RESUMO
Gemtuzumab ozogamicin (GO) is a CD33 monoclonal antibody-drug conjugate currently in use to treat myeloid malignancies. A unique adverse effect of this medication is destruction of CD33 positive macrophages resulting in reduced clearance of free hemoglobin leading to grossly red plasma. This build-up of free hemoglobin can potentially lead to end organ damage and prevent performance of clinically necessary laboratory evaluation. We present a case of a pediatric patient who developed this adverse effect and was successfully treated with therapeutic plasma exchange (TPE). We also present results from a systematic review of the medical literature and share data from a query of the United States Food and Drug Administration (FDA) Adverse Event Reporting system for GO-related hemoglobin scavenging impairment. Among reported cases, patients undergoing TPE and those receiving steroids had improved outcomes. Practitioners should be aware of this rare drug side-effect and the potential utility of TPE for these patients.
Assuntos
Gemtuzumab , Hemoglobinas , Troca Plasmática , Humanos , Gemtuzumab/uso terapêutico , Troca Plasmática/métodos , Hemoglobinas/análise , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Masculino , Aminoglicosídeos/efeitos adversos , Feminino , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
T/myeloid mixed phenotype acute leukaemia (MPAL) is a rare aggressive acute leukaemia with poorly understood pathogenesis. Herein, we report two cases of T/myeloid MPAL harbouring BCL11B-associated structural variants that activate TLX3 (TLX3::BCL11B-TLX3-activation) by genome sequencing and transcriptomic analyses. Both patients were young males with extramedullary involvement. Cooperative gene alterations characteristic of T/myeloid MPAL and T-lymphoblastic leukaemia (T-ALL) were detected. Both patients achieved initial remission following lineage-matched ALL-based therapy with one patient requiring a lineage-switched myeloid-based therapy. Our study is the first to demonstrate the clinicopathological and genomic features of TLX3::BCL11B-TLX3-activated T/myeloid MPAL and provide insights into leukaemogenesis.
Assuntos
Proteínas Repressoras , Humanos , Masculino , Proteínas Repressoras/genética , Adulto , Proteínas de Fusão Oncogênica/genética , Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/patologia , Proteínas Supressoras de Tumor/genética , Proteínas de Homeodomínio/genéticaRESUMO
Improvements in survival have been made over the past two decades for childhood acute myeloid leukemia (AML), but the approximately 40% of patients who relapse continue to have poor outcomes. A combination of checkpoint-inhibitor nivolumab and azacitidine has demonstrated improvements in median survival in adults with AML. This phase I/II study with nivolumab and azacitidine in children with relapsed/refractory AML (NCT03825367) was conducted through the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium. Thirteen patients, median age 13.7 years, were enrolled. Patients had refractory disease with multiple reinduction attempts. Twelve evaluable patients were treated at the recommended phase II dose (established at dose level 1, 3 mg/kg/dose). Four patients (33%) maintained stable disease. This combination was well tolerated, with no dose-limiting toxicities observed. Grade 3-4 adverse events (AEs) were primarily hematological. Febrile neutropenia was the most common AE ≥ grade 3. A trend to improved quality of life was noted. Increases in CD8+ T cells and reductions in CD4+/CD8+ T cells and demethylation were observed. The combination was well tolerated and had an acceptable safety profile in pediatric patients with relapsed/refractory AML. Future studies might explore this combination for the maintenance of remission in children with AML at high risk of relapse.
RESUMO
BACKGROUND: The potential for cefepime prophylaxis to reduce bloodstream infections (BSIs) in pediatric patients with acute myelogenous leukemia (AML) has been incompletely characterized. METHODS: A retrospective quasi-experimental study of patients under 21 years of age admitted with AML from 2010 through 2018 at two affiliated pediatric tertiary-care hospitals before and after the adoption of routine cefepime prophylaxis for afebrile AML patients during profound neutropenia. RESULTS: The rate of BSIs per 1000 neutropenia days was significantly lower in the prophylaxis group than the baseline group (2.6 vs 15.5, incidence rate ratio [IRR] 0.17, 95% CI 0.09-0.32). Interrupted time-series analysis showed that a sharp reduction in BSIs coincided with the implementation of prophylaxis. Bacteremia with viridans group streptococci was frequent in the baseline group but not observed after adopting prophylaxis. Despite the increased use of cefepime, the rate of cefepime-nonsusceptible BSIs per 1000 neutropenia days decreased (1.6 vs 4.1, IRR 0.40, 95% CI 0.16-0.99). The median number of febrile neutropenia episodes per patient also decreased in the prophylaxis group, as did the proportion of patients admitted to the intensive care unit (ICU) (22/51 (43.1%) vs 26/38 (68.4%); risk difference -25.3%, 95% CI -44.4 to -2.8). A trend was observed toward an increased proportion of patients with Clostridioides difficile infection in the prophylaxis group (10/51 (19.6%) vs 3/38 (7.9%); risk difference 11.7%, 95% CI -3.4 to 29.0). CONCLUSIONS: Cefepime prophylaxis was associated with a significant reduction in BSIs, febrile neutropenia, and ICU admission among pediatric AML patients.
