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Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.
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Chronic graft-versus-host disease (GvHD) treatment response is assessed using National Institutes of Health (NIH) Consensus Criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GvHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well-studied. We aimed to characterize 6-month patientreported response, determine associated chronic GvHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GvHD symptom burden measures correlated with patient-reported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) versus not improved (about the same, a little worse, moderately worse, very much worse). At six months, 270 (71%) patients perceived chronic GvHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GvHD response criteria (kappa 0.18). Notably, patient-reported response at six months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GvHD clinical trials and drug development.
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Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Calidad de Vida , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/terapia , Enfermedad Crónica , Medición de Resultados Informados por el PacienteRESUMEN
Acute myeloid leukemia (AML) in older patients has a poor prognosis, low complete remission (CR) rates, and poor overall survival (OS). Preclinical studies have shown synergistic effects of epigenetic priming with hypomethylating agents followed by cytarabine. Based on these data, we hypothesized that an induction regimen using epigenetic priming with decitabine, followed by cytarabine would be effective and safe in older patients with previously untreated AML. Here, we conducted a phase 2 trial in which older patients with previously untreated AML received an induction regimen consisting of 1 or 2 courses of decitabine 20 mg/m2 intravenously (IV) for 5 days followed by cytarabine 100 mg/m2 continuous IV infusion for 5 days. Forty-four patients (median age 76 years) were enrolled, and CR/CRi was achieved by 26 patients (59% of all patients, 66.7% of evaluable patients). Fourteen of 21 (66.7%) patients with adverse cytogenetics achieved CR including six out of seven evaluable patients with TP53 mutations. The 4- and 8-week mortality rates were 2.3% and 9.1%, respectively, with median OS of 10.7 months. These results suggest epigenetic priming with decitabine followed by cytarabine should be considered as an option for first-line therapy in older patients with AML. This trial was registered at www.clinicaltrials.gov as # NCT01829503.
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Citarabina , Leucemia Mieloide Aguda , Anciano , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Decitabina , Epigénesis Genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Inducción de Remisión , Resultado del TratamientoRESUMEN
Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Anciano , Humanos , Estudios Retrospectivos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Sulfonamidas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of patients with nontransplant short-TL are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for posttransplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL, and 26% of IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (P = .0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, P = .0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated that short-TL, rare variants, and lower pretransplant platelet counts were associated with BM dysfunction. Pretransplant TL measurement and genetic testing for rare telomere gene variants identified IPF-LTRs at increased risk for hematologic complications. Our findings support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates.
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Fibrosis Pulmonar Idiopática , Telomerasa , Humanos , Estudios Retrospectivos , Receptores de Trasplantes , Telomerasa/genética , Telomerasa/metabolismo , Pulmón/metabolismo , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/cirugía , Fibrosis Pulmonar Idiopática/patología , Telómero/genética , Telómero/metabolismo , Telómero/patologíaRESUMEN
Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
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Acetamidas/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Acetamidas/administración & dosificación , Acetamidas/efectos adversos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Adulto Joven , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
PURPOSE: Central venous catheters (CVCs) are widely used in acute myeloid leukemia (AML) patients. Complications associated with CVCs are frequently encountered and contribute to morbidity and mortality. Prospective studies investigating and comparing complications of different types of CVCs in AML patients and their effects on the quality of life are limited. METHODS: We conducted a prospective observational study and evaluated the complications associated with the use of CVCs in adult AML patients during induction chemotherapy and evaluated quality of life outcomes as reported by the patients during and after their hospitalization. RESULTS: Fifty newly diagnosed patients with AML (median age, 59 years) who received intensive induction chemotherapy were enrolled in the study. Twenty-nine patients (58%) had a peripherally inserted central catheters (PICCs) placed and 21 (42%) patients received a Hickmann tunneled central catheter (TCC). Three percent of cases developed catheter-related thrombosis in PICCs and no thrombosis in TCCs. Catheter-related bloodstream infection was diagnosed in 8% of patients. CVC occlusion occurred in 44 patients (88%). The total number of occlusion events was 128; 97% of patients with PICCs and 76% of patients with TCCs (p = 0.003). All patients reported that the use of CVC simplified their course of treatment. Most patients reported similar restrictions in activity associated with TCCs and PICCs. CONCLUSION: The present study demonstrates that thrombosis and catheter-related bloodstream infections remain important complications of CVCs in AML patients. Occlusion rates were higher with the use of PICCs and the use of CVCs impacted the quality of life.
