Resumen

Este ensayo aleatorizado de fase III estudia la eficacia del mesilato de imatinib en combinación con dos regímenes de quimioterapia diferentes para el tratamiento de pacientes con leucemia linfoblástica aguda (LLA) con cromosoma Filadelfia positivo de diagnóstico reciente. Se ha demostrado que el mesilato de imatinib mejora los resultados en niños y adolescentes con LLA con cromosoma Filadelfia positivo (Ph+) cuando se administra con quimioterapia intensiva, pero esta combinación presenta numerosos efectos secundarios. Este ensayo evalúa si un régimen de quimioterapia diferente puede ser tan eficaz como el más potente, pero con menos efectos secundarios, al administrarse junto con imatinib. El ensayo también evalúa la eficacia de la combinación de quimioterapia e imatinib en otro grupo de pacientes con un tipo de LLA similar a la LLA Ph+. Este tipo de LLA se denomina "LLA con fusión de clase ABL positiva" y, debido a su similitud con la LLA Ph+, se cree que responderá bien a la combinación de agentes utilizados para tratar la LLA Ph+.

Edad: De 1 a 21 años

Género: Todos

Fecha de inicio: 08/08/2017

Fecha de finalización principal (estimada): 09/30/2027

Fecha estimada de finalización del estudio: 09/30/2027

Acepta voluntarios sanos: No

Propósito y descripción del ensayo

PRIMARY OBJECTIVE: I. To compare disease-free survival (DFS) of standard risk (SR) pediatric Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone. SECONDARY OBJECTIVES: I. To compare DFS of SR pediatric Ph+ and ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. II. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk (HR) Ph+ ALL patients. III. To determine event-free survival (EFS) of HR pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib. IV. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients between the two randomized arms. V. To evaluate EFS and overall survival (OS) of all eligible Ph+ALL patients enrolled on the study. VI. To evaluate OS in SR Ph+ ALL patients. VII. To evaluate OS in HR Ph+ ALL patients. VIII. To evaluate EFS and OS of all eligible ABL-class fusion positive ALL patients enrolled on the study. EXPLORATORY OBJECTIVES: I. To describe the toxicities associated with post-HSCT administration of imatinib in HR Ph+ALL patients. II. To evaluate the long-term toxicities in SR Ph+ ALL patients treated with chemotherapy plus imatinib (no transplant), overall and between both randomized arms. III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy. IIIa. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome. IIIb. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays. IV. To determine and validate if IKZF1 deletions alone (IKZF1del) or with other transcription factor deletions (ie, IKZF1 plus subtype \[IKZF1plus\]) or other identified genetic lesions predict poor outcomes in Ph+/ABL-class Ph-like ALL in patients treated on AALL1631. V. To determine the frequency and prognostic significance of p190 and p210 BCR::ABL1 fusion variants in pediatric Ph+ ALL/ABL-class Ph-like ALL. VI. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine and methotrexate) during the maintenance phase in SR Ph+ ALL patients. VIa. To identify factors associated with poor adherence. VIb. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined). VII. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and identify factors associated with poor adherence. VIII. To compare DFS of SR ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. IX. Other secondary and exploratory aims described above for Ph+ ALL patients (either SR or HR), if applicable, will be evaluated in ABL-class fusion positive ALL patients. X. Secondary and exploratory aims described above for Ph+ ALL patients (either SR or HR), if applicable and feasible, will be evaluated in the super set of Ph+ and ABL-class fusion positive ALL patients. XI. To determine the potential therapeutic impact of major secondary events via pharmacologic inhibitor screens in existing/engineered cell models of Ph+ and ABL-class Ph-like ALL harboring secondary events and to test the in vivo activity of the most compelling candidate compounds from pilot studies using patient-derived xenograft (PDX) models established from Ph+ and ABL-class Ph-like ALL samples collected from patients treated on AALL1631. XII. To decipher the molecular and cellular heterogeneity of chronic myelogenous leukemia (CML)-like versus typical Ph+ ALL via single-cell genomics and functional assays and investigate CML-like phenotypes via single-cell ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) sequencing to identify distinct transcriptomic and mutational profiles that will provide novel opportunities for diagnostic and therapeutic interventions. OUTLINE: INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days 1-14. INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate intrathecally (IT) on day 29. INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or subcutaneously (SC) on days 3-6, 10-13, 17-20, and 24-27, and methotrexate IT on days 10 and 24. POST-INDUCTION THERAPY: Patients classified as standard risk are randomized to 1 of 2 arms. Patients with high risk are assigned to Arm C. ARM A (SR patients assigned to ARM A): CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and pegaspargase or calaspargase pegol IV over 1-2 hours on day 5, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high dose cytarabine IV over 3 hours on days 1-3, dexamethasone PO BID or IV on days 1-5, etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 38-41 and 45-48, and methotrexate IT on days 38 and 45in the absence of disease progression or unexpected toxicity. INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity. MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of cycles 1, 2, and 3, and mercaptopurine PO on days 1-84. Cycles with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity. ARM B (SR PATIENTS ASSIGNED TO ARM B): INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63, vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium or levoleucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or IM on day 4 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 43 in the absence of disease progression or unexpected toxicity. INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 23 in the absence of disease progression or unexpected toxicity. MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for cycle 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for cycle 1 and 2). Cycles repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity. ARM C (HR PATIENTS): CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone, leucovorin calcium or levoleucovorin, high dose cytarabine, and pegaspargase or calaspargase pegol as in Arm A Consolidation Block 1, and filgrastim SC or IV on day 7 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate, ifosfamide, leucovorin calcium or levoleucovorin, dexrazoxane hydrochloride, daunorubicin hydrochloride, pegaspargase or calaspargase pegol, and filgrastim as Arm A Consolidation Block 2 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide, methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase or calaspargase pegol, and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence of disease progression or unexpected toxicity. HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm A. POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in the absence of disease progression or unexpected toxicity. After completion of study treatment, patients are followed up every year for 3 years.