Assuntos
Neutropenia Febril , Leucemia Mieloide Aguda , Sepse , Humanos , Criança , Cefepima/uso terapêutico , Estudos Retrospectivos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
BACKGROUND: Patients with hematological malignancies and hematopoietic stem cell transplantation (HSCT) recipients are at risk of developing invasive fungal infections, but the quantitative risk posed by exposure to airborne mold spores in the community has not been well characterized. METHODS: A single-institution, retrospective cohort study was conducted of pediatric patients treated for hematological malignancies and HSCT recipients between 2014 and 2018. Patients with invasive fungal disease (IFD) due to molds or endemic fungi were identified using published case definitions. Daily airborne mold spore counts were obtained from a local National Allergy Bureau monitoring station and tested for association with IFD cases by 0-inflated Poisson regression. Patients residing outside the region or with symptom onset more than 2 weeks after admission were excluded from the primary analysis. RESULTS: Sixty cases of proven or probable IFD were identified, of whom 47 cases had symptom onset within 2 weeks of admission and were therefore classified as possible ambulatory onset. The incidence of ambulatory-onset IFD was 1.2 cases per 10000 patient-days (95% CI, 0.9-1.7). A small excess of ambulatory-onset IFD was seen from July through September, during which period spore counts were highest, but this seasonal pattern did not reach statistical significance (Pâ =â .09). No significant association was found between IFD cases and community mold spore counts over intervals from 1 to 6 weeks before symptom onset. CONCLUSIONS: There was no significant association between IFD cases and community airborne mold spore counts among pediatric hematological malignancy and HSCT patients in this region.
RESUMO
BACKGROUND: Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML. METHODS: In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles. The primary endpoint was rate of complete response (CR) and CR with incomplete blood count recovery (CRi) within the first four cycles. RESULTS: Seventeen patients enrolled and received one or more dose of lenalidomide. Median age was 12 years (range 5-18 years), median white blood cell count was 3.7 × 109 /L, and median peripheral blood blast count was 1.0 × 109 /L. One patient (5.9%) with a complex karyotype including del(5q) achieved CRi after two cycles of lenalidomide. This responder proceeded to a second hematopoietic stem cell transplantation and has remained without evidence of disease for 3 years. All patients experienced one or more of grades 3-4 treatment-emergent adverse event (TEAE). The most common grades 3-4 TEAEs were thrombocytopenia (58.8%), febrile neutropenia (47.1%), anemia (41.2%), and hypokalemia (41.2%). CONCLUSIONS: In this population of pediatric patients with R/R AML, safety data were consistent with the known safety profile of lenalidomide. As only one patient responded, further evaluation of lenalidomide at the dose and schedule studied is not warranted in pediatric AML, with the possible exception of patients with del(5q).
Assuntos
Lenalidomida/uso terapêutico , Leucemia Mieloide Aguda , Adolescente , Idoso , Criança , Pré-Escolar , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma Folicular , Indução de Remissão , Resultado do TratamentoRESUMO
New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.
Assuntos
Jejum/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores para Leptina/metabolismo , Fatores de Transcrição/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Simulação por Computador , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias , Fator 1 de Ligação ao Domínio I Regulador Positivo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Receptores para Leptina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
BACKGROUND: Central venous access devices (CVADs) play an important role in the management of pediatric oncology patients; unfortunately, they are also associated with potentially serious complication rates. We hypothesized that, despite the significantly different disease courses typical of acute lymphoblastic leukemia and acute myelogenous leukemia, there would be identifiable risk factors for premature CVAD removal. METHODS: We retrospectively studied clinical characteristics and procedure records for all patients admitted with a leukemia diagnosis at our institution from May 2009 to July 2014. RESULTS: Our observed perioperative complication rate was 6%; over 70% of lines had at least one long-term complication (thrombosis, catheter-related bloodstream infection, or unexplained line malfunction). Obesity (odds ratio [OR], 6.9; 95% CI, 1.62-29.43), preoperative dosage of packed red blood cells (in mL/kg; OR, 3.13; 1.07-9.21), bloodstream infection (OR, 5.75; 1.69-19.56) were associated with increased risk of premature catheter removal; unexplained malfunction was associated with a lower risk (OR, 0.28; 0.09-0.93). CONCLUSIONS: Obesity, the preoperative dosage of packed red blood cells, the presence of a bloodstream infection, and unexplained line malfunction are significant predictors of premature CVAD removal in a pediatric leukemia population.
