RESUMEN
HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/µL, 1 points), absolute B-cell counts (<100/µL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.
Asunto(s)
COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , Anticuerpos Antivirales , Formación de Anticuerpos , COVID-19/prevención & control , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Pueblos del Este de Asia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , ARN Mensajero , SARS-CoV-2 , Receptores de Trasplantes , Vacunación , JapónRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival for patients with hematological malignancy, especially for those highly at risk of relapse. However, disease relapse after allo-HSCT remains the most common cause of treatment failure and death, even with conventional chemotherapy and donor lymphocyte infusion. Disease relapse in allo-HSCT can be reduced via pre-emptive treatment based on measurable residual disease and maintenance therapy for patients at high risk of relapse as promising treatment strategies. Recently, the development of novel agents and cellular therapies with high antitumor activity and less toxicity, which can be used in the post-transplant setting, has increased their clinical applications in the therapeutic approach. This review examines the current landscape and future strategies for maintenance therapy, mainly for AML and ALL after allo-HSCT.
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Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Recurrencia Local de Neoplasia , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography-tandem mass spectrometry. METHODS: Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 µm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode. RESULTS: The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10-1000 ng/mL, r 2 > 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias -4.2% to 1.9%), precision (intraday CV ≤ 7.9%; interday CV ≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML. CONCLUSIONS: The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.
Asunto(s)
Leucemia Mieloide Aguda , Espectrometría de Masas en Tándem , Compuestos de Anilina , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Límite de Detección , Mutación , Pirazinas , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/uso terapéuticoRESUMEN
Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Trastornos Linfoproliferativos/tratamiento farmacológico , Metotrexato/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Quinasas Janus/antagonistas & inhibidores , Estimación de Kaplan-Meier , Linfoma no Hodgkin/mortalidad , Trastornos Linfoproliferativos/inducido químicamente , Trastornos Linfoproliferativos/mortalidad , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Prednisona/administración & dosificación , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Rituximab/administración & dosificación , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.
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Trasplante de Células Madre Hematopoyéticas/tendencias , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante/tendencias , Adolescente , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Retratamiento/mortalidad , Retratamiento/tendencias , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Acondicionamiento Pretrasplante/mortalidad , Resultado del Tratamiento , Adulto JovenRESUMEN
The etiology and pathogenesis of acute myeloid leukemia (AML) have been elucidated at chromosomal and genetic levels. The classification and prognosis for its treatment has clearly involved specific chromosomal aberrations and genetic mutations. The recent comprehensive genomic analysis represented by next-generation sequencers has led to discovering new genetic mutations in AML. These findings have not only been applied clinically as prognostic factors and MRD markers but also contributed to the development of new molecular-targeting drugs. Many new drugs have already been approved in the USA and Europe, and new stratified treatments have tried to incorporate them. With the advent of venetoclax, treatment strategies, especially for patients with poor prognosis and who are unfit, have been substantially revised, and the maintenance therapy for AML is also being reevaluated in accordance to the National Comprehensive Cancer Network guidelines. This article will review the current status of AML treatment in Japan and according to Western guidelines.
Asunto(s)
Leucemia Mieloide Aguda , Aberraciones Cromosómicas , Genómica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , PronósticoRESUMEN
Schizophyllum commune, a basidiomycete fungus, is a quite rare cause of invasive sinusitis for which no standard treatment has yet been established. We report herein a 59-year-old woman who developed S. commune rhinosinusitis after remission induction chemotherapy for her acute myeloid leukemia. No causative microorganisms were identified in the sinus lavage fluid culture, whereas nucleotide sequencing of the internal transcribed spacer region using endoscopic sinus biopsy specimen could confirm the pathogen as S. commune. Liposomal amphotericin B and voriconazole (VRCZ) treatment ameliorated both her clinical symptoms and laboratory findings. The patient was successfully treated with allogeneic stem cell transplantation, under continuous VRCZ administration, without aggravation of S. commune sinusitis. Molecular diagnosis and prompt intervention with suitable antifungal drugs may be crucial to manage this rare infectious complication.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Infecciones Fúngicas Invasoras/complicaciones , Leucemia Mieloide Aguda/terapia , Rinitis/microbiología , Schizophyllum/patogenicidad , Sinusitis/microbiología , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/microbiología , Leucemia Mieloide Aguda/complicaciones , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Rinitis/complicaciones , Rinitis/diagnóstico , Rinitis/tratamiento farmacológico , Schizophyllum/genética , Schizophyllum/aislamiento & purificación , Sinusitis/complicaciones , Sinusitis/diagnóstico , Sinusitis/tratamiento farmacológico , Trasplante Homólogo , Resultado del Tratamiento , Voriconazol/uso terapéuticoRESUMEN
Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.
