RESUMO
BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has shown promising disease responses in patients with high-risk B-cell malignancies. However, its use may be related to complications such as immune-mediated complications, infections, and end-organ dysfunction. The incidence of post-CAR T-cell therapy acute kidney injury (AKI) in the children, adolescent, and young adult (CAYA) patient population is largely unreported. METHODS: The objectives of this study were to determine the incidence of AKI in CAYA patients with high-risk B-cell malignancies treated with CD19-CAR T-cell therapy, evaluate potential risk factors for developing AKI, and determine patterns of kidney function recovery. We conducted a retrospective analysis of 34 CAYA patients treated with CD19-CAR T-cell at a single institution. RESULTS: There was a cumulative incidence of any grade AKI by day 30 post-infusion of 20% (n = 7), with four cases being severe AKI (stages 2-3) and one patient requiring kidney replacement therapy. All episodes of AKI developed within the first 14 days after receiving CAR T-cell therapy and 50% of patients with AKI recovered kidney function to baseline within 30 days post-infusion. No evaluated pre-treatment risk factors were associated with the development of subsequent AKI; there was an association between AKI and cytokine release syndrome and neurotoxicity. We conclude that the risk of developing AKI following CD19-CAR T-cell therapy is highest early post-infusion, with most cases of AKI being severe. CONCLUSIONS: Frequent monitoring to facilitate early recognition and subsequent management of kidney complications after CD19-CAR T-cell therapy may reduce the severity of AKI in the CAYA patient population.
Assuntos
Injúria Renal Aguda , Antígenos CD19 , Imunoterapia Adotiva , Humanos , Injúria Renal Aguda/terapia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/epidemiologia , Adolescente , Masculino , Feminino , Estudos Retrospectivos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Criança , Adulto Jovem , Incidência , Pré-Escolar , Antígenos CD19/imunologia , Fatores de Risco , Adulto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologiaRESUMO
Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, are commonly used for pharmacologic prophylaxis of graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT). Unfortunately, their use is associated with significant toxicities. While intolerance to CNI is well defined, there is very little information on how they impact outcomes after HCT in children. Our retrospective study in a cohort of 82 children shows a high intolerance rate of 39% in this population associated with lower event-free survival and a higher transplant-related mortality.
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Antibody-mediated autoimmune-like hepatitis is a rare and challenging occurrence after hematopoietic cell transplant (HCT). We present the case of a 16-year-old male patient with Ph+ ALL who underwent matched sibling donor HCT and developed autoimmune-like hepatitis after receiving ponatinib for post-HCT maintenance, evidenced by marked plasma cell infiltrate on liver biopsy. He was successfully treated with steroids and daratumumab, an anti-CD38-monoclonal antibody. The dramatic response in this patient warrants expanded investigation of daratumumab for plasma cell-mediated disorders post-HCT. It further highlights that identifying mechanisms of immune-mediated injury can allow for directed therapy and limit exposure to broad immune suppression.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Hepatite Autoimune , Plasmócitos/efeitos dos fármacos , Adolescente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/etiologia , Humanos , MasculinoRESUMO
Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia/efeitos adversos , Células Matadoras Naturais/transplante , Falência Hepática/etiologia , Linfo-Histiocitose Hemofagocítica/etiologia , Neuroblastoma/terapia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Pré-Escolar , Ferritinas/sangue , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Lactente , Falência Hepática/terapia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Neuroblastoma/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/terapia , Condicionamento Pré-Transplante/efeitos adversosRESUMO
Post-transplant lymphoproliferative disorder (PTLD) related plasma cell neoplasms are rare in pediatric patients. We report a pediatric liver transplant recipient with plasma cell myeloma type PTLD. Cytogenetics included 1q duplication, associated with poor prognosis in adult multiple myeloma, and t(8;14). High-risk cytogenetics has not been reported in pediatric plasma cell myeloma type PTLD. The patient was treated with bortezomib, dexamethasone, and lenalidomide with subsequent autologous stem cell transplant. He achieved a 6-year remission, demonstrating tolerance to and efficacy of this modern myeloma regimen in a pediatric patient. Unfortunately, he subsequently died from complications of repeat liver transplant.
