RESUMO
Reactivation or primary infection with double-stranded DNA viruses is common in recipients of solid organ transplants (SOTs) and is associated with significant morbidity and mortality. Treatment with conventional antiviral medications is limited by toxicities, resistance, and a lack of effective options for adenovirus (ADV) and BK polyomavirus (BKPyV). Virus-specific T cells (VSTs) have been shown to be an effective treatment for infections with ADV, BKPyV, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Most of these studies have been conducted in stem cell recipients, and no large studies have been published in the SOT population to date. In this study, we report on the outcome of quadrivalent third-party VST infusions in 98 recipients of SOTs in the context of an open-label phase 2 trial. The 98 patients received a total of 181 infusions, with a median of 2 infusions per patient. The overall response rate was 45% for BKPyV, 65% for cytomegalovirus, 68% for ADV, and 61% for Epstein-Barr virus. Twenty percent of patients with posttransplant lymphoproliferative disorder had a complete response and 40% of patients had a partial response. All the VST infusions were well tolerated. We conclude that VSTs are safe and effective in the treatment of viral infections in SOT recipients.
RESUMO
BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.
Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Transtornos Linfoproliferativos , Transtornos Mieloproliferativos , Transplante de Órgãos , Criança , Humanos , Masculino , Feminino , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Estudos Prospectivos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Linfoma não Hodgkin/complicações , Linfoma Difuso de Grandes Células B/patologia , Transtornos Mieloproliferativos/complicações , Estudos Retrospectivos , Transplante de Órgãos/efeitos adversosRESUMO
Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.
Assuntos
Linfoma de Burkitt , Transtornos Linfoproliferativos , Transplante de Órgãos , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Linfoma de Burkitt/terapia , Linfoma de Burkitt/tratamento farmacológico , Transplante de Órgãos/efeitos adversos , Ciclofosfamida/uso terapêutico , Rituximab/uso terapêutico , Prednisona/uso terapêutico , Transtornos Linfoproliferativos/etiologia , Resultado do Tratamento , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Post-transplant lymphoproliferative disease (PTLD) remains a major complication of transplantation. PTLD is a rare entity and very heterogenous making consensus on diagnosis and treatment very challenging. The majority are Epstein-Barr virus (EBV) driven, CD20+ B-cell proliferations. PTLD does occur following hematopoietic stem cell transplant (HSCT), but due to the relative short risk period and efficacy of pre-emptive therapy, PTLD following HSCT will not be discussed in this review. This review will focus on the epidemiology, role of EBV, clinical presentation, diagnosis and evaluation and the current and emerging treatment strategies for pediatric PTLD following solid organ transplantation.
Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos , Humanos , Criança , Adolescente , Adulto Jovem , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo/efeitos adversos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/etiologiaRESUMO
Multiagent immunochemotherapy affords excellent outcomes in pediatric non-Hodgkin lymphoma (NHL); however, scarce data exist for patients unfit for intensive treatment. Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is well tolerated and efficacious in elderly adults with NHL; however, its use has not been described in pediatrics. In this retrospective, single-center study, six children with mature B-cell NHL and significant comorbidities received anti-CD20 therapy with GemOx (rituximab or obinutuzumab or ofatumumab with gemcitabine and oxaliplatin [R/O-GemOx]). R/O-GemOx was well tolerated and resulted in complete response in two of three patients with newly diagnosed NHL and one of three patients with primary refractory NHL. R/O-GemOx is a viable treatment option for children with NHL who cannot tolerate intensive therapy.
