Eficacia y seguridad de L-asparaginasa erwinia y L-asparaginasa E. Coli pegilada en el tratamiento de pacientes con leucemia linfoblástica aguda que presentam hipersensibilidad a L-asparaginasa E. coli nativa / Efficacy and safety of L-asparaginase erwinia and L-asparaginase E. coli pegylated in the treatment of patients with acute lymphoblastic leukemia who are hypersensitive to L-asparaginase E. coli native

INTRODUÇÃO: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del uso de L-asparaginasa Erwinia y L-asparaginasa E. coli pegilada para el tratamiento de pacientes con leucemia linfoblástica aguda que presentan hipersensibilidad a L-asparaginasa E. coli nativa. Aspectos Generales: La leucemia es el tipo de cáncer más común en niños, representando aproximadamente el 30% de todos los tipos de cáncer diagnosticados en niños; siendo la leucemia linfoblástica aguda (LLA) uno de los dos tipos de leucemias más comunes. Adicionalmente, alrededor del 60% de todos los casos de LLA ocurre en pacientes menores de 20 años. Así, LLA es un tipo de leucemia de alta importancia dentro de población joven. Tecnología Sanitaria de Interés: Las células neoplásicas en la leucemia linfoblástica aguda (LLA) no sintetizan las cantidades necesarias del aminoácido L-asparagina; por lo que requieren de funtes externas (i.e., L-asparagina extracelular). La L-asparaginasa, es una enzima que cataliza la conversión de L-asparagina más agua, en ácido aspártico y amoniaco, ocasionando que los niveles de L-asparagina extracelular disminuyan; y que por los tanto las células d ela LLA no cuenten con L-asparagina extracelular. Así, estas células neoplásicas se quedan sin fuentes de L-asparagina, y no pueden sintetizar proteínas de gran imporancia para su supervivencia, ocasionando su muerte. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura a la eficacia y seguridad del uso de L-asparaginasa Erwinia y L-asparaginasa E. coli pegilada para el tratamiento de pacientes niños y adultos con leucemia linfoblástica aguda que presentan hipersensibilidad a L-asparaginasa E. coli nativa. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE) Y National Library of Medicine (Pubmed-Medline). RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica hasta marzo del 2017 para el sustento del uso de L-asparaginasa Erwinia en el tratamiento de leucemia linfoblástica aguda en pacientes niños y adultos que presentan hipersensibilidad a L-asparaginasa E. coli nativa. Se presente la evidencia disponible según el tipo de publicación priorizada en los criterios de inclusión (i.e., GP, ETS, RS y ECA fase III), siendo los ensayos de fase III o en su defecto ensayos controlados y aleatorizados la principal considerada. CONCLUSIONES: El presente dictamen evaluó la mejor evidencia disponible hasta marco 2017 en relación al uso de L-asparaginasa Erwinia y L-asparaginasa E. coli pegilada para el tratamiento de pacientes niños, adolescentes, y adultos con leucemia linfoblástica aguda, que presentan hipersensibilidad a L-asparaginasa E. coli nativa. El Instituto de Tecnologías Sanitarias-IETSI, aprueba el uso de L-asparaginasa Erwinia como parte del esquema quimioterápico utilizada para el tratamiento de pacientes niños, adolescentes, y adultos con leucemia linfoblástica aguda, que presentan hipersensibilidad grado 2 o más a L-asparaginasa E. coli nativa. La vigencia de este dictamen preliminar es de dos años a partir de la fecha de publicación. Asimismo, el Instituto de Tecnologías Sanitarias-IETSI, no aprueba el uso de L-asparaginasa E. coli pegilada en el tratamiento de pacientes niños, adolescentes, y adultos con leucemia linfoblástica aguda, que presentan hipersensiblidad grado 2 o más a L-asparaginasa E. coli nativa.

Efeitos de osmólitos na L- asparaginase II de Erwinia chrysanthemi em meio aquoso / Effects of omolytes in L- asparaginase II from Erwinia chrysanthemi in aqueous medium

