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Background & aims: Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications. Methods: DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant. Results: We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications. Conclusions: The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348).
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We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Condicionamento Pré-Transplante , Doadores não RelacionadosRESUMO
Background: Allogeneic hematopoietic cell transplantation is indicated for refractory hematologic cancer and some nonmalignant disorders. Survival is limited by recurrent cancer and organ toxicity. Objective: To determine whether survival has improved over the past decade and note impediments to better outcomes. Design: The authors compared cohorts that had transplants during 2003 to 2007 versus 2013 to 2017. Survival outcome measures were analyzed, along with transplant-related complications. Setting: A center performing allogeneic transplant procedures. Participants: All recipients of a first allogeneic transplant during 2003 to 2007 and 2013 to 2017. Intervention: Patients received a conditioning regimen, infusion of donor hematopoietic cells, then immunosuppressive drugs and antimicrobial approaches to infection control. Measurements: Day-200 nonrelapse mortality (NRM), recurrence or progression of cancer, relapse-related mortality, and overall mortality, adjusted for comorbidity scores, source of donor cells, donor type, patient age, disease severity, conditioning regimen, patient and donor sex, and cytomegalovirus serostatus. Results: During the 2003-to-2007 and 2013-to-2017 periods, 1148 and 1131 patients, respectively, received their first transplant. Over the decade, decreases were seen in the adjusted hazards of day-200 NRM (hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.89]), relapse of cancer (HR, 0.76 [CI, 0.61 to 0.94]), relapse-related mortality (HR, 0.69 [CI, 0.54 to 0.87]), and overall mortality (HR, 0.66 [CI, 0.56 to 0.78]). The degree of reduction in overall mortality was similar for patients who received myeloablative versus reduced-intensity conditioning, as well as for patients whose allograft came from a matched sibling versus an unrelated donor. Reductions were also seen in the frequency of jaundice, renal insufficiency, mechanical ventilation, high-level cytomegalovirus viremia, gram-negative bacteremia, invasive mold infection, acute and chronic graft-versus-host disease, and prednisone exposure. Limitation: Cohort studies cannot determine causality, and current disease severity criteria were not available for patients in the 2003-to-2007 cohort. Conclusion: Improvement in survival and reduction in complications were substantial after allogeneic transplant. Relapse of cancer remains the largest obstacle to better survival outcomes. Primary Funding Source: National Institutes of Health.
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Transplante de Células-Tronco Hematopoéticas/mortalidade , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/terapia , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Modelos de Riscos Proporcionais , Recidiva , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
Mortality from cytomegalovirus disease after marrow transplantation can be reduced by treatment with antiviral drugs based on the detection of viremia and organ involvement. We examined autopsy liver specimens to determine the frequency, extent and outcome of cytomegalovirus hepatitis and whether cytomegalovirus hepatitis occurred in the absence of cytomegalovirus disease elsewhere. Autopsy specimens from 50 transplant patients were evaluated for cytomegalovirus-infected cells, in five groups of 10, according to extent of CMV during life and at autopsy. Liver sections were examined by routine light microscopy, immunohistochemistry and in situ DNA hybridization. Clinical and laboratory data collected during the last 30 days of life were analysed as markers of liver cytomegalovirus infection. Cytomegalovirus-infected cells were detected in the livers of 10/10 patients with cytomegalovirus infection during life and widespread cytomegalovirus at autopsy; in 3/20 livers from patients with cytomegalovirus infection during life but negative liver cultures at autopsy; and in 1/10 livers from cytomegalovirus-seropositive patients who had been without other evidence of cytomegalovirus infection. Histology detected a lower density of cytomegalovirus-bearing cells per unit area of liver, compared to immunohistochemistry and in situ hybridization. No cytomegalovirus-infected cells were detected in livers from cytomegalovirus-seronegative controls. No distinctive clinical or laboratory findings correlated with liver cytomegalovirus detection. CMV liver disease is common in allografted patients with disseminated CMV but may rarely be isolated to the liver, best demonstrated with IHC and ISH. Massive hepatic necrosis from CMV was not seen in any autopsy liver in this study.