Assuntos
Infecções Relacionadas a Cateter/etiologia , Cateterismo Venoso Central/instrumentação , Cateteres Venosos Centrais/efeitos adversos , Falha de Equipamento/estatística & dados numéricos , Leucemia Mieloide Aguda/terapia , Complicações Pós-Operatórias/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Infecções Relacionadas a Cateter/epidemiologia , Cateterismo Venoso Central/efeitos adversos , Criança , Pré-Escolar , Remoção de Dispositivo/estatística & dados numéricos , Feminino , Humanos , Lactente , Masculino , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
We describe a case of acute leukemia of ambiguous lineage with a novel cytogenetic abnormality. A 1-year-old boy presented with abnormal complete blood count findings, and was found to have blasts and mild dysgranulopoiesis. The blasts showed immunophenotypic evidence of myeloid and T-lineage differentiation. Subsequent cytogenetic analysis showed r(2)(p25q31) as the sole stem line cytogenetic defect with clonal evolution. While cytogenetic abnormalities can have a critical role in the classification and prognostication of acute lymphoblastic and acute myeloid leukemia, the significance of cytogenetic abnormalities in acute leukemia of ambiguous lineage remains unclear. This finding has not been reported previously to the best of our knowledge.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 2 , Leucemia/diagnóstico , Leucemia/genética , Medula Óssea/patologia , Linhagem da Célula , Citometria de Fluxo , Humanos , Imunofenotipagem , Lactente , Cariotipagem , MasculinoRESUMO
BACKGROUND: Subclinical cardiotoxicity occurs in childhood cancer survivors following moderate and high anthracycline doses. However, less is known about the subclinical changes in left ventricular (LV) structure that occur after very low anthracycline doses of ≤ 100 mg/m(2). This study was designed to assess LV function and key structural parameters following very low doses of anthracycline. PROCEDURE: Conventional 2-dimensional echocardiograms with Doppler were obtained in 91 survivors of childhood cancer exposed to ≤ 100 mg/m(2), an average of 9.8 years from diagnosis. LV structural measurements were converted into Z-scores. The Z-score distributions were compared to those of the normal population. Diastolic and systolic function were quantified. RESULTS: The cohort demonstrated a decreased posterior wall thickness (mean Z-score -1.01) and mildly decreased LV end diastolic (mean Z-score -0.85) and systolic (mean Z-score -0.84) dimensions compared to the normal population (P < 0.001). Further, 28% of patients (n = 25) had abnormal LV posterior wall thickness, ≥ 2 standard deviations below the mean (Z-score ≤ -2). There were no patients with diastolic dysfunction or symptomatic systolic dysfunction, however four patients demonstrated abnormal SF ≤ 28%. CONCLUSIONS: A significant proportion of patients exposed to very low doses of anthracycline demonstrate subclinical abnormalities in LV structure, despite the absence of radiation or other risk factors. While we cannot say whether these structural changes will result in clinically significant cardiac disease, the reported progressive nature of these findings raises concern that there may truly be no safe dose of anthracycline.
Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Sobreviventes , Função Ventricular Esquerda/efeitos dos fármacos , Adolescente , Adulto , Criança , Estudos de Coortes , Estudos Transversais , Ecocardiografia , Feminino , Seguimentos , Humanos , Masculino , Neoplasias/mortalidade , Neoplasias/patologia , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Specific hospital discharge criteria following the initial diagnosis of children with acute lymphoblastic leukemia (ALL) have not been reported. This retrospective cohort study was designed to identify risk factors for readmission during induction therapy, to assist with development of discharge guidelines. PROCEDURE: We reviewed the records of 142 consecutive children with newly diagnosed B-precursor ALL and found 129 eligible patients. Chi square, t-test, and multivariate logistic regression analysis were used to compare differences in absolute neutrophil count (ANC), NCI risk status, age, type of corticosteroid administered, and other potential risk factors for readmission during induction therapy. RESULTS: ANC at initial hospital discharge was the only significant predictor of readmission for fever during induction therapy (P = 0.006) by multivariate analysis. Specifically an ANC