Asunto(s)
Inhibidores de la Calcineurina/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped/prevención & control , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Ácido Micofenólico/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Calcineurina/administración & dosificación , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/terapia , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Incidencia , Infecciones/epidemiología , Infecciones/etiología , Japón/epidemiología , Estimación de Kaplan-Meier , Recuento de Leucocitos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Neutrófilos , Recuento de Plaquetas , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor-induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve-related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve-related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; Pâ¯=â¯.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; Pâ¯=â¯.036), whereas there was no significant difference among the latter 2 groups (Pâ¯=â¯.889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve-related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.
Asunto(s)
Inhibidores de la Calcineurina/efectos adversos , Encefalitis Viral/etiología , Herpesvirus Humano 6/patogenicidad , Dolor/inducido químicamente , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/patología , Adulto JovenRESUMEN
Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.
Asunto(s)
Bacteriemia/etiología , Tracto Gastrointestinal/patología , Enfermedad Injerto contra Huésped/complicaciones , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Bacteriemia/patología , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Chemotherapy-induced nausea and vomiting (CINV) are generally evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). The Multinational Association for Supportive Care in Cancer (MASCC) developed the MASCC Antiemesis Tool (MAT) to facilitate recognition for CINV between patients and oncology specialists. In the present study, MAT and CTCAE were comparatively assessed in Japanese patients with hematological malignancies. A total of 61 patients were eligible for this study. The CTCAE data were collected from an electronic medical record system. The patients were asked to complete the Japanese version of MAT in the hospital, on the first and fourth days after the start of chemotherapy. The percentages of patients in whom nausea was completely controlled, with severity scores of zero, ranged from 70.5 to 82.0% for CTCAE and from 59.0 to 75.4% for MAT, during the first five days after the chemotherapy. The percentages of patients who had no vomiting ranged from 93.4 to 96.7% for CTCAE and from 90.2 to 98.4% for MAT. During the observation periods, the day-to-day response profiles of patients who received antiemetic treatment were comparable between CTCAE and MAT cohorts, and these two assessment tools showed good, positive correlations for nausea severity scores. The present study shows that the MAT is a useful tool for assessing the severity of CINV in patients with hematological malignancy, is comparable to CTCAE, and facilitates the identification of poor cancer care conditions by medical staff.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias Hematológicas/tratamiento farmacológico , Náusea/inducido químicamente , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Vómitos/inducido químicamente , Adulto , Anciano , Antieméticos/uso terapéutico , Femenino , Hospitales , Humanos , Japón , Masculino , Persona de Mediana Edad , Náusea/prevención & control , Vómitos/prevención & control , Adulto JovenRESUMEN
The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib (PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50 and 100 mg) in 28-day cycles after a lead-in dose on Day -5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in the present study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia (n = 9), muscle spasms (n = 5), alopecia, decreased appetite (n = 4 each), and increased blood creatinine phosphokinase, constipation and diarrhea (n = 3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial.
Asunto(s)
Antineoplásicos/administración & dosificación , Bencimidazoles/administración & dosificación , Neoplasias Hematológicas/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Proteína con Dedos de Zinc GLI1/genética , Administración Oral , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hematológicas/genética , Humanos , Japón , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacología , Resultado del TratamientoRESUMEN
Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.