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Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Citomegalovirus , Hepatite Viral Humana/diagnóstico , Hepatite Viral Humana/etiologia , Adulto , Autopsia , Transplante de Medula Óssea/métodos , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/mortalidade , DNA Viral , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Hepatite Viral Humana/metabolismo , Hepatite Viral Humana/mortalidade , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Índice de Gravidade de DoençaRESUMO
Sirolimus-based graft vs. host disease (GVHD) prophylaxis is associated with higher incidence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after allogeneic hematopoietic cell transplantation (HCT). However, whether the clinical manifestations and prognosis of VOD/SOS differs when diagnosed in the setting of sirolimus-based GVHD prophylaxis is not well studied. To address this question, we examined presenting features and treatment outcome of VOD/SOS cases identified in a large retrospective cohort of consecutive HCT procedures (n = 818 total, sirolimus (SIR)/tacrolimus (TAC) n = 308, and methotrexate (MTX) or mycophenolate mofetil (MMF)/TAC n = 510). In multivariate analysis, sirolimus-based GVHD prophylaxis (p = 0.006, HR 3.33, 1.94-5.7) increased risk for VOD/SOS. A total of 58 patients were clinically diagnosed with VOD/SOS (SIR/TAC 38/308, 12.3%, vs. MTX or MMF/TAC 20/510, 3.9%). VOD/SOS diagnosed following SIR/TAC prophylaxis demonstrated later time of onset (median 39 vs. 26 days; p = 0.005), less severe hyperbilirubinemia (Bili > 2, 65% vs. 90% p = 0.04), lesser degree of weight gain (weight gain > 5%, 52% vs 80%, p = 0.04), and more frequent complete resolution of hepatic injury (79% vs. 55%, p = 0.05). Presenting features and natural history of VOD/SOS in the context of SIR/TAC GVHD prophylaxis differ and thus warrant particular clinical attention to later hepatic injury in these patients.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Sirolimo/efeitos adversos , Adulto , Idoso , Aloenxertos , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Hepatopatia Veno-Oclusiva/sangue , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sirolimo/administração & dosagemRESUMO
Treatment of hematological malignancy with antibody-drug conjugates (ADCs) may cause liver injury. ADCs deliver a toxic moiety into antigen-expressing tumor cells, but may also injure hepatic sinusoids (sinusoidal obstruction syndrome; SOS). We studied patients who received an anti-CD22/calicheamicin conjugate (inotuzumab ozogamicin; InO) to gain insight into mechanisms of sinusoidal injury, given that there are no CD22+ cells in the normal liver, but nonspecific uptake of ADCs by liver sinusoidal endothelial cells (LSECs). Six hundred thirty-eight patients (307 with acute lymphocytic leukemia [ALL], 311 with non-Hodgkin's lymphoma [NHL]) were randomized to either InO or standard chemotherapy (controls). While blinded to treatment assignment, we reviewed all cases with hepatobiliary complications to adjudicate the causes. Frequency of SOS among patients who received InO was 5 of 328 (1.5%), compared to no cases among 310 control patients. Drug-induced liver injury (DILI) developed in 26 (7.9%) InO recipients and 3 (1%) controls. Intrahepatic cholestasis (IHC) was observed in 4.9% of InO recipients and in 5.5% of controls. Subsequent to the randomization study, 113 patients with ALL underwent allogeneic hematopoietic cell transplantation (HCT); frequency of SOS in those previously exposed to InO was 21 of 79 (27%) versus 3 of 34 (9%) in controls. An exploratory multivariate model identified a past history of liver disease and thrombocytopenia before conditioning therapy as dominant risk factors for SOS after transplant. Conclusion: Frequencies of SOS and DILI after inotuzumab ozogamicin treatment were 1.5% and 7.9%, respectively, compared to none and 1% among controls who received standard chemotherapy. These data suggest that ADCs that do not target antigens present in the normal liver have a relatively low frequency of SOS, but a relatively high frequency of DILI.