Assuntos
Hospedeiro Imunocomprometido , Transplante de Fígado/efeitos adversos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , MasculinoRESUMO
Despite intensive therapies, pediatric patients with relapsed or refractory solid tumors have poor outcomes and need novel treatments. Immune therapies offer an alternative to conventional treatment options but require the identification of differentially expressed antigens to direct antitumor activity to sites of disease. B7-H3 (CD276) is an immune regulatory protein that is expressed in a range of malignancies and has limited expression in normal tissues. B7-H3 is highly expressed in pediatric solid tumors including osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, neuroblastoma, and many rare tumors. In this article we review B7-H3-targeted chimeric antigen receptor (B7-H3-CAR) T cell therapies for pediatric solid tumors, reporting preclinical development strategies and outlining the landscape of active pediatric clinical trials. We identify challenges to the success of CAR T cell therapy for solid tumors including localizing to and penetrating solid tumor sites, evading the hostile tumor microenvironment, supporting T cell expansion and persistence, and avoiding intrinsic tumor resistance. We highlight strategies to overcome these challenges and enhance the effect of B7-H3-CAR T cells, including advanced CAR T cell design and incorporation of combination therapies.
RESUMO
Chimeric antigen receptor (CAR) T cell (CAR-T) therapy has emerged as a revolutionary cancer treatment modality, particularly in children and young adults with B cell malignancies. Through clinical trials and real-world experience, much has been learned about the unique toxicity profile of CAR-T therapy. The past decade brought advances in identifying risk factors for severe inflammatory toxicities, investigating preventive measures to mitigate these toxicities, and exploring novel strategies to manage refractory and newly described toxicities, infectious risks, and delayed effects, such as cytopenias. Although much progress has been made, areas needing further improvements remain. Limited guidance exists regarding initial administration of tocilizumab with or without steroids and the management of inflammatory toxicities refractory to these treatments. There has not been widespread adoption of preventive strategies to mitigate inflammation in patients at high risk of severe toxicities, particularly children. Additionally, the majority of research related to CAR-T toxicity prevention and management has focused on adult populations, with only a few pediatric-specific studies published to date. Given that children and young adults undergoing CAR-T therapy represent a unique population with different underlying disease processes, physiology, and tolerance of toxicities than adults, it is important that studies be conducted to evaluate acute, delayed, and long-term toxicities following CAR-T therapy in this younger age group. In this pediatric-focused review, we summarize key findings on CAR-T therapy-related toxicities over the past decade, highlight emergent CAR-T toxicities, and identify areas of greatest need for ongoing research.
Assuntos
Receptores de Antígenos Quiméricos , Humanos , Criança , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de Antígenos de Linfócitos T , Linfócitos T , Imunoterapia Adotiva/efeitos adversos , Fatores de RiscoRESUMO
Patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT) have a poor prognosis. Although proceeding to subsequent HCT can provide potential for long-term survival, there are limited data to guide which patients are most likely to benefit and which HCT strategies are best in this heavily pretreated population. The goals of this study were to describe the clinical outcomes of subsequent HCT in pediatric patients with relapsed hematologic malignancies in a cohort enriched for haploidentical donors, and to evaluate the associations of patient-, disease-, and treatment-related factors with survival. We retrospectively evaluated patients who underwent a subsequent HCT for management of post-HCT relapse at a single institution between 2000 and 2021. Among 106 patients who underwent a second allogeneic HCT, the 1-year event-free survival (EFS) was 34% and 1-year overall survival (OS) was 46%, with a 5-year EFS of 26% and 5-year OS of 31%. Only disease-related factors were associated with outcome after second HCT-specifically, the interval between HCTs and the presence or absence of active disease at the time of HCT. In this cohort, patient- and treatment-related factors were not associated with differences in EFS or OS. Patients undergoing a third or fourth HCT (n = 13) had comparable survival outcomes to those undergoing a second HCT. Our experience highlights that a subsequent HCT has curative potential for a subset of patients who relapse after HCT, including those who undergo a subsequent HCT from a haploidentical donor. Although relapse and treatment-related toxicities remain major challenges, our study indicates that achieving complete remission prior to subsequent HCTs has the potential to further improve outcomes.
Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Recidiva , Humanos , Criança , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/mortalidade , Masculino , Feminino , Pré-Escolar , Adolescente , Estudos Retrospectivos , Lactente , Resultado do Tratamento , Transplante Homólogo , Intervalo Livre de Doença , PrognósticoRESUMO
BACKGROUND: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. METHODS: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. RESULTS: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72-98) and 88% (95% CI: 67-96); ≥ CR2 were 81% (95% CI: 61-92) and 68% (95% CI: 47-82) and refractory disease were 32% (95% CI: 11-54) and 20% (95% CI: 6-40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64-87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/µL and 140/µL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). CONCLUSION: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611).
Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais , Células T de Memória , Condicionamento Pré-Transplante , Transplante Haploidêntico , Humanos , Feminino , Masculino , Células Matadoras Naturais/transplante , Células Matadoras Naturais/imunologia , Criança , Adolescente , Transplante Haploidêntico/métodos , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante/métodos , Neoplasias Hematológicas/terapia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/etiologia , Lactente , Adulto Jovem , Adulto , Resultado do Tratamento , Efeito Enxerto vs LeucemiaRESUMO
The tremendous successes of CD19-directed CAR T cells in children and young adults with B-cell acute lymphoblastic leukemia (B-ALL) has led to the more widespread use of this important treatment modality. With an ability to induce remission and potentially lead to long-term survival in patients with multiply relapsed/chemotherapy refractory disease, more children are now receiving this therapy with the hope of inducing a long-term durable remission (with or without consolidative hematopoietic cell transplantation). While overcoming the acute toxicities was critical to its broad implementation, the emerging utilization requires close evaluation of subacute and delayed toxicities alongside a consideration of late effects and issues related to survivorship following CAR T cells. In this underexplored area of toxicity monitoring, this article reviews the current state of the art in relationship to delayed toxicities while highlighting areas of future research in the study of late effects in children and young adults receiving CAR T cells.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Adulto Jovem , Antígenos CD19 , Progressão da Doença , Seguimentos , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
Medical nutrition therapy (MNT) is a key component of supportive care for children undergoing hematopoietic stem cell transplantation. During the transplant process, several complications and side effects may be encountered that require alteration of the nutrition support, interventions, and monitoring provided. The focus of this review is to discuss current guidelines and research for the provision of MNT to these patients, along with recommendations on how to bridge the gap in MNT knowledge.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Terapia Nutricional , Criança , Humanos , Apoio Nutricional , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
As chimeric antigen receptor (CAR) T-cell therapy is increasingly integrated into clinical practice across a range of malignancies, identifying and treating inflammatory toxicities will be vital to success. Early experiences with CD19-targeted CAR T-cell therapy identified cytokine release syndrome and neurotoxicity as key acute toxicities and led to unified initiatives to mitigate the influence of these complications. In this section, we provide an update on the current state of CAR T-cell-related toxicities, with an emphasis on emerging acute toxicities affecting additional organ systems and considerations for delayed toxicities and late effects.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos de Linfócitos T/genética , Imunoterapia Adotiva/efeitos adversos , Linfócitos T , Neoplasias/tratamento farmacológicoRESUMO
CONTEXT: Early integration of palliative care (PC) in hematopoietic cell transplantation (HCT) has demonstrated benefits, yet barriers remain, including perceived lack of patient/caregiver receptivity despite no data on attitudes toward PC and limited patient/caregiver reported outcomes in pediatric HCT. OBJECTIVES: This study aimed to evaluate perceived symptom burden and patient/parent attitudes toward early PC integration in pediatric HCT. METHODS: Following IRB approval, consent/assent, eligible participants were surveyed at St. Jude Children's Research Hospital including English-speaking patients aged 10-17, 1-month to 1-year from HCT, and their parents/primary-caregivers, as well as parent/primary-caregivers of living HCT recipients Assuntos