Asunto(s)
Anticuerpos Monoclonales Humanizados/toxicidad , Enfermedad Injerto contra Huésped/inducido químicamente , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia-Linfoma de Células T del Adulto/complicaciones , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Enfermedad Aguda , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/terapia , Masculino , Persona de Mediana Edad , Inducción de Remisión/métodos , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante HomólogoAsunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Portador Sano/diagnóstico , Infecciones por HTLV-I/diagnóstico , Virus Linfotrópico T Tipo 1 Humano/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Infecciones Asintomáticas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Portador Sano/sangre , Portador Sano/inmunología , Portador Sano/virología , Estudios de Seguimiento , Anticuerpos Anti-HTLV-I/sangre , Anticuerpos Anti-HTLV-I/inmunología , Infecciones por HTLV-I/inducido químicamente , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Receptor de Muerte Celular Programada 1/inmunología , Estudios RetrospectivosRESUMEN
The introduction of reduced-intensity conditioning (RIC) regimens has made possible allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML). However, the optimal timing of allo-HCT in these patients and its relative risks and benefits when compared with chemotherapies have not been determined. This retrospective study by the Fukuoka Blood and Marrow Transplant Group compared RIC allo-HSCT with non-transplant therapies, the choice based on donor availability, in AML patients in their first complete remission (CR1). The prognostic value of various patient characteristics and disease-specific variables were investigated in 299 patients aged ≥60 years with AML in CR1. Among the 107 patients aged 60-65 years, 54 of whom received allo-HCT and 53 of whom continued chemotherapies; allo-HCT, adverse-risk group, and hematopoietic cell transplantation-comorbidity index were significant predictors of survival outcomes. Among 192 patients aged ≥66 years deemed ineligible for allo-HCT, relapse and Karnofsky performance status after induction therapy were significant predictors of survival outcomes. Findings from this study may facilitate a new standard of care for older AML patients in CR1 who are considered candidates for allo-HCT.
Asunto(s)
Análisis Citogenético/métodos , Determinación de la Elegibilidad/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión/métodos , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodosRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.
Asunto(s)
Antígeno CD47/metabolismo , Citofagocitosis/inmunología , Regulación hacia Abajo , Células Madre Hematopoyéticas/metabolismo , Linfohistiocitosis Hemofagocítica/etiología , ADP-Ribosil Ciclasa 1/metabolismo , Adolescente , Adulto , Anciano , Antígenos CD34/metabolismo , Antígenos de Diferenciación/genética , Antígeno CD47/genética , Línea Celular , Citocinas/farmacología , Regulación hacia Abajo/efectos de los fármacos , Humanos , Mediadores de Inflamación/farmacología , Activación de Macrófagos/inmunología , Macrófagos/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Mutación , Interferencia de ARN , Receptores Inmunológicos/genética , Adulto JovenRESUMEN
Infection is a major contributor to non-relapse mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Detecting infectious diseases in febrile patients during pretransplant conditioning is crucial for subsequent transplant success. Procalcitonin (PCT) is an auxiliary diagnostic marker of severe bacterial infections and has been proposed as a useful predictor of infection in patients undergoing allo-HSCT. Pre-transplant use of anti-thymocyte globulin (ATG) can cause side effects, such as fever and hypotension, which must be distinguished from infectious diseases. Although ATG administration may increase PCT levels, data on PCT levels in febrile patients after ATG administration are limited. Furthermore, no studies have compared PCT levels during allo-HSCT conditioning using ATG or non-ATG regimens. To investigate whether ATG increases PCT levels during febrile episodes in pre-transplant conditioning and whether PCT could be used to discriminate infections during this period, we analyzed 17 ATG and 59 non-ATG patients with fever and who underwent PCT level measurements during pre-transplant conditioning. Our findings revealed that ATG administration was the only significant factor that increased PCT positivity during fever (p = 0.01). In contrast, infectious diseases did not affect PCT positivity in the ATG group (p = 0.24). Furthermore, bloodstream infection was a significant risk factor for PCT positivity in patients who received non-ATG regimens (p < 0.01). Incorporating PCT levels into the diagnostic workup for infectious diseases requires careful consideration, particularly for patients receiving ATG regimens.
RESUMEN
The "human leukocyte antigen (HLA) supertype" is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Humanos , Pronóstico , Estudios Retrospectivos , Antígenos HLA , Antígenos de Histocompatibilidad , Antígenos HLA-B/genética , Recurrencia , Alelos , Prueba de HistocompatibilidadRESUMEN
Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34+ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.