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1.
J Natl Compr Canc Netw ; 19(9): 1079-1109, 2021 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-34551384

RESUMEN

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Humanos , Inmunofenotipificación , Oncología Médica , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto Joven
2.
J Natl Compr Canc Netw ; 17(5): 414-423, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-31085755

RESUMEN

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.


Asunto(s)
Guías de Práctica Clínica como Asunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Manejo de la Enfermedad , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología
3.
Biol Blood Marrow Transplant ; 24(10): 2040-2046, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29933069

RESUMEN

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.


Asunto(s)
Citometría de Flujo , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Acondicionamiento Pretrasplante , Donante no Emparentado , Proteínas WT1/sangre , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Neoplasia Residual , Trasplante Homólogo
4.
J Natl Compr Canc Netw ; 15(9): 1091-1102, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28874594

RESUMEN

The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Historia del Siglo XXI , Humanos
5.
J Natl Compr Canc Netw ; 13(10): 1240-79, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26483064

RESUMEN

Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org.


Asunto(s)
Guías de Práctica Clínica como Asunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Factores de Riesgo
7.
J Natl Compr Canc Netw ; 10(7): 858-914, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22773801

RESUMEN

The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Humanos , Neoplasia Residual , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Factores de Riesgo
8.
Leukemia ; 36(6): 1508-1515, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35422096

RESUMEN

Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) patients suffer risk of chemotherapy-associated toxicities and poor outcomes. We evaluated tisagenlecleucel in 16 patients with DS-ALL in two phase 2 trials (ELIANA [NCT02435849], ENSIGN [NCT02228096]) and a phase 3b, managed access protocol (B2001X [NCT03123939]). Patients were 5-22 years old, had a median of two prior lines of therapy (range, 1-4), and four (25%) had prior stem cell transplants. Fourteen of 16 patients (88%) achieved complete remission (CR) or CR with incomplete blood count recovery (CRi); 12 of 14 (86%) with CR/CRi were minimal residual disease-negative. With a median follow-up of 13.2 months (range, 0.5-49.3 months), six patients (43%) relapsed after CR (three, CD19-negative; three, unknown) between 80-721 days post-infusion. Ongoing remissions in nine patients ranged from 6-48 months. Any-grade and grade 3/4 AEs occurred in 16 and 14 patients, respectively; 44% experienced grade 3/4 cytokine release syndrome and 13% experienced grade 3/4 neurological events. Grade 3/4 prolonged cytopenias occurred in 44% of patients. No grade 3/4 infections were observed. Tisagenlecleucel expansion and long-term persistence were consistent with previous reports. Comparable to ALL patients without DS, tisagenlecleucel produced high remission rates, manageable side-effects, and promising long-term outcomes in pediatric/young adult patients with DS-ALL.


Children with Down syndrome have a 20 times higher risk of developing a type of blood cancer called Down syndrome-associated acute lymphoblastic leukemia (ALL). Children who develop Down syndrome-associated ALL typically receive chemotherapy to treat their cancer; however, they can experience severe toxicity or other consequences from these therapies, especially stem cell transplant, and have a poor prognosis if their disease returns after treatment. These children need an effective but less toxic treatment option. Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that specially modifies the patient's own T-cells to recognize and attack the cancer cells. Tisagenlecleucel is approved for use in children and young adults with ALL whose disease reappears after two or more treatments or whose disease doesn't respond to treatment. Here we present data from 16 patients across three clinical studies showing that tisagenlecleucel is well-tolerated and an effective treatment option for children and young adults with Down syndrome-associated ALL, and was similar to what is observed in patients without Down syndrome. Taken together, patients with Down syndrome-associated ALL have unique medical needs, and tisagenlecleucel may help them live longer, avoid stem cell transplantation, and the toxicity from chemotherapy.


Asunto(s)
Síndrome de Down , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Antígenos CD19 , Niño , Preescolar , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Síndrome de Liberación de Citoquinas , Síndrome de Down/complicaciones , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T , Inducción de Remisión , Adulto Joven
9.
Blood Cancer Discov ; 3(1): 66-81, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-35019853

RESUMEN

We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03-9.97; P < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18-10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44-7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87-50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33-4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19- (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion. SIGNIFICANCE: Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies.See related commentary by Ghorashian and Bartram, p. 2.This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Antígenos CD19 , Niño , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Receptores de Antígenos de Linfocitos T , Recurrencia , Adulto Joven
10.
Blood Rev ; 50: 100848, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33994222

