain an awareness for the possible association between HIV lipodystrophy and symptomatic epidural lipomatosis.

Chemotherapy-induced hypersensitivity reactions.

PURPOSE/OBJECTIVES: To assist clinical nurses in understanding the complex nature of chemotherapy-induced hypersensitivity reactions as well as effectively preventing or managing these reactions. DATA SOURCES: Published articles and abstracts, pertinent book chapters, computerized databases. DATA SYNTHESIS: Most available chemotherapy drugs can cause hypersensitivity reactions, but certain drug groups frequently are associated with these reactions (e.g., asparaginases, taxanes, platinum compounds, epipodophyllotoxins). Preventing hypersensitivity reactions is the primary goal; however, understanding the principles of managing these reactions is critical because hypersensitivity reactions can occur despite using appropriate prevention strategies. CONCLUSIONS: Chemotherapy-induced hypersensitivity reactions are potentially life-threatening. Nurses working with chemotherapy drugs must understand which drugs are associated with a high risk of causing hypersensitivity reactions and must be prepared to attempt to prevent or manage reactions. IMPLICATIONS FOR NURSING: The potentially life-threatening nature of hypersensitivity reactions to chemotherapy requires that nurses have a plan to manage them. This may include a written policy on staff education and training, appropriate equipment, and medications.

Myocardial ischemia in a patient with acute lymphoblastic leukemia during L-asparaginase therapy.

Haemostatic abnormalities may occur in 1-2% of patients treated with L-asparaginase. Here, we present the second case of a myocardial infarction, developing in a patient with acute lymphoblastic leukemia (ALL), in the course of L-asparaginase treatment. In our patient and in the only one reported case from the literature, a recent exposure to vincristine and daunorubicin was also reported, but induction chemotherapy program was completed as scheduled, with the only withdrawal of L-asparaginase. Myocardial infarction should be included in the list of thrombotic complications possibly associated with L-asparaginase treatment, or with a combination of L-asparaginase and vinca alkaloids/anthracycline.

[Iatrogenic hyperlipidemia after l-asparaginase and glucocorticoid treatment in two children with acute lymphoblastic leukemia]. / Jatrogenna hiperlipidemia w przebiegu leczenia L-asparaginaza i glikokortykosteroidami u dwojga dzieci z ostra bialaczka limfoblastyczna.

L-asparaginase and glucocorticosteroides are the main drugs used in the first-line treatment in children with acute lymphoblastic leukaemia. One of the observed side effects in the increase of serum level of triglycerides is synergistic manner. The paper describes two children with acute lymphoblastic leukaemia. In these patients we could observe remarkable hypertriglyceridemia, and hypercholesterolaemia with the increase of LDL-cholesterol after applying high doses of L-asparaginase and glucocorticosteroids simultaneously. The above-mentioned disorders were transient. In the analysis of the possible reasons of this pathology we took into consideration family predispositions, the transient deficit of lipoprotein lipase induced by L-asparaginase, improper diet and hyperthyroidismus.

Minimising the long-term adverse effects of childhood leukaemia therapy.

Malignancies in childhood occur with an incidence of 13-14 per 100,000 children under the age of 15 years. Acute lymphoblastic leukaemia with an incidence of 29% is the most common paediatric malignancy, whereas acute myeloid leukaemias account for about 5%. The treatment of acute leukaemias consists of sequential therapy cycles (induction, consolidation, intensification, maintenance therapy) with different cytostatic drugs over a time period of up to 1.5-3 years. Over the last 25 years of clinical trials, a significant rise in the rate of complete remissions as well as an increase in long-term survival has been achieved. Therefore, growing attention is now focused on the long-term effects of antileukaemic treatment. Several cytostatic drugs administered in the treatment of acute leukaemia in childhood are known to cause long-term adverse effects. Anthracyclines may induce chronic cardiotoxicity, alkylating agents are likely to cause gonadal damage and secondary malignancies and the use of glucocorticoids may cause osteonecrosis. Most of the long-term adverse effects have not been analysed systematically. Approaches to minimising long-term adverse effects without jeopardising outcome have included: the design of new drugs such as a liposomal formulation of anthracyclines, the development of anthracycline-derivates with lower toxicity, the development of cardioprotective agents or, more recently, the use of targeted therapy;alternative administration schedules like continuous infusion or timed sequential therapy; and risk group stratification by the monitoring of minimal residual disease. Several attempts have been made to minimise the cardiotoxicity of anthracyclines: decreasing concentrations delivered to the myocardium by either prolonging infusion time or using liposomal formulated anthracyclines or less cardiotoxic analogues, or the additional administration of cardioprotective agents. The advantage of these approaches is still controversial, but there are ongoing clinical trials to evaluate the long-term effects. The use of new diagnostic methods, such as diagnosis of minimal residual disease, which allow reduction or optimisation of dose, offer potential advantages compared with conventional treatment in terms of reducing the risk of severe long-term adverse effects. Most options for minimising long-term adverse effects have resulted from theoretical models and in vitro studies, but only some of the modalities such as the use of dexrazoxane, the continuous infusion of anthracyclines or timed sequential therapy, have been evaluated in prospective, randomised studies in patients. Future approaches to predict severe toxicity may be based upon pharmacogenetics and gene profiling.