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Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Inotuzumab Ozogamicina/efeitos adversos , Linfoma não Hodgkin/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Gastroenterologistas , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva/etiologia , HumanosRESUMO
BACKGROUND AND OBJECTIVES: Kidney injury is a significant complication for patients undergoing hematopoietic cell transplantation (HCT), but few studies have prospectively examined changes in GFR in long-term survivors of HCT. We described the association between changes in GFR and all-cause mortality in patients up to 10 years after HCT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective, observational cohort study of adult patients undergoing HCT at the Fred Hutchinson Cancer Center in Seattle, Washington from 2003 to 2015. Patients were followed from baseline, before conditioning therapy, until a maximum of 10 years after transplant. We used Cox proportional hazard models to examine the association between creatinine eGFR and all-cause mortality. We used time-dependent generalized estimating equations to examine risk factors for decreases in eGFR. RESULTS: A total of 434 patients (median age, 52 years; range, 18-76 years; 64% were men; 87% were white) were followed for a median 5.3 years after HCT. The largest decreases in eGFR occurred within the first year post-transplant, with the eGFR decreasing from a median of 98 ml/min per 1.73 m2 at baseline to 78 ml/min per 1.73 m2 by 1 year post-HCT. Two thirds of patients had an eGFR<90 ml/min per 1.73 m2 at 1 year after transplant. When modeled as a continuous variable, as eGFR declined from approximately 60 ml/min per 1.73 m2, the hazard of mortality progressively increased relative to a normal eGFR of 90 ml/min per 1.73 m2 (P<0.001). For example, when compared with an eGFR of 90 ml/min per 1.73 m2, the hazard ratios for eGFR of 60, 50, and 40 ml/min per 1.73 m2 are 1.15 (95% confidence interval, 0.87 to 1.53), 1.68 (95% confidence interval, 1.26 to 2.24), and 2.67 (95% confidence interval, 1.99 to 3.60), respectively. Diabetes, hypertension, acute graft versus host disease, and cytomegalovirus infection were independently associated with a decline in GFR, whereas calcineurin inhibitor levels, chronic graft versus host disease, and albuminuria were not. CONCLUSIONS: Adult HCT recipients have a high risk of decreased eGFR by 1 year after HCT. Although eGFR remains fairly stable thereafter, a decreased eGFR is significantly associated with higher risk of mortality, with a progressively increased risk as eGFR declines.
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Taxa de Filtração Glomerular , Transplante de Células-Tronco Hematopoéticas/mortalidade , Adolescente , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/etiologia , Adulto JovemRESUMO
Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3) in the duodenum or colon. We observed that 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with extensive mucosal injury. TRIAL REGISTRATION: ClinicalTrials.gov NCT00408681.
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Doença Enxerto-Hospedeiro/fisiopatologia , Mucosa Intestinal/efeitos dos fármacos , Compostos de Lítio/farmacologia , Adulto , Feminino , Humanos , Mucosa Intestinal/fisiopatologia , Compostos de Lítio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Adulto JovemRESUMO
We examined the hypothesis that plasma biomarkers and concomitant clinical findings after initial glucocorticoid therapy can accurately predict failure of graft-versus-host-disease (GVHD) treatment and mortality. We analyzed plasma samples and clinical data in 165 patients after 14 days of glucocorticoid therapy and used logistic regression and areas under receiver-operating characteristic curves (AUC) to evaluate associations with treatment failure and nonrelapse mortality (NRM). Initial treatment of GVHD was unsuccessful in 49 patients (30%). For predicting GVHD treatment failure, the best clinical combination (total serum bilirubin and skin GVHD stage: AUC, .70) was competitive with the best biomarker combination (T cell immunoglobulin and mucin domain 3 [TIM3] and [interleukin 1 receptor family encoded by the IL1RL1 gene, ST2]: AUC, .73). The combination of clinical features and biomarker results offered only a slight improvement (AUC, .75). For predicting NRM at 1 year, the best clinical predictor (total serum bilirubin: AUC, .81) was competitive with the best biomarker combination (TIM3 and soluble tumor necrosis factor receptor-1 [sTNFR1]: AUC, .85). The combination offered no improvement (AUC, .85). Infection was the proximate cause of death in virtually all patients. We conclude that after 14 days of glucocorticoid therapy, clinical findings (serum bilirubin, skin GVHD) and plasma biomarkers (TIM3, ST2, sTNFR1) can predict failure of GVHD treatment and NRM. These biomarkers reflect counter-regulatory mechanisms and provide insight into the pathophysiology of GVHD reactions after glucocorticoid treatment. The best predictive models, however, exhibit inadequate positive predictive values for identifying high-risk GVHD cohorts for investigational trials, as only a minority of patients with high-risk GVHD would be identified and most patients would be falsely predicted to have adverse outcomes.