RESUMEN

Despite excellent cure rates in newly diagnosed patients with B-cell acute lymphoblastic leukemia (B-ALL), therapies that improve outcomes for children with relapsed or refractory (r/r) B-ALL are needed. Chimeric antigen receptor (CAR)-T cell therapy has demonstrated durable responses and a manageable safety profile in children, adolescents, and young adults less than 26 years old with r/r B-ALL, including patients who have relapsed after allogeneic stem cell transplant. This comprehensive review summarizes current data, management practices, and future directions for the treatment of r/r B-ALL in pediatric and young adult patients with CAR-T cell therapy, including patient selection, patient preparation, and CAR-T cell infusion, as well as monitoring and management of short- and long-term safety events, long-term surveillance, and survivorship. Clinical trials registration number: N/A.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Adolescente , Adulto , Antígenos CD19/inmunología , Niño , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Resultado del Tratamiento , Adulto Joven
11.
Transplant Cell Ther ; 27(2): 163.e1-163.e7, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33830025

RESUMEN

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) from HLA-identical related donors using cyclosporine (CSP) and mycophenolate mofetil (MMF) for postgrafting immunosuppression is effective therapy for hematologic cancers. However, graft-versus-host-disease (GVHD) remains a major cause of morbidity and mortality. Pilot data suggested lower acute GVHD incidence with tacrolimus/MMF compared to historical experience using CSP/MMF after nonmyeloablative HCT. In a phase II multicenter trial, we evaluated the effect of tacrolimus/MMF for GVHD prophylaxis after HLA-identical related donor peripheral blood HCT in patients with hematologic malignancies (n = 150) using conditioning with 2 Gy total body irradiation (TBI) for patients with a preceding (within 6 months) planned autologous HCT (n = 50) or combined with 90 mg/m2 fludarabine for those without recent autologous HCT (n = 100). Oral tacrolimus was given from days -3 to 56 (tapered by day +180 if no GVHD). Oral MMF was given from days 0 to 27. Patient median age was 57 (range, 20 to 74) years. The cumulative incidences (CI) of day 100 grade II to IV and III to IV acute GVHD were 27% and 4%, respectively. With median follow-up of 10.3 (range, 3.1 to 14.5) years, the 5-year CI of chronic extensive GVHD was 48%. One-year and 5-year estimates of nonrelapse mortality, relapse/progression, survival, and progression-free survival were 9% and 13%, 35% and 50%, 73% and 53%, and 56% and 37%, respectively. GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute GVHD and compared favorably with results from a concurrent trial using CSP/MMF. A randomized phase III trial to investigate tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT is warranted.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Recurrencia Local de Neoplasia , Tacrolimus/uso terapéutico
12.
Blood Adv ; 5(23): 4980-4991, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34432863

RESUMEN

Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N = 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N = 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-γ in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 < 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses <1% at baseline and posttreatment time points in a majority of patients and no effect on transgene expansion or persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.


Asunto(s)
Linfoma de Células B Grandes Difuso , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animales , Niño , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Supervivencia sin Progresión , Receptores de Antígenos de Linfocitos T/genética
13.
J Immunother Cancer ; 9(8)2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34353848

RESUMEN

BACKGROUND: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse. METHODS: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel. RESULTS: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion. CONCLUSIONS: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/uso terapéutico , Adolescente , Antineoplásicos Inmunológicos/farmacología , Niño , Preescolar , Femenino , Humanos , Masculino
14.
CPT Pharmacometrics Syst Pharmacol ; 8(5): 285-295, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30848084

RESUMEN

Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or corticosteroids on the expansion rate was observed. This work represents the first mixed-effect model-based analysis of chimeric antigen receptor-T cell therapy and may be clinically impactful as future studies examine prophylactic interventions in patients at risk of higher grade cytokine release syndrome and the effects of these interventions on chimeric antigen receptor-T cell expansion.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfoma de Células B Grandes Difuso/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/administración & dosificación , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos Fase II como Asunto , Femenino , Semivida , Humanos , Inmunoterapia Adoptiva , Masculino , Modelos Teóricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Adulto Joven
15.
Clin Cancer Res ; 24(24): 6175-6184, 2018 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-30190371

RESUMEN

PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN). RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 × 106/kg; patients >50 kg: 0.1 to 2.5 × 108 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response. CONCLUSIONS: Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.


Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Terapia Genética , Inmunoterapia Adoptiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfocitos T , Adolescente , Adulto , Animales , Antígenos CD19/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Niño , Preescolar , Femenino , Terapia Genética/efectos adversos , Terapia Genética/métodos , Humanos , Inmunidad Humoral , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Recuento de Linfocitos , Masculino , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Transgenes/genética , Resultado del Tratamiento , Adulto Joven
16.
Mol Cancer Ther ; 5(3): 693-703, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16546984