A L- asparaginase é uma enzima aplicada no tratamento de Leucemia Linfoide Aguda, que atua na hidrólise da L- asparagina, privando a célula tumoral de um aminoácido essencial para o seu crescimento. A L- asparaginase, como outros biofármacos, deve ser estável, manter sua atividade específica e formar poucos agregados. A fim de manter a integridade do biofármaco, são utilizados adjuvantes nas formulações farmacêuticas, e dentre os mais importantes estão os osmólitos. Essas moléculas protegem a estrutura nativa da proteína, sendo capazes de interferir na formação de agregados e garantir a estabilidade proteica. O presente trabalho teve o objetivo de estudar o efeito dos osmólitos sacarose, sorbitol, arginina e glicina na atividade específica, estabilidade, cinética e caracterização de agregados na solução de L- asparaginase II de Erwinia chrysanthemi. Os resultados mostraram que a maioria dos osmólitos testados aumentou a atividade específica e a estabilidade da enzima, o que pode estar relacionado com o aumento da velocidade máxima e do kcat observados no ensaio cinético realizado com sacarose e sorbitol. Um perfil diferente de agregados foi encontrado para cada tipo de osmólito. A presença de sacarose ou sorbitol resultou na menor quantidade de agregados na faixa de, respectivamente, 100 a 200 e 200 a 300 nm em relação a enzima sem osmólito. Por outro lado, aumento no número total de agregados e presença de moléculas de alto peso molecular (300 a 500 nm) foram observados nas soluções enzimáticas contendo, respectivamente, glicina e arginina. Dessa forma, os resultados obtidos neste trabalho poderão auxiliar na produção e escolha da formulação de biofármacos, e, consequentemente, melhorar o tratamento medicamentoso de pacientes.

L L-Asparaginase is an enzyme applied in the treatment of Acute Lymphoblastic Leukemia, which acts on the hydrolysis of L- asparagine, depriving the tumor cell of an essential amino acid for its growth. L-asparaginase, as other biopharmaceuticals, must be stable, maintain its specific activity and form few aggregates. In order to maintain the integrity of the biopharmaceutical, adjuvants are used in the pharmaceutical formulations, and among the most importants adjuvants are the osmolytes. These molecules protect the native structure of the protein, being able of interfering in the formation of aggregates and guarantee protein stability. The present work had the objective of studying the effect of the osmolytes sucrose, sorbitol, arginine and glycine in the specific activity, stability, kinetic and aggregates characterization, in L- asparaginase II solution of Erwinia chrysanthemi. The results showed that the majority of the tested osmolytes increased the specific activity of the enzyme and its stability, which may be related to the augment of maximum velocity and kcat observed in the kinetic assay performed with sucrose and sorbitol. A different profile of aggregates was found for each type of osmolyte. The presence of sucrose or sorbitol resulted in the least amount of aggregates in the range of, respectively, 100-200 and 200-300nm in relation to the enzyme without osmolyte. On the other hand, increase in the total number of aggregates and the presence of high molecular weight molecules (300 to 500 nm) were observed in the enzymatic solutions containing, respectively, glycine and arginine. Thus, the results obtained in this work may help in the production and choice of the formulation of biopharmaceuticals and, consequently, improve the drug treatment of patients.

Leucemia linfoblástica aguda estirpe B Philadelphia negativa en adolescentes y adultos jóvenes: Resultados del Protocolo Terapéutico LLA 15-30, Programa Nacional de Cáncer del Adulto (PANDA), Ministerio de Salud, Chile / Adolescent and young adult Philadelphia negative B cell acute lymphoblastic leukemia: Results of the Chilean protocol LLA 15-30

Background: Intensified treatment of Philadelphia chromosome negative acute lymphoblastic leukemia (Ph(-)ALL) in adolescents by pediatric teams, with fve years disease free survival (DFS) rate of 65%, encouraged the use of intensified protocols in patients between 15 and 30 years, improving the DFS from 45% to 60-80%. The protocol LLA 15-30 for patients between 15 and 30 years with Ph(-)ALL, based on the Children’s Oncology Group (COG) protocol AALL0232 resulting in a five years DFS of 78%, was started in 2007 by the PANDA national program. Aim: To report the results of the prospective cohort study evaluating the results of this protocol four years after its implementation. Patients and Methods: Between January 2007 and December 2010, 68 Ph(-) ALL patients, aged between 15-30 years (75% males) were incorporated. Survival was evaluated using Kaplan-Meier and log-rank tests. Results: Fifty percent of patients were of high risk. A complete response was achieved in 91%, early death occurred in 6% and induction failure in 3%. Median follow-up was 23 months. Overall survival, disease free survival and relapse rates at 35 months were 61.8, 67.5% and 31% respectively. Conclusions: LLA 15-30 protocol significantly improved three-year overall survival from 31 to 62%. The 20% difference observed with AALL0232 protocol is explained by the high rate of relapse. Improving provider and patient compliance with protocols may eliminate this gap.

Testicular relapse in childhood acute lymphoblastic leukemia: The challenges and lessons.