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Bilirrubina/sangue , Doença Enxerto-Hospedeiro , Receptor Celular 2 do Vírus da Hepatite A/sangue , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Prednisolona/administração & dosagem , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de TempoAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Hepatopatia Veno-Oclusiva , Leucemia Mieloide Aguda , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Feminino , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/metabolismo , MasculinoRESUMO
BACKGROUND: Gilbert's syndrome is a common inherited disorder of bilirubin metabolism, characterised by mild, unconjugated hyperbilirubinaemia. However, the effect of Gilbert's syndrome on the disposition of some drugs can lead to unexpected toxicity. We tested the hypothesis that patients undergoing myeloablative conditioning and haemopoietic cell transplantation would have different mortality outcomes depending on whether or not they had laboratory evidence of Gilbert's syndrome. METHODS: In this retrospective cohort study, we used clinical and laboratory data of patients who had haemopoietic cell transplantation from Jan 1, 1991, to Dec 31, 2011. Patients were included if they had received high-dose conditioning regimens of cyclophosphamide plus total body irradiation (CY/TBI), busulfan plus cyclophosphamide (BU/CY), busulfan plus melphalan plus thioTEPA (BUMELTT), or melphalan before transplant. Patients were excluded if their original consent forms to report transplant outcomes were not signed, if consent was withdrawn, or if they were a prisoner. Patients with Gilbert's syndrome were defined as having laboratory values before the start of conditioning therapy for unconjugated serum bilirubin concentrations of at least 17·1 µmol/L (≥1 mg/dL), normal conjugated serum bilirubin, and no evidence of hepatitis, cholestasis, or haemolysis. We assessed the association of Gilbert's syndrome with overall mortality and non-relapse mortality using adjusted Cox regression models at day 200 after transplantation. FINDINGS: Our study cohort was 3379 patients-1855 (55%) allograft and 1524 (45%) autograft recipients. 211 (6%) patients had Gilbert's syndrome and 3168 (94%) did not have this condition. Most patients were adults (median age 45·8 years [IQR 33·2-55·5]) with haematological malignancies. For overall mortality 664 (20%) patients had died by day 200 after transplant (47 [22%] of 211 who had Gilbert's syndrome vs 617 [19%] of 3168 who did not have Gilbert's syndrome), and for non-relapse mortality 499 (92%) patients had died before relapse was recorded (38 [18%] who had Gilbert's syndrome vs 461 [15%] who did not have Gilbert's syndrome). The effect of Gilbert's syndrome on the risk of overall mortality and non-relapse mortality by transplant day 200 varied between the conditioning regimens and donor groups. In patients conditioned with a myeloablative regimen that contained busulfan (n=1131), those with Gilbert's syndrome (n=60) were at a significantly increased risk of death and non-relapse mortality by day 200 compared with those without Gilbert's syndrome (n=1071; hazard ratio [HR] 2·30, 95% CI 1·47-3·61, p=0·00030; and 2·77, 1·71-4·49, p<0·0001). In patients who received CY/TBI or melphalan conditioning regimens, those with Gilbert's syndrome had similar outcomes to those without Gilbert's syndrome (overall mortality at day 200 HR 0·90, 95% CI 0·60-1·34, p=0·60; non-relapse mortality at day 200: 0·90, 0·56-1·45, p=0·65). Analyses of causes of death and busulfan disposition provided no mechanistic explanation for the differences in mortality. INTERPRETATION: Overall mortality and non-relapse mortality at day 200 after transplant were significantly worse in patients with Gilbert's syndrome who received busulfan-containing myeloablative conditioning regimens, compared with non-Gilbert's syndrome patients. Patients with Gilbert's syndrome should receive busulfan-containing myeloablative conditioning regimens with caution. FUNDING: US National Institutes of Health.