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Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Cateterismo Periférico , Catéteres Venosos Centrales , Leucemia Mieloide Aguda , Adulto , Infecciones Relacionadas con Catéteres/epidemiología , Cateterismo Venoso Central/efectos adversos , Cateterismo Periférico/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Humanos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Factores de RiesgoRESUMEN
In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front-line setting. Recently, time-to-event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post-autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six-month [hazard ratio (HR) = 7·68], 12-month (HR = 6·68), and 18-month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non-relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high-risk group with inferior post-relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up-front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células del Manto/terapia , Adulto , Anciano , Femenino , Humanos , Linfoma de Células del Manto/diagnóstico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Trasplante AutólogoRESUMEN
Previously reported experimental and clinical data suggest that proteasome inhibition may have immunomodulatory activity relevant to graft-versus-host disease (GVHD). To explore the safety and activity of carfilzomib in advanced chronic GVHD, we conducted a multicenter pilot phase II trial through the Chronic GVHD Consortium. Carfilzomib was administered at 20 mg/m2 on day 1, then 36 mg/m2 on days 8 and 15 of a 28-day treatment cycle (cycle 1), and then 36 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle (cycles 2 to 6). The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immunosuppressive therapy. A total of 20 subjects were enrolled at 4 institutions. The median time from chronic GVHD onset to enrollment was 1.5 years (interquartile range, 0.5 to 3.7 years). Chronic GVHD was National Institutes of Health category moderate (30%) or severe (70%), predominantly classic (90% versus overlap 10%), and involved multiple diverse organ sites. The number of previous lines of systemic therapy for chronic GVHD was ≤2 in 6 patients (30%) and ≥3 in the other 14 (70%). Doses were held primarily for infection (50% of total held doses); only 3 patients (15%) completed all planned doses of the 6 cycles of carfilzomib. Serious adverse effects occurred in 40% of the patients, and 7 patients died, between .3 and 9 months after the last carfilzomib dose, but no deaths were attributed to carfilzomib. The 6-month treatment failure rate was not significantly improved versus the historical benchmark rate (40% versus 44%; Pâ¯=â¯.36). Overall survival was 80% at 6 months and 65% at 12 months. Failure-free survival at 12 months was 32%. These pilot phase II data suggest that carfilzomib therapy in this advanced chronic GVHD population did not improve over the expected 6-month treatment failure rates achieved under conventional practices and is not recommended for further study for this indication.
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Enfermedad Injerto contra Huésped , Enfermedad Crónica , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Humanos , Oligopéptidos/uso terapéutico , RecurrenciaRESUMEN
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Factores de Riesgo , Acondicionamiento PretrasplanteRESUMEN
Chronic graft-versus-host disease (cGVHD) is the leading late complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients receive multiple lines of systemic therapy until cGVHD resolves, but about 15% remain on systemic treatment for more than 7 years after cGVHD diagnosis. This study describes the clinical and biological factors of patients who present with cGVHD persisting for ≥7 years (persistent cGVHD). Patients with persistent cGVHD (n = 38) and those with cGVHD for <1 year (early cGVHD) (n = 83) were enrolled in a prospective cross-sectional natural history study. Patients in the persistent cGVHD group were a median of 10.2 years from cGVHD diagnosis (range 7-27 years). Fifty-eight percent of persistent cGVHD patients (22/38) were receiving systemic immunosuppression, compared to 88% (73/83) in the early cGVHD group. In multivariable analysis, bone marrow (BM) stem cell source, presence of ENA autoantibodies, higher NIH lung score, higher platelet counts, and higher IgA levels were significantly associated with persistent cGVHD. A high sensitivity panel of serum biomarkers including seven cytokines diagnostic for cGVHD was analyzed and showed significantly lower levels of BAFF and CXCL10 in patients with persistent cGVHD. In conclusion, standardly accepted clinical measures of disease severity may not accurately reflect disease activity in patients with persistent cGVHD. However, many patients with persistent cGVHD are still receiving systemic immunosuppression despite lacking evidence of disease activity. Development of reliable clinical biomarkers of cGVHD activity may help guide future systemic treatments.