Background : Relapse of disease is documented in 15-20% of children with acute lymphoblastic leukemia (ALL). Although testicular relapse is rare with modern risk-adapted treatment protocols, earlier, the testes were a frequently encountered site of relapse and were designated as "drug sanctuaries". Purpose : This descriptive study was designed to assess the pattern of testicular relapse and to identify high-risk factors. Materials and Methods : Data obtained from case records of 407 boys with ALL were analyzed. Fine needle aspiration cytology was carried out in children presenting with painless enlargement of testi(e)s. Bone marrow aspiration and cerebrospinal fluid examination were performed concomitantly to confirm or exclude disease at these sites. Results : Testicular relapse was documented in 30 boys. It was isolated in 17 patients and associated with bone marrow and/or central nervous system relapse in 13. At relapse, nine boys were over the age of 10 years. The majority were very early and early relapsers. Hyperleucocytosis was documented in five of 30 and seven of 137 relapsers and nonrelapsers, respectively (P = 0.04). Twelve of the 30 boys with testicular relapse were treated with testicular irradiation, reinduction and maintenance therapy. The estimated median overall survival was 33 months. Conclusion : Testicular relapse, which depends on the therapy administered, may manifest several months/years after completion of treatment. The high incidence of testicular relapse in our series implicates the need of revaluation of our protocol and incorporation of high/intermediate dose methotrexate therapy upfront.

[L-Asparginase effect with 6000U/m2 on lipid profile in children with acute lymphoblastic leukemia]

One of the major etiologies of lipid disorders in malignancies is the use of chemotherapy drugs, the most important of which is L-Asparginase. Studies in different centers with high dosages of L-Asparginase demonstrated different results. The aim of this study is to evaluate the effect of L-Asparginase at a dose of 6000 U/m2 on lipid profile in Iranian children with newly diagnosed acute lymphoblastic leukemia in Mofid Children Hospital of Tehran. We performed a nonrandomized trial in which all children with newly diagnosed acute lymphoblastic leukemia [ALL] aged <15 years participated. Every case serves as his/her own control. The cholesterol, triglyceride [TG], HDL, LDL, VLDL, APOA, APOB and LPa were evaluated in three stages: before, during and 2 months after treatment with L-Asparginase after which the results were compared. In our study, 82 newly ALL diagnosed patients with the mean age of 6 years [within the age range of 0.12-14 and SD of 3.5] were evaluated. Mean seum level of TG in pretreatment stage was 163.9 mg% and during treatment with L-Asparginase 123 mg% demonstrating significant decline in TG serum level after administration of L-Asparginase [p=0.002]. Mean serum level of cholesterol before administration of L-Asparginase was 151mg% and during treatment 140 showing no statistically significant difference [p= 0.061]. LPa level in pretreatment phase was 24mg% and during treatment 14 showing a statistically significant difference [p= 0.0001]. L-Aspar resulted in decline in TG serum level and increase in HDL though with no significant difference in cholesterol level. Overall, L-Asparginase even at a dose of 6000U/M2 does not raise blood level of triglyceride and cholesterol

Treatment Outcome of Adult Acute Lymphocytic Leukemia with VPD (L) Regimen: analysis of Prognostic Factors

BACKGROUND: Because of the relative paucity of data regarding the clinical outcome in adult patients with acute lymphocytic leukemia (ALL) in Korea, we analyzed clinical courses in adult ALL patients treated with VPD (L) regimen (vincristine, prednisolone, daunorubicin, L-asparaginase) at the Seoul National University Hospital, and evaluated prognostic factors influencing the outcome. METHODS: Patients with ALL newly diagnosed between October 1994 and June 2000 at our hospital were analyzed retrospectively. Fifty-three patients were evaluable. Induction chemotherapy consisted of VPD with (46 cases) or without L-asparaginase (7 cases). After complete remission (CR), consolidation therapy, CNS prophylaxis and maintenance chemotherapy were administered. RESULTS: Ages ranged from 16 to 67 (median 30). CR rate was 86.8% (46/53) and no significant prognostic factor was found for the CR rate. With a median follow-up time of 27.2 months (range 12.9~83.0 months) in living patients, the median overall survival (OS) for all cases was 16.7 months (13.4~20.1 months, 95% C.I.) and the estimated 4-year OS rate was 25.4%+/-8.9%. The median relapse-free survival (RFS) was 12.2 months (8.4~16.0 months, 95% C.I.), and 3-year RFS rate was 29.9%+/-10.2%. Poor prognostic factors for OS were Ph chromosome (p=0.005) and T-cell immunophenotype (p=0.03). For RFS they were Ph chromosome (p=0.01) and the presence of a mediastinal mass (p=0.03). CONCLUSION: Despite an initial excellent response to the VPD (L) regimen, newer therapeutic strategies, including more intensive postremission therapies, are urgently needed because of the high relapse rate. Future therapeutic approaches need to be stratified according to several prognostic factors.

Chemotherapy related fatal neurotoxicity during induction in acute lymphoblastic leukemia.