Transplante de Células-Tronco Hematopoéticas
, Cuidados Paliativos
, Humanos
, Criança
, Pacientes
, Pais
, Qualidade de Vida
, Atitude
, Cuidadores
RESUMO
CD19-specific chimeric antigen receptor (CAR) T-cell therapy has shown promising disease responses in patients with high-risk B-cell malignancies. Treatment with CD19-CAR T-cell therapy is also associated with the risk of morbidity and mortality, primarily related to immune-mediated complications (cytokine release syndrome [CRS] and neurotoxicity [NTX]), infections, and end-organ dysfunction. Despite these well-described systemic toxicities, the incidence of post-CAR T-cell therapy acute kidney injury (AKI) in the children, adolescent and young adult (CAYA) patient population is largely unreported. The objectives of this study were to determine the incidence of AKI in CAYA patients with high-risk B-cell malignancies treated with CD19-CAR T-cell therapy, evaluate potential risk factors for developing AKI, and determine patterns of kidney function recovery. In this retrospective analysis of 34 CAYA patients treated with CD19-CAR T-cell at a single institution, we found a cumulative incidence of any grade AKI by day 30 post-infusion of 20% (n=7), with 4 cases being severe AKI (Stage 2-3) and one patient requiring kidney replacement therapy. All episodes of AKI developed within the first 14 days after receiving CAR T-cell therapy and 50% of patients with AKI recovered kidney function to baseline within 30 days post-infusion. No evaluated pre-treatment risk factors were associated with the development of subsequent AKI; there was an association between AKI and CRS and NTX. We conclude that the risk of developing AKI following CD19-CAR T-cell therapy is highest early post-infusion, with most cases of AKI being severe. Although most patients with AKI in our cohort had recovery of kidney function, frequent monitoring to facilitate early recognition and subsequent management of kidney complications after CD19-CAR T-cell therapy may reduce the severity of AKI in the CAYA patient population.
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CD19-specific chimeric antigen receptor (CAR) T cell therapy has changed the treatment paradigm for pediatric, adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, data on the associated infectious disease challenges in this patient population are scarce. Knowledge of infections presenting during treatment, and associated risk factors, is critical for pediatric cellular therapy and infectious disease specialists as we seek to formulate effective anti-infective prophylaxis, infection monitoring schemas, and empiric therapy regimens. In this work we describe our institutional experience in a cohort of 38 pediatric and AYA patients with CD19-positive malignancy treated with lymphodepleting chemotherapy (fludarabine/cyclophosphamide) followed by a single infusion of CD19-CAR T cells (total infusions, n=39), including tisagenlecleucel (n=19; CD19/4-1BB) or on an institutional clinical trial (n=20; CD19/4-1BB; NCT03573700). We demonstrate that infections were common in the 90 days post CAR T cells, with 19 (50%) patients experiencing a total of 35 infections. Most of these (73.7%) occurred early post infusion (day 0 to 28; infection density of 2.36 per 100 patient days-at-risk) compared to late post infusion (day 29 to 90; infection density 0.98 per 100 patient days-at-risk), respectively. Bacterial infections were more frequent early after CAR T cell therapy, with a predominance of bacterial blood stream infections. Viral infections occurred throughout the post infusion period and included primarily systemic reactivations and gastrointestinal pathogens. Fungal infections were rare. Pre-infusion disease burden, intensity of bridging chemotherapy, lymphopenia post lymphodepleting chemotherapy/CAR T cell infusion and development of CAR-associated hemophagocytic lymphohistiocytosis (carHLH) were all significantly associated with either infection density or time to first infection post CAR T cell infusion. A subset of patients (n=6) had subsequent CAR T cell reinfusion and did not appear to have increased risk of infectious complications. Our experience highlights the risk of infections after CD19-CAR T cell therapy, and the need for continued investigation of infectious outcomes as we seek to improve surveillance, prophylaxis and treatment algorithms.