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Bilirrubina/efeitos adversos , Bilirrubina/fisiologia , Bussulfano/efeitos adversos , Bussulfano/uso terapêutico , Doença de Gilbert/complicações , Doença de Gilbert/mortalidade , Doença de Gilbert/fisiopatologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto , Bilirrubina/sangue , Bussulfano/farmacocinética , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Hepatopatia Veno-Oclusiva/induzido quimicamente , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Tiotepa/uso terapêutico , Transplante Autólogo/efeitos adversos , Transplante Homólogo/efeitos adversos , Washington , Irradiação Corporal TotalRESUMO
Historically, diagnosis of enigmatic pulmonary disease after hematopoietic cell transplantation (HCT) required lung biopsy, but recent advancements in diagnosis and therapy for respiratory infections have changed how clinicians approach pulmonary abnormalities. We examined temporal trends in the use of lung biopsy after HCT. We retrospectively reviewed patients who underwent their first allogeneic HCT at the Fred Hutchinson Cancer Research Center between the years 1993 to 1997, 2003 to 2007, and 2013 to 2015 and subsequently underwent surgical lung biopsy for any reason. Lung biopsy between cohorts were analyzed using a Cox proportional hazards model with death and relapse considered competing risks. Of 1418 patients, 52 (3.7%) underwent 54 post-HCT surgical lung biopsies during 1993 to 1997 compared with 24 (2.1%) and 25 biopsies in the 2003 to 2007 cohort; 2 cases of surgical lung biopsies out of 786 HCT recipients occurred during the 2013 to 2015 cohort (.25%). The median time to biopsy post-HCT was 71.5 days (IQR, 31 to 89) for the early cohort and 97 days (IQR, 42 to 124) for the late cohort, for an overall biopsy incidence of .15 and .075 per 1000 patient days in the first year after HCT, respectively. Patients in the 2003 to 2007 cohort were less likely to undergo a lung biopsy (adjusted HR, .50; 95% CI, .29 to .83; P = .008) when compared with patients in the early cohort, but more patients in the early cohort underwent lung biopsy without antecedent bronchoscopy (25/54 [46%] versus 3/25 [12%], P = .005). Although infections were a more common finding at biopsy in the early cohort (35/1418 versus 8/1148, P < .001), the number of biopsies demonstrating noninfectious lesions was similar between the two cohorts (19/1418 versus 17/1148, P = .76). Fungal infections were the major infectious etiology in both cohorts (32/35 [91%] versus 5/8 [63%], P = .07), but there was a significant reduction in the number of Aspergillus species found at biopsy between the cohorts (30/54 versus 1/25, P < .001). A similar percentage underwent biopsy with therapeutic intent for invasive fungal disease in the 2 cohorts (8/54 [15%] versus 4/25 [16%]). Surgical evaluation of lung disease in HCT recipients significantly declined over a span of 2 decades. The decline from the years 1993 to 1997 compared with 2003 to 2007 was because of a reduction in the number of biopsies for post-transplant infections due to aspergillosis, which is temporally related to improved diagnostic testing by minimally invasive means and the increased use of empiric therapy with extended-spectrum azoles. This practice of primary nonsurgical diagnostic and treatment approaches to pulmonary disease post-HCT have continued, shown by low numbers of surgical biopsies over the last 3 years.