Neurotoxicity is a common complication during cancer chemotherapy. It is estimated that 3-10% of children with acute lymphoblastic leukemia (ALL) experience acute, transient neurotoxicity during induction chemotherapy. Fatal acute neurotoxicity is rarely encountered. Neurological evaluation of children with ALL at diagnosis and during treatment is of value in order to diagnose neurological complications early so that appropriate intervention can be adopted. This communication describes the profile of two children with unexpected, acute fatal neurologic toxicity during induction chemotherapy for ALL.

Treatment of acute lymphoblastic leukaemia in adults with modified BFM regimen.

Sixty-two adults with acute lymphoblastic leukaemia (ALL) were treated with a modified BFM regimen. Forty-two (70%) achieved complete remission (CR). Twenty-one percent of all evaluable patients and 32.4 percent of complete responders are in continuous complete remission (CCR) at a median follow-up of 41 months (range 24-81 months). Long-term survival was better in T- ALL (47.1%) when compared to precursor-B ALL (4.8%) (P < 0.04).

Tumores testiculares primarios en niños / Primary testicular tumors in children

Se analizan 37 niños con tumores testiculares de células germinales atendidos en el Hospital Luis Calvo Mackenna entre l968-1984. Los tipos histológicos fueron 26 carcinomas embrionarios infantiles (C.E.I.) 7 teratomas inmaduros y 4 teratomas maduros. Los 26 carcinomas embrionarios se trataron con orquiectomía total, 5 con orquiectomía exclusiva, 5 con orquiectomía y linfadenectomía (histología negativa) y 16 con orquiectomía y quimioterapia M.A.C. (metotrexato, actinomicina D y ciclofosfamida). Los últimos 12 pacientes ingresados se controlaron con alfafetoproteina. De los 7 teratomas inmaduros la orquiectomía fue exclusiva en 2, en 2 se agregó linfadenectomía y en 3 quimioterapia (M.A.C.). En los 4 teratomas maduros se utilizó orquiectomía exclusiva. Fallecieron 4/33 pacientes con tumores malignos de células germinales todos CEI, de estos 2 eran Estadio II y se trataron con orquiectomía exclusiva. 2 Estadio I tratados con orquiectomía y linfadenectomía recayeron y fallecieron. Los 29 restantes están vivos sin evidencia de enfermedad entre a y 16 años, a pesar de que recayeron 5 CEI, 3 de los cuales se trataron con PVB (cis-platinum, vinblastina y bleomicina) con buen resultado. Los tumores de células germinales testiculares malignos, en Estadio I pueden ser tratados solo con cirugía y controlados con niveles de alfafetoproteina y radiografía de tórax. Si recidivan (menos del l5%), pueden ser curados con quimioterapia (PBV)

Resultados del tratamiento del linfoma no Hodgkin del niño: protocolo L278 modificado / Results of the treatment of non-Hodgkin's lymphoma in child: modified L278 protocol

Entre enero de 1983 y julio de l984, un grupo de 14 niños con linfoma no Hodgkin (LNH), 12 del sexo masculino y 2 del femenino (6:1) y edades entre los 2 y 10 años, fueron tratados con el protocolo L278 modificado (Hospital Nacional de Niños de Costa Rica). La modificación se realizó agregando una fase de consolidación después de la inducción, con methotrexate (MTX) (1 g/m2, iv) y rescate leucovorínico (20 mg/m2 im/po c/6 horas por 3 dosis) en los casos de LNH de células B o abdominales y citosín arabinósida (Ara C) (1200 mg/m2 iv) y L asparaginosa (10000 U/m2 im c/48 horas por 4 dosis), en los casos de LNH de células T o mediastinales. En la fase de prevención de recaída al SNC, se agregó Ara C intrarraquídea (60 mg, 50 mg y 30 mg a los niños de más de 3, 2 y 1 año respectivamente) cada 2 semanas por 3 dosis. Los demás medicamentos se aplicaron en la misma forma que en el protocolo L278, pero se acortó la fase de mantenimiento en los E III y IV de 18 a 15 meses. Doce casos eran abdominales: 10 en E III, uno en E II y uno en E IV (médula ósea infiltrada). Uno se localizó en mediastino (E III) y uno en ganglios cervicales (E I). En 10 casos la histología fue indiferenciado no Burkitt, en uno Burkitt y en tres no fue clasificable. Diez pacientes se laparotomizaron, en otros tres el diagnóstico se hizo por biopsia y en uno por citología. Los 14 presentaron remisión inicial completa; un niño, en E IV, recayó en SNC y médula ósea y falleció a los cinco meses del diagnóstico; otro, en E III abdominal, falleció a los nueve meses de remisión comprobada por autopsia, debido a miocardiopatía por adriamicina. Doce niños, fuera de tratamiento, se encuentran en remisión completa con una sobrevida de 15 a 30 meses