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Developing CAR T cells for acute myeloid leukemia (AML) has been hampered by a paucity of targets that are expressed on AML blasts and not on hematopoietic progenitor cells (HPCs). Here we demonstrate that GRP78 is expressed on the cell surface of primary AML blasts but not HPCs. To target GRP78, we generate T cell expressing a GRP78-specific peptide-based CAR, which show evidence of minimal fratricide post activation/transduction and antigen-dependent T cell differentiation. GRP78-CAR T cells recognize and kill GRP78-positive AML cells without toxicity to HPCs. In vivo, GRP78-CAR T cells have significant anti-AML activity. To prevent antigen-dependent T cell differentiation, we block CAR signaling and GRP78 cell surface expression post activation by using dasatinib during GRP78-CAR T cell manufacturing. This significantly improves their effector function in vitro and in vivo. Thus, targeting cell surface GRP78-positive AML with CAR T cells is feasible, and warrants further active exploration.
Assuntos
Membrana Celular/metabolismo , Chaperona BiP do Retículo Endoplasmático/imunologia , Células-Tronco Hematopoéticas/imunologia , Leucemia Mieloide Aguda/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Dasatinibe/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genética , Camundongos Endogâmicos NOD , Camundongos SCID , Linfócitos T/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pediatric patients with high-risk hematologic malignancies who experience relapse after a prior allogeneic hematopoietic cell transplant (HCT) have an exceedingly poor prognosis. A second allogeneic HCT offers the potential for long-term cure but carries high risks of both subsequent relapse and HCT-related morbidity and mortality. Using haploidentical donors for HCT (haploHCT) can expand the donor pool and potentially enhance the graft-versus-leukemia effect but is accompanied by a risk of graft-versus-host disease (GVHD). The goal of this protocol was to intensify the antileukemia effect of haploHCT for pediatric patients with hematologic malignancies that relapsed after prior allogeneic HCT, while limiting regimen-associated toxicities. This phase II clinical trial evaluated a sub-myeloablative preparative regimen consisting of anti-thymocyte globulin, clofarabine, cytarabine, busulfan, and cyclophosphamide, in combination with plerixafor to sensitize leukemic blasts. Participants received a mobilized peripheral blood unmanipulated haploidentical donor graft with one dose of post-transplant cyclophosphamide as GVHD prophylaxis, followed by natural killer (NK) cell addback. Here we report the clinical outcomes and immune reconstitution of 17 participants treated on the study and 5 additional patients treated on similar single-patient treatment plans. Of the 22 participants analyzed, 12 (55%) had active disease at the time of HCT. The regimen provided robust immune reconstitution, with 21 participants (95%) experiencing neutrophil engraftment at a median of 14 days after HCT. In this high-risk population, the overall survival was 45% (95% confidence interval [CI], 24%-64%), with a 12-month event-free survival of 31% (95% CI, 14%-51%) and cumulative incidence of relapse at 12 months of 50% (95% CI, 27%-69%). Four participants (18%) remain in remission at >5 years follow-up. Expected HCT-related organ-specific toxicities were observed, and 13 participants (59%) experienced acute or chronic GVHD. This intensified but sub-myeloablative regimen, followed by a high-dose unmanipulated haploidentical graft, post-transplantation cyclophosphamide, and NK cell infusion, resulted in adequate immune reconstitution but failed to overcome the elevated risks of relapse and treatment-related morbidity in this high-risk population.