RESUMEN

Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural killer cells and CTLs following noxious stimuli, including foreign invaders. Here, we took advantage of the properties of these two functionally divergent molecules to create a molecular agent that specifically activates Granzyme B within tumor cells. We designed Survivin and Granzyme B-induced apoptosis (SAGA), which consists of a fusion of the Survivin gene promoter to the coding sequence of active Granzyme B. In cultured human tumor cells transfected with SAGA DNA, Granzyme B is rapidly expressed and results in significant tumor cell death. In vivo, mice harboring human ovarian tumors had statistically significant clinical responses to SAGA treatment that were magnified following combination therapy with SAGA and paclitaxel. At the completion of a 3-week therapeutic trial, 3 of 15 animals were free of disease in the SAGA-treated group, and an additional eight animals had tumors that were nonpalpable and only detected on surgical resection. In contrast, 15 of 15 animals in the control and paclitaxel-only-treated groups had tumors at end of therapy. Treatment with SAGA with or without paclitaxel also prevented disease dissemination in 19 of 20 animals. These results strongly suggest that SAGA has the potential to be a potent agent for the treatment of primary and recurrent human ovarian carcinoma. Moreover, we predict that SAGA will be useful therapeutically in any human cancer that expresses Survivin.


Asunto(s)
Fusión Artificial Génica , Carcinoma/terapia , Terapia Genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias/genética , Neoplasias Ováricas/terapia , Serina Endopeptidasas/genética , Animales , Apoptosis , Carcinoma/tratamiento farmacológico , Carcinoma/secundario , Proliferación Celular , Terapia Combinada , Femenino , Granzimas , Humanos , Proteínas Inhibidoras de la Apoptosis , Ratones , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Paclitaxel/uso terapéutico , Regiones Promotoras Genéticas , Survivin , Transfección
17.
Onco Targets Ther ; 10: 4355-4367, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28919785

RESUMEN

TK1 is an enzyme involved in DNA synthesis and repair. TK1 is usually found elevated in cancer patients' serum, which makes it a useful tumor proliferation biomarker that strongly correlates with cancer stage, metastatic capabilities, and recurrence risk. In this study, we show that TK1 is upregulated and localizes on the plasma membrane of Burkitt's lymphoma, acute promyelocytic leukemia, T cell leukemia, and acute lymphoblastic leukemia (ALL). Using flow cytometry, we confirmed that TK1 localizes on the surface of Raji, HL60, and Jurkat cell lines and on ALL clinical samples. Using fluorescent microscopy, we found a strong association of TK1 with the plasma membrane in Raji, HL60, and Jurkat cell lines. These findings were also confirmed by scanning electron microscopy. Our study also shows that this phenomenon does not occur on normal resting or proliferating lymphocytes. In addition, we show that membrane TK1 is found in all oligomeric forms ranging from monomer to tetramer and exhibits enzymatic activity. These findings suggest TK1 as a possible target for immunotherapy with the potential to be utilized in the treatment of hematological cancers.

18.
J Clin Oncol ; 35(36): 4003-4011, 2017 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-29040031

RESUMEN

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.


Asunto(s)
Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Anciano , Método Doble Ciego , Femenino , Enfermedad Injerto contra Huésped/etiología , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/uso terapéutico , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Tacrolimus/uso terapéutico , Adulto Joven
19.
Int J Hematol ; 102(6): 729-31, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26497867

RESUMEN

Busulfan is a commonly used chemotherapeutic agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). It has been associated with sinusoidal-obstructive syndrome(SOS) as a life-threatening complication of myeloablative allo-HCT, yet it has not been found to cause severe hepatocellular injury, even in cases of significant accidental overdose.We report the case of a 31-year-old male with a history of high-risk myelodysplastic syndrome transitioning to acute myeloid leukemia, who in complete remission underwent allo-HCT using myeloablative busulfan­fludarabine conditioning, and who developed hepatic failure. While he met clinical criteria for SOS and was treated with defibrotide,liver biopsy demonstrated severe subacute hepatic necrosis and lacked characteristics of SOS. Further evaluation revealed that the patient was homozygous for the HFE H63D gene mutation, associated with hereditary hemochromatosis.Both Busulfan and iron overload related to HFE H63D homozygosity can cause oxidative stress resulting in cellular injury, and the cumulative effects of these risk factors are possibly responsible for the severe hepatocellular injury in this case, making our patient the first-known case of subacute hepatic necrosis related to busulfan administration.


Asunto(s)
Busulfano/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Antígenos de Histocompatibilidad Clase I/genética , Homocigoto , Leucemia Mieloide Aguda/cirugía , Fallo Hepático Agudo/etiología , Proteínas de la Membrana/genética , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Enfermedad Aguda , Adulto , Aloinjertos , Busulfano/uso terapéutico , Diagnóstico Diferencial , Hemocromatosis/genética , Proteína de la Hemocromatosis , Enfermedad Veno-Oclusiva Hepática , Humanos , Leucemia Mieloide Aguda/etiología , Hígado/patología , Fallo Hepático Agudo/diagnóstico , Fallo Hepático Agudo/patología , Masculino , Mutación , Síndromes Mielodisplásicos/complicaciones , Necrosis/etiología , Estrés Oxidativo , Riesgo , Factores de Riesgo
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