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Biópsia/estatística & dados numéricos , Técnicas e Procedimentos Diagnósticos/tendências , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pneumopatias/diagnóstico , Adolescente , Adulto , Algoritmos , Aspergilose , Azóis/uso terapêutico , Biópsia/história , Broncoscopia , Diagnóstico por Imagem/métodos , Técnicas e Procedimentos Diagnósticos/estatística & dados numéricos , Feminino , História do Século XX , História do Século XXI , Humanos , Pneumopatias/etiologia , Pneumopatias/terapia , Masculino , Pessoa de Meia-Idade , Micoses/diagnóstico , Micoses/etiologia , Micoses/cirurgia , Micoses/terapia , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/etiologia , Infecções Respiratórias/cirurgia , Infecções Respiratórias/terapia , Estudos Retrospectivos , Adulto JovemRESUMO
Hepatitis C virus (HCV) infection is not uncommon in cancer patients. Over the past 5 years, treatment of chronic HCV infection in patients with hematologic malignancies has evolved rapidly as safe and effective direct-acting antivirals (DAAs) have become the standard-of-care treatment. Today, chronic HCV infection should not prevent a patient from receiving cancer therapy or participating in clinical trials of chemotherapy because most infected patients can achieve virologic cure. Elimination of HCV from infected cancer patients confers virologic, hepatic, and oncologic advantages. Similar to the optimal therapy for HCV-infected patients without cancer, the optimal therapy for HCV-infected patients with cancer is evolving rapidly. The choice of regimens with DAAs should be individualized after thorough assessment for potential hematologic toxic effects and drug-drug interactions. This study presents clinical scenarios of HCV-infected patients with hematologic malignancies, focusing on diagnosis, clinical and laboratory presentations, complications, and DAA therapy. An up-to-date treatment algorithm is presented.
Assuntos
Antivirais/uso terapêutico , Neoplasias Hematológicas/complicações , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Adulto , Quimioterapia Combinada , Feminino , Hepatite C Crônica/etiologia , Hepatite C Crônica/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Treatment of acute graft-versus-host disease (GVHD) has evolved from a one-size-fits-all approach to a more nuanced strategy based on predicted outcomes. Lower and time-limited doses of immune suppression for patients predicted to have low-risk GVHD are safe and effective. In more severe GVHD, prolonged exposure to immunosuppressive therapies, failure to achieve tolerance, and inadequate clinical responses are the proximate causes of GVHD-related deaths. This article presents acute GVHD-related scenarios representing, respectively, certainty of diagnosis, multiple causes of symptoms, jaundice, an initial therapy algorithm, secondary therapy, and defining futility of treatment.
Assuntos
Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Terapia de Imunossupressão , Fígado/patologia , Doença Aguda , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Terapia de Imunossupressão/efeitos adversos , Terapia de Imunossupressão/métodos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/imunologiaRESUMO
Busulfan is a commonly used chemotherapeutic agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). It has been associated with sinusoidal-obstructive syndrome(SOS) as a life-threatening complication of myeloablative allo-HCT, yet it has not been found to cause severe hepatocellular injury, even in cases of significant accidental overdose.We report the case of a 31-year-old male with a history of high-risk myelodysplastic syndrome transitioning to acute myeloid leukemia, who in complete remission underwent allo-HCT using myeloablative busulfanfludarabine conditioning, and who developed hepatic failure. While he met clinical criteria for SOS and was treated with defibrotide,liver biopsy demonstrated severe subacute hepatic necrosis and lacked characteristics of SOS. Further evaluation revealed that the patient was homozygous for the HFE H63D gene mutation, associated with hereditary hemochromatosis.Both Busulfan and iron overload related to HFE H63D homozygosity can cause oxidative stress resulting in cellular injury, and the cumulative effects of these risk factors are possibly responsible for the severe hepatocellular injury in this case, making our patient the first-known case of subacute hepatic necrosis related to busulfan administration.