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Citocinas/sangre , Enfermedad Injerto contra Huésped/sangre , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Adulto , Anciano , Aloinjertos , Biomarcadores , Niño , Enfermedad Crónica , Estudios Transversales , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Acondicionamiento Pretrasplante , Adulto JovenRESUMEN
Background: Prior studies have shown that outcomes of hematopoietic stem cell transplantation (HSCT) in human immunodeficiency virus (HIV)-positive patients have been similar to outcomes in HIV-negative patients since effective implementation of highly active antiretroviral therapy by 1998, but they are limited by small sample size or noninclusion of recent data. Methods: We queried National Inpatient Sample, a large inpatient data set in the United States, from 1998 to 2012 for HSCT, using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure code 41.0. HIV-positive patients were identified by the presence of ICD-9-CM diagnostic codes 042, 043, 044, V08, and 079.53. The primary outcome was in-hospital mortality rate, and the secondary outcome the in-hospital complication rate of HSCT. Outcomes were assessed by means of univariate, multivariate regression and matched-pair analysis. Results: A total of 39517 patients who underwent HSCT were identified. Among these, 108 patients had HIV infection. There were no differences in in-hospital mortality rates or rates of intubation, sepsis, bacteremia, or graft-vs-host disease between HIV-positive and HIV-negative patients after allogeneic or autologous HSCT. In allogeneic HSCT, HIV-positive patients had a significantly higher incidence of nontuberculous mycobacterial and cytomegalovirus infection than HIV-negative patients. Conclusion: Although HIV-positive patients may have a higher risk of certain opportunistic infections, they are not at higher risk of serious in-hospital complications of HSCT. Allogeneic and autologous HSCT can be safely performed in HIV-positive patients.
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Infecciones por VIH/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mortalidad Hospitalaria , Adulto , Infecciones por Citomegalovirus/epidemiología , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Infecciones por VIH/tratamiento farmacológico , Seropositividad para VIH , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud/estadística & datos numéricos , Infecciones Oportunistas/epidemiología , Factores de Riesgo , Trasplante Autólogo , Trasplante Homólogo/efectos adversos , Estados Unidos/epidemiologíaRESUMEN
Graft-versus-host disease (GvHD) assessment has been shown to be a challenge for healthcare professionals, leading to the development of the eGVHD App (www.uzleuven.be/egvhd). In this study, we formally evaluated the accuracy of using the App compared to traditional assessment methods to assess GvHD. Our national multicenter randomized controlled trial involved seven Belgian transplantation centers and 78 healthcare professionals selected using a 2-stage convenience sampling approach between January and April 2017. Using a 1:1 randomization stratified by profession, healthcare professionals were assigned to use either the App ("APP") or their usual GvHD assessment aids ("No APP") to assess the diagnosis and severity score of 10 expert-validated clinical vignettes. Our main outcome measure was the difference in accuracy for GvHD severity scoring between both groups. The odds of being correct were 6.14 (95%CI: 2.83-13.34) and 6.29 (95%CI: 4.32-9.15) times higher in favor of the "APP" group for diagnosis and scoring, respectively (P<0.001). App-assisted GvHD severity scoring was significantly superior for both acute and chronic GvHD, with an Odds Ratio of 17.89 and 4.34 respectively (P<0.001) and showed a significantly increased inter-observer agreement compared to standard practice. Despite a mean increase of 24 minutes (95%CI: 20.45-26.97) in the time needed to score the whole GvHD test package in the "APP" group (P<0.001), usability feedback was positive. The eGVHD App shows superior GvHD assessment accuracy compared to standard practice and has the potential to improve the quality of outcome data registration in allogeneic stem cell transplantation.