Assuntos
Gencitabina , Linfoma não Hodgkin , Adulto , Humanos , Criança , Adolescente , Idoso , Rituximab , Oxaliplatina , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Desoxicitidina , Resultado do TratamentoRESUMO
CD19-directed chimeric antigen receptor T lymphocytes (CAR-T) have led to durable remissions in children with refractory and/or multiply relapsed B-lymphoblastic leukemia. For those who relapse or lose B-cell aplasia post CAR-T, the role of CAR-T reinfusion is unclear. We report two cases of durable remission with tisagenlecleucel reinfusion despite failure to achieve or maintain B-cell aplasia, and compare these cases to six additional children who received multiple tisagenlecleucel infusions at our institution. Our experience suggests that reinfusion is safe and may be a definitive therapy for a small subset of patients. Reinfusion can also reintroduce remission and/or B-cell aplasia, allowing for subsequent therapies.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Criança , Humanos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Indução de Remissão , Antígenos CD19 , Proteínas Adaptadoras de Transdução de Sinal , Imunoterapia AdotivaRESUMO
Autologous hematopoietic cell transplant (aHCT) has a significant survival advantage in patients with high-risk (HR) neuroblastoma. Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication and may result in chronic renal disease leading to delay in subsequent posttransplant therapy and limitations of treatment options. Dinutuximab represents an important therapeutic advance in the treatment of pediatric HR neuroblastoma, but historically has not been administered in patients with GFR < 60 mL/m2 /min. Here, we present the safe outcome of dinutuximab administration while on renal replacement therapy in two cases of HR neuroblastoma with end-stage renal disease secondary to TA-TMA.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Falência Renal Crônica/tratamento farmacológico , Neuroblastoma/terapia , Diálise Renal , Criança , Pré-Escolar , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/patologia , Masculino , Neuroblastoma/patologia , PrognósticoRESUMO
No guidelines exist for which intensive chemotherapy regimen is best in pediatric or young adult patients with high-risk posttransplant lymphoproliferative disorder (PTLD). We retrospectively reviewed patients with PTLD who received interval-compressed short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (SC-EPOCH) regimens at our institution. Eight patients were included with median age of 12 years. All patients achieved a complete response with a manageable toxicity profile. Two patients developed second, clonally unrelated, EBV-positive PTLD and one patient had recurrence at 6 months off therapy. No graft rejection occurred during therapy. All eight patients are alive with median follow-up of 29 months.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transtornos Linfoproliferativos , Transplante de Órgãos/efeitos adversos , Criança , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Complicações Pós-Operatórias , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Vincristina/uso terapêutico , Adulto JovemRESUMO
Autologous CD19-directed chimeric antigen receptor T lymphocyte (CAR-T) therapy is an approved and effective treatment for the management of patients with refractory and multiply relapsed B cell precursor acute lymphoblastic leukemia (B-ALL). Experience using this therapy in pediatric patients with extramedullary (EM) disease is limited, in part because these patients have frequently been excluded from clinical trials owing to concerns for an increased risk of immune effector cell-associated neurotoxicity syndrome (ICANS). We infused 7 patients with refractory or multiply relapsed B-ALL who presented with isolated EM relapse with tisagenlecleucel. Six patients had isolated central nervous system (CNS) leukemia, and 1 patient had an isolated testicular relapse. An initial complete response was seen in all patients, with 5 patients remaining in CAR-T-induced remission at a median of 18 months from first infusion. Reversible ICANS was seen in 1 patient with CNS leukemia. Durable B cell aplasia occurred in 3 patients, with a median time to B cell recovery of 6.5 months in the other patients. These data suggest that CAR-T therapy has promising safety and efficacy in treating EM leukemia, although definitive conclusions are limited by the small size of the cohort and limited follow-up period.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Antígenos CD19 , Terapia Baseada em Transplante de Células e Tecidos , Criança , Humanos , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft-versus-host disease.
Assuntos
Ataxia Telangiectasia/terapia , Reparo do DNA/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Doença de Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Linfócitos T/transplante , Ataxia Telangiectasia/etiologia , Ataxia Telangiectasia/patologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Criança , Dano ao DNA , Infecções por Vírus Epstein-Barr/virologia , Feminino , Doença de Hodgkin/etiologia , Doença de Hodgkin/patologia , Humanos , Imunoterapia/métodos , Lactente , Masculino , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Linfócitos T/imunologia , Ativação ViralRESUMO
Chimeric antigen receptor T cells (CAR-T) are an effective and potentially durable treatment for refractory and multiply relapsed B-cell acute lymphoblastic leukemia. Neurotoxicity is frequent after CAR-T cell therapy. Mechanisms driving neurotoxicity are incompletely understood, and symptoms can range from transient and mild to severe and life-threatening. Providers have exercised caution in providing CAR-T to patients with neurological comorbidities or extramedullary disease. Here, we report three patients with prior significant neurologic morbidity who safely tolerated CAR-T cell infusion after bridging therapy with conventional chemotherapy.