Assuntos
Bussulfano/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Antígenos de Histocompatibilidade Classe I/genética , Homozigoto , Leucemia Mieloide Aguda/cirurgia , Falência Hepática Aguda/etiologia , Proteínas de Membrana/genética , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adulto , Aloenxertos , Bussulfano/uso terapêutico , Diagnóstico Diferencial , Hemocromatose/genética , Proteína da Hemocromatose , Hepatopatia Veno-Oclusiva , Humanos , Leucemia Mieloide Aguda/etiologia , Fígado/patologia , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/patologia , Masculino , Mutação , Síndromes Mielodisplásicas/complicações , Necrose/etiologia , Estresse Oxidativo , Risco , Fatores de RiscoAssuntos
Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Alanina Transaminase/sangue , Gerenciamento Clínico , Medicina Baseada em Evidências , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/etiologia , Hepatite C Crônica/virologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Guias de Prática Clínica como Assunto , Sociedades Médicas , Doadores de Tecidos , Transplantados , Estados UnidosRESUMO
We identified plasma biomarkers that presaged outcomes in patients with gastrointestinal graft-versus-host disease (GVHD) by measuring 23 biomarkers in samples collected before initiation of treatment. Six analytes with the greatest accuracy in predicting grade 3-4 GVHD in the first cohort (74 patients) were then tested in a second cohort (76 patients). The same 6 analytes were also tested in samples collected at day 14 ± 3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiver-operating characteristic (ROC) curve for each analyte were used to determine associations with outcome. Best models in the GVHD onset and landmark analyses were determined by forward selection. In samples from the second cohort, collected a median of 4 days before start of treatment, levels of TIM3, IL6, and sTNFR1 had utility in predicting development of peak grade 3-4 GVHD (area under ROC curve, 0.88). Plasma ST2 and sTNFR1 predicted nonrelapse mortality within 1 year after transplantation (area under ROC curve, 0.90). In the landmark analysis, plasma TIM3 predicted subsequent grade 3-4 GVHD (area under ROC curve, 0.76). We conclude that plasma levels of TIM3, sTNFR1, ST2, and IL6 are informative in predicting more severe GVHD and nonrelapse mortality.
Assuntos
Biomarcadores/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença Aguda , Adulto , Idoso , Feminino , Gastroenteropatias/sangue , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Gastroenteropatias/mortalidade , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Transplante Homólogo , Adulto JovemRESUMO
The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence.
Assuntos
Antineoplásicos/uso terapêutico , Doença Enxerto-Hospedeiro/terapia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Transplante de Medula Óssea , Doença Crônica , Consenso , Contraindicações , Gerenciamento Clínico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Humanos , Fármacos Fotossensibilizantes , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante HomólogoRESUMO
We conducted a phase III study to test the hypothesis that initial therapy with "lower dose" prednisone is effective and safe for patients with newly diagnosed acute graft-versus-host disease. We hypothesized that a 50% decrease in the initial dose of prednisone for treatment of acute graft-versus-host disease would suffice to control graft-versus-host disease without increasing the incidence of secondary treatment. Patients with grade IIa manifestations (upper gastrointestinal symptoms, stool volumes <1.0 L/day, rash involving <50% of the body surface, no hepatic dysfunction; n=102) were randomized to start treatment with prednisone at 1 mg/kg/day or 0.5 mg/kg/day. Those with grade IIb or higher manifestations (rash involving ≥50% of the body surface, stool volumes ≥1.0 L/day or hepatic involvement; n=62) were randomized to start treatment with prednisone at 2 mg/kg/day or 1 mg/kg/day. The primary study end point (a ≥33% relative reduction of the mean cumulative prednisone dose by day 42 after initial treatment with lower dose prednisone) was not reached. With a median follow up of 36 months (range 7-53), initial treatment with lower dose prednisone appeared to be effective for patients presenting with grade IIa manifestations since it did not increase the likelihood of requiring secondary immunosuppressive therapy. Further exploratory analyses suggested that for patients presenting with skin-predominant grade IIb or higher manifestations, initial treatment with lower dose prednisone was associated with an increased risk of requiring secondary immunosuppressive therapy (41% vs. 7%; P=0.001). In summary, initial treatment of newly diagnosed acute graft-versus-host disease with lower dose prednisone is effective. Within the statistical limitations of the study, results showed no suggestion that initial use of lower dose prednisone adversely affected survival.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Exantema/induzido quimicamente , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida/tendências , Resultado do Tratamento , Adulto JovemRESUMO
The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.