Criterios de elegibilidad

Edad: De 1 a 21 años

Género: Todos

Acepta voluntarios sanos: No

Criterios de inclusión:

* Para los pacientes inscritos en APEC14B1 antes de su inscripción en AALL1631, se ha cumplido el requisito de muestra de médula ósea para diagnóstico.

* Para los pacientes que no se hayan inscrito previamente en APEC14B1 antes de su inscripción en AALL1631, se debe disponer de una muestra diagnóstica basal (o una muestra de sangre periférica con blastos si no se dispone de una muestra de médula ósea) para desarrollar una sonda de EMR.

* Además, los informes de laboratorio que detallen la evidencia de fusión BCR::ABL1 o fusión de clase ABL deben enviarse para una revisión central rápida dentro de las 72 horas posteriores a la inscripción en el estudio.

* \>= 1 año (365 días) y =\< 21 años al momento del diagnóstico de leucemia linfoblástica aguda (LLA)

* Ph+ (fusión BCR::ABL1): leucemia linfoblástica aguda (LLA) de novo de diagnóstico reciente (LLA-B o LLA-T) o leucemia aguda de fenotipo mixto (definición de la reunión MPAL de la Organización Mundial de la Salud [OMS] de 2016) con evidencia definitiva de fusión BCR::ABL1 mediante cariotipo, hibridación in situ con fluorescencia (FISH) y/o metodologías moleculares.

* Fusión de clase ABL: LLA-B de diagnóstico reciente con evidencia definitiva de fusiones de clase ABL. Las fusiones de clase ABL se definen como aquellas que involucran los siguientes genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. Los métodos de detección incluyen hibridación in situ con fluorescencia (FISH, por ejemplo, usando sondas de señales de separación o colocalización), reacción en cadena de la polimerasa con transcripción inversa (RT-PCR) multiplex o simple, secuenciación de ARN del transcriptoma completo o basada en paneles (por ejemplo, TruSight RNA Pan-Cancer Panel; Illumina, San Diego, California [CA], Estados Unidos de América [USA] o similar).

* Los pacientes Ph+ deben haber comenzado previamente la terapia de inducción, que incluye vincristina, un corticosteroide, pegaspargasa, con o sin antraciclina, y/u otra quimioterapia citotóxica estándar.

* Los pacientes Ph+ no han recibido más de 14 días de terapia de inducción con múltiples agentes comenzando con la primera dosis de vinCRIStina.

* Los pacientes Ph+ pueden haber comenzado a tomar imatinib antes de ingresar al estudio, pero no han recibido más de 14 días de imatinib.

* Los pacientes con fusión de clase ABL deben haber completado previamente las 4 o 5 semanas de quimioterapia de inducción con múltiples agentes (fase IA de inducción).

* Los pacientes con fusión de clase ABL pueden haber comenzado a usar imatinib durante la IA de inducción, al mismo tiempo o después de la primera dosis de vincristina.

* Los pacientes deben tener un estado funcional correspondiente a las puntuaciones del Eastern Cooperative Oncology Group (ECOG) de 0, 1 o 2.

* Bilirrubina directa =\< 2,0 mg/dL

* Fracción de acortamiento ≥ 27% según ecocardiograma

* Fracción de eyección ≥ 50% mediante angiografía con radionúclidos o ecocardiograma.

* Intervalo QT corregido, QTc \< 480 ms

* Nota: No es necesario repetir el ecocardiograma ni el electrocardiograma si se realizaron en el momento del diagnóstico inicial de LLA o posteriormente, antes de la inscripción en el estudio.

* Aclaramiento de creatinina o tasa de filtración glomerular (TFG) radioisotópica ≥ 70 mL/min/1,73 m² o creatinina sérica dentro de los límites normales según la edad/sexo, como se indica a continuación:

* 1 a \< 2 años: creatinina sérica máxima 0,6 mg/dL (tanto en hombres como en mujeres)

* 2 a \< 6 años: creatinina sérica máxima 0,8 mg/dL (tanto en varones como en mujeres)

* 6 a \< 10 años: creatinina sérica máxima 1 mg/dL (tanto en hombres como en mujeres)

* 10 a \< 13 años: creatinina sérica máxima 1,2 mg/dL (tanto en hombres como en mujeres)

* 13 a \< 16 años: creatinina sérica máxima 1,5 mg/dL (hombres), 1,4 mg/dL (mujeres)

* \>= 16 años: creatinina sérica máxima 1,7 mg/dL (hombres), 1,4 mg/dL (mujeres)

Criterios de exclusión:

* Antecedentes conocidos de leucemia mieloide crónica (LMC)

* LLA que se desarrolla después de un cáncer previo tratado con quimioterapia citotóxica

* Infección activa no controlada o enfermedad sistémica activa que requiere soporte vasopresor continuo o ventilación mecánica.

* Síndrome de Down

* Embarazo y lactancia materna

* Pacientes femeninas embarazadas, ya que se han observado toxicidades fetales y efectos teratogénicos con varios de los fármacos en estudio. Se requiere una prueba de embarazo para las pacientes femeninas en edad fértil.

* Lactating females who plan to breastfeed their infants

* Pacientes sexualmente activos con potencial reproductivo que no hayan aceptado utilizar un método anticonceptivo eficaz durante la duración del tratamiento según el protocolo.

* Pacientes con síndrome de QT largo congénito, antecedentes de arritmias ventriculares o bloqueo cardíaco

* Tratamiento previo con dasatinib o cualquier TKI distinto de imatinib.