Assuntos
Imunoterapia Adotiva/efeitos adversos , Doenças do Sistema Nervoso , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adolescente , Criança , Pré-Escolar , Comorbidade , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapiaAssuntos
Tumor Desmoplásico de Pequenas Células Redondas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Criança , Tumor Desmoplásico de Pequenas Células Redondas/diagnóstico por imagem , Tumor Desmoplásico de Pequenas Células Redondas/metabolismo , Tumor Desmoplásico de Pequenas Células Redondas/terapia , Humanos , Masculino , Neoplasias da Glândula Submandibular/diagnóstico por imagem , Neoplasias da Glândula Submandibular/metabolismo , Neoplasias da Glândula Submandibular/terapiaRESUMO
Viral infections are a major source of morbidity and mortality in the context of immune deficiency and immunosuppression following allogeneic hematopoietic cell (allo-HCT) and solid organ transplantation (SOT). The pharmacological treatment of viral infections is challenging and often complicated by limited efficacy, the development of resistance, and intolerable side effects. A promising strategy to rapidly restore antiviral immunity is the adoptive transfer of virus-specific T cells (VST). This therapy involves the isolation and ex vivo expansion or direct selection of antigen-specific T cells from healthy seropositive donors, followed by infusion into the patient. This article provides a practical guide to VST therapy by reviewing manufacturing techniques, donor selection, and treatment indications. The safety and efficacy data of VSTs gathered in clinical trials over nearly 30 years is summarized. Current challenges and limitations are discussed, as well as opportunities for further research and development.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante de Órgãos , Sepse , Viroses , Humanos , Linfócitos T , Viroses/terapia , Transferência Adotiva/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Signaling via the intracellular second messenger cyclic AMP (cAMP) has long been implicated in the repression of megakaryocytic differentiation. However, the mechanisms by which cAMP signaling impairs megakaryopoiesis have never been elucidated. In a human CD34(+) cell culture model, we show that the adenylyl cyclase agonist forskolin inhibits megakaryocytic differentiation in a protein kinase A-dependent manner. Using this system to screen for downstream effectors, we identified the transcription factor E2A as a key target in a novel repressive signaling pathway. Specifically, forskolin acting through protein kinase A-induced E2A down-regulation and enforced expression of E2A overrode the inhibitory effects of forskolin on megakaryopoiesis. The dependence of megakaryopoiesis on critical thresholds of E2A expression was confirmed in vivo in haploinsufficient mice and ex vivo using shRNA knockdown in human progenitors. Using a variety of approaches, we further identified p21 (encoded by CDKN1A) as a functionally important megakaryopoietic regulator residing downstream of E2A. These results thus implicate the E2A-CDKN1A transcriptional axis in the control of megakaryopoiesis and reveal the lineage-selective inhibition of this axis as a likely mechanistic basis for the inhibitory effects of cAMP signaling.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , AMP Cíclico/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Megacariócitos/metabolismo , Sistemas do Segundo Mensageiro/fisiologia , Trombopoese/fisiologia , Transcrição Gênica/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/fisiologia , AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Células HEK293 , Humanos , Megacariócitos/citologia , Camundongos , Camundongos MutantesRESUMO
Inotuzumab ozogamicin (InO) is an antibody drug conjugate composed of a humanized monoclonal antibody targeting the cell surface receptor CD22 coupled to a cytotoxic calicheamicin payload via an acid labile linker. InO has shown significant activity in relapsed and refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in both single agent and combination chemotherapy regimens in adult and pediatric trials. Its use in newly diagnosed elderly patients has also been established while clinical trials investigating its use in newly diagnosed pediatric patients and fit adults are ongoing. Notable toxicities include sinusoidal obstruction syndrome (SOS), particularly in patients who undergo hematopoietic stem cell transplantation (HSCT) after InO as well as myelosuppression and B-cell aplasia which confer increased infection risk, particularly in combination with cytotoxic chemotherapy. In the relapsed/refractory (R/R) setting, the planned subsequent curative therapy modality must be considered when using InO to mitigate SOS risk if proceeding to HSCT and account for potential B-cell aplasia if proceeding to chimeric antigen receptor CAR-T therapy. Studies exploring mechanisms of resistance or failure of InO are ongoing but modulation or loss CD22 expression, alternative CD22 splicing, and high Bcl-2 expression have been implicated. In this review, we will summarize the currently available data on InO, with an emphasis on pediatric trials, and explore future directions including combinatorial therapy.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Idoso , Humanos , Criança , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals.
Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Predisposição Genética para Doença , Síndrome , Insuficiência de Múltiplos Órgãos , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genéticaRESUMO
Bridging therapy (BT) given during the period between T-cell collection and initiation of lymphodepleting chemotherapy is indicated for most children with B-cell acute lymphoblastic leukemia (B-ALL) undergoing treatment with tisagenlecleucel (tisa-cel), a CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy. Both conventional chemotherapy agents and B-cell directed antibody-based therapies such as antibody-drug conjugates and bispecific T-cell engagers have been used as systemic forms of BT. The purpose of this retrospective study was to evaluate if there are detectable differences in clinical outcomes based on the type of BT given (conventional chemotherapy or inotuzumab). A retrospective analysis was performed on all patients treated with tisa-cel at Cincinnati Children's Hospital Medical Center for B-ALL with bone marrow disease (with or without extramedullary disease). Patients who did not receive systemic BT were excluded. Only 1 patient received blinatumomab as BT and was therefore not included in this analysis to focus the analysis on the use of inotuzumab. Pre-infusion characteristics and post-infusion outcomes were collected. Fisher's exact test was used for categorical variables, and t-test or Mann-Whitney test was used for continuous parametric and non-parametric variables respectively. Mantel-Cox was used for survival analyses. Thirty-two patients received BT before CD19 CAR-T for medullary leukemia; 24 received conventional chemotherapy, and 8 received inotuzumab ozogamicin (InO). Cohorts were evenly matched regarding CAR-T indication, recipient age, and median CAR-T cell dose. There were no significant differences between the groups for attaining a minimal residual disease (MRD)-negative complete response after CAR-T, the percentage of patients who maintained prolonged B-cell aplasia, or the median duration of B-cell aplasia. Thirty-seven percent of patients in the conventional chemotherapy group and 43% in the antibody-based therapy group relapsed, with a median time to relapse in both groups of 5 months. No differences in event-free survival, the cumulative incidence of relapse, or overall survival were seen between the two groups. Initial response to tisa-cel, relapse rate, and survival were similar between patients who received BT with conventional chemotherapy or InO therapy. Because low disease burden at the time of infusion is a positive prognostic factor, choice of bridging regimen should focus on therapy that is anticipated to effectively lower disease burden and minimize treatment-related toxicity. Given the limitations associated with the single center retrospective analysis, a larger, multicenter study is needed to further explore these findings.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Criança , Inotuzumab Ozogamicina/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Estudos Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , RecidivaRESUMO
Infections with double-stranded DNA viruses are a common complication after hematopoietic stem cell transplantation (HSCT) and cause significant morbidity and mortality in the post-transplantation period. Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and young adults. Owing to a greater degree of HLA matching between the recipient and stem cell donor, DD VSTs potentially persist longer in circulation compared to TP VSTs, because they are collected from a well-matched donor. However, TP VSTs are more easily accessible, particularly for smaller transplantation centers that do not have VST manufacturing capabilities, and more economical than creating a customized product for each transplant recipient. We conducted the present study to compare clinical efficacy and safety outcomes for DD VSTs and TP VSTs in a large cohort of pediatric and young adult HSCT recipients and to determine whether DD VSTs are associated with improved outcomes owing to potentially longer persistence in the recipient's circulation. This retrospective cohort study included 145 patients who received VSTs at Cincinnati Children's Hospital Medical Center (CCHMC) between 2017 and 2021 for the treatment of adenovirus, BK virus, cytomegalovirus, and/or Epstein-Barr virus. Viruses were detected using quantitative polymerase chain reaction. Patients received VSTs on a DD (NCT02048332) or TP (NCT02532452) protocol, and VST products for both protocols were manufactured in an identical fashion. The primary study outcome was clinical response to VSTs, evaluated 4 weeks after VST administration, defined as decrease in viral load to under the inclusion thresholds, or resolution of symptoms of invasive viral infection, without the need for additional conventional antiviral