Assuntos
Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Criança , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Compostos Heterocíclicos , Humanos , RecidivaRESUMO
Outcomes for pediatric patients with acute myeloid leukemia (AML) remain poor, highlighting the need for improved targeted therapies. Building on the success of CD19-directed immune therapy for acute lymphocytic leukemia (ALL), efforts are ongoing to develop similar strategies for AML. Identifying target antigens for AML is challenging because of the high expression overlap in hematopoietic cells and normal tissues. Despite this, CD123 and CD33 antigen targeted therapies, among others, have emerged as promising candidates. In this review we focus on AML-specific T cell engaging bispecific antibodies and chimeric antigen receptor (CAR) T cells. We review antigens being explored for T cell-based immunotherapy in AML, describe the landscape of clinical trials upcoming for bispecific antibodies and CAR T cells, and highlight strategies to overcome additional challenges facing translation of T cell-based immunotherapy for AML.
RESUMO
Chimeric antigen receptor (CAR) T cells targeting CD19 have been successful treating patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL) and B cell lymphomas. However, relapse after CAR T cell therapy is still a challenge. In addition, preclinical and early clinical studies targeting acute myeloid leukemia (AML) have not been as successful. This can be attributed in part to the presence of an AML microenvironment that has a dampening effect on the antitumor activity of CAR T cells. The AML microenvironment includes cellular interactions, soluble environmental factors, and structural components. Suppressive immune cells including myeloid derived suppressor cells and regulatory T cells are known to inhibit T cell function. Environmental factors contributing to T cell exhaustion, including immune checkpoints, anti-inflammatory cytokines, chemokines, and metabolic alterations, impact T cell activity, persistence, and localization. Lastly, structural factors of the bone marrow niche, secondary lymphoid organs, and extramedullary sites provide opportunities for CAR T cell evasion by AML blasts, contributing to treatment resistance and relapse. In this review we discuss the effect of the AML microenvironment on CAR T cell function. We highlight opportunities to enhance CAR T cell efficacy for AML through manipulating, targeting, and evading the anti-inflammatory leukemic microenvironment.
RESUMO
STUDY OBJECTIVE: We sought to improve emergency care for adolescents with abnormal uterine bleeding (AUB) by developing a clinical effectiveness guideline (CEG) and assessing its effect on quality of care. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: A stakeholder engagement group designed a CEG algorithm for emergency AUB management. Pediatric residents received CEG training and their knowledge and attitudes were assessed using pre- and post intervention surveys. International Classification of Diseases ninth and 10th revision codes identified electronic health record data for patients who presented to the pediatric emergency department for AUB 6 months before and after CEG implementation. A weighted, 20-point scoring system consisting of prioritized aspects of history, laboratory studies, and management was developed to quantify the quality of care provided. MAIN OUTCOME MEASURES: Descriptive statistics, χ2 test, Wilcoxon rank sum test, and a run chart were used for analysis. RESULTS: Pediatric residents reported higher confidence and knowledge scores post CEG implementation. Of the 91 patients identified, 62 met inclusion criteria. Median score was 14 ± 7 before CEG implementation and 15.5 ± 6 after. The Wilcoxon rank sum test showed a difference in AUB evaluation and management scores (P = .09) after implementation of the CEG. Run chart data showed no shifts or trends (overall median score, 14 points). Pre- and post implementation, points were deducted most frequently for not assessing personal/family clotting disorder history. The largest improvements in care were with appropriate medication dosing and disposition. CONCLUSION: We designed a CEG and educational intervention for AUB management in a pediatric emergency department. These findings suggest our CEG might be an effective tool to improve emergency AUB care for adolescents and could increase trainees' confidence in managing this condition, although additional cycles are needed.