medication following VST administration. Secondary outcomes included graft-versus-host-disease, transplant-associated thrombotic microangiopathy, renal function, hospital length of stay, and overall survival at 30 days and 100 days after VST administration and 1 year after HSCT. Statistical analysis was performed using the Fisher exact test or chi-square test. An unpaired t test was used to compare continuous variables. The study group comprised 77 patients in the DD cohort and 68 patients in the TP cohort. Eighteen patients in the TP cohort underwent HSCT at CCHMC, and the other 50 underwent HSCT at other institutions and presented to CCHMC solely for VST administration. There was no statistically significant difference in clinical response rates between DD and TP cohorts (65.6% versus 62.7%; odds ratio [OR], 1.162; 95% confidence interval [CI], .619 to 2.164; P = .747). There were no significant differences in secondary outcomes between the 2 cohorts. The percentage of patients requiring multiple infusions for a clinical response did not differ significantly between the DD and TP cohorts (38.2% versus 32.5%; OR, .780; 95% CI, .345 to 1.805; P = .666). We found no significant difference in clinical response rate between DD VSTs and TP VSTs and a similar safety profile. Our data suggest that TP VSTs may be sufficient to control viral infection until immune reconstitution occurs despite the potential for more rapid VST clearance compared to DD VSTs. The lack of significant differences between DD VSTs and TP VSTs is an important finding, indicating that it is not necessary for every transplant center to manufacture customized DD VSTs, and that TP VSTs are a satisfactory substitute.
Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Viroses , Criança , Humanos , Adulto Jovem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4 , Estudos Retrospectivos , Linfócitos T , Transplante Homólogo , Viroses/etiologia , Viroses/terapiaRESUMO
Chimeric antigen receptor T cells targeting CD19 (CART-19) have shown remarkable efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We investigated whether prior use of inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, may impact CAR T-cell manufacturing or efficacy via pre-CART-19 depletion of the B-cell compartment. In this international, retrospective analysis, 39 children and young adults receiving InO before (n = 12) and/or after (n = 27) T-cell apheresis as bridging therapy to CART-19 treatment were analyzed. Median age at infusion was 13 years (range 1.4-23 years). Thirty-four out of 39 patients (87.2%) obtained complete remission. With a median follow-up of 18.2 months after CART-19 infusion, 12-month event-free survival (EFS) was 53.3% (95% confidence interval (CI): 38.7-73.4) and overall survival (OS) was 77.8% (95% CI: 64.5-93.9). Seventeen patients (44%) relapsed with a median of 159 days (range 28-655) after CART-19 infusion. No difference in day 28 minimal residual disease negative complete response rate, 12-month OS/EFS, or incidence of CD19-positive or -negative relapses was observed among patients receiving InO before or after apheresis. Compared to published data for patients treated with CART-19 therapy without prior InO exposure, response and OS/EFS for patients treated with InO prior to CART-19 are similar.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Adulto Jovem , Humanos , Criança , Lactente , Pré-Escolar , Adolescente , Adulto , Inotuzumab Ozogamicina , Estudos Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Terapia Baseada em Transplante de Células e TecidosRESUMO
SRP54 mutations have recently been implicated in congenital neutropenia (CN) and the in-frame deletion, p.Thr117del, is the most common pathogenic mutation reported. The largest study of SRP54-mutated CN to-date followed 23 patients for a median of 15 years. No patients developed a hematologic malignancy in that study. Given the known risk of leukemia in other CNs it is crucial to know whether patients with SRP54-mutated CN have an increased risk of leukemia. We report the first case of leukemia in a patient with SRP54-mutated CN. A 15-year-old male with SRP54-mutated CN (p.Thr117del) was diagnosed with acute myeloid leukemia with myelodysplasia-related changes on a screening bone marrow evaluation. Next generation sequencing of the leukemia cells identified CSF3R and RUNX1 mutations. These mutations commonly co-exist in CN-associated malignancies and suggest leukemogenesis in SRP54-mutated CN may occur in a similar manner to other CNs. He was successfully treated with CPX-351 followed by hematopoietic cell transplant (HCT) and remains in remission at a follow-up time of 9 months. Although conclusions from this single report must be limited, this has potentially significant implications for both screening and treatment practices for these patients, including the role and timing of HCT.