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Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/terapia , Personal de Salud , Aplicaciones Móviles , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Predicting the duration of systemic therapy in patients with chronic graft-versus-host disease (cGVHD) is of critical clinical importance when counseling patients and for treatment planning. cGVHD characteristics associated with this outcome have not been studied in severely affected patients. The National Institutes of Health (NIH) cGVHD scoring provides a standardized set of organ severity measures that could represent clinically useful and reproducible predictive characteristics. We analyzed 227 previously treated patients most with moderate (n = 54) or severe (n = 170) cGVHD defined by NIH criteria who were prospectively enrolled in a natural history protocol (NCT00092235). Patients received a median of 4 prior systemic therapy regimens and were seen at the NIH for a single time-point visit and were then monitored for survival and ability to discontinue cGVHD systemic therapy. With a median follow-up of 71.1 months, the cumulative incidence of systemic therapy discontinuation was 9.5% (95% confidence interval, 6.0% to 13.9%) at 2 years and 27.7% (95% confidence interval, 20.9% to 34.8%) by 5 years after the initial visit. Factors associated with a higher incidence of immunosuppression discontinuation included lower NIH global severity (P = .019) and lung (P = .030) scores and less extensive deep sclerosis (<37% body surface area, P = .024). Lower patient- and clinician-reported 0 to 10 severity NIH scores and noncyclosporine prophylaxis regimens were also associated with higher incidence of immunosuppression discontinuation (P <.05). In conclusion, we found low success rates for immune suppression discontinuation in previously treated patients who were severely affected with cGVHD. NIH scoring and clinical measures provide new standardized disease-specific tools to predict discontinuation of systemic therapy.
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Enfermedad Injerto contra Huésped/inmunología , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Adolescente , Adulto , Cuidados Posteriores , Anciano , Niño , Preescolar , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND AIMS: Activated NK cells (aNK) generated by expansion of a human interleukin-2-dependent NK cell line (NK-92) were shown to mediate strong anti-leukemia activity. This phase 1 study evaluated feasibility, safety, and activity of aNK cells adoptively transferred to patients with refractory/relapsed acute myeloid leukemia (AML). In addition, effects of these aNK cells on the patient's immune system were evaluated. METHODS: Two cell-dose levels (1 × 109 cells/m2 and 3 × 109 cells/m2) were used. One treatment course consisted of two infusions of the same cell dose, each cell infusion delivered 24 h apart. The aNK cells were administered in the outpatient setting. RESULTS: Seven patients with refractory/relapsed AML were treated with a total of 20 aNK cell infusions. None of the 7 patients experienced dose-limiting toxicities during the aNK cell administration or during 21 days of the post-infusion observation period. No grade 3-4 toxicities (probable or definite) related to aNK cell infusions occurred. Activity was transient in 3 of 7 patients. No significant changes in the patient's lymphocyte counts, subsets frequency, phenotype or activity were observed post-infusion. Cell dose-dependent effects in the plasma levels of several cytokines were observed. DISCUSSION: The trial demonstrated the safety and feasibility of adoptive cell therapy with "off-the-shelf" aNK cells in patients with refractory/relapsed AML. These data provide the foundation for future combination immunotherapy trials and for the optimization of aNK cell based therapies in patients with AML.
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Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/trasplante , Leucemia Mieloide Aguda/terapia , Anciano , Anciano de 80 o más Años , Trasplante de Células/efectos adversos , Trasplante de Células/métodos , Citocinas/sangre , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Interleucina-2/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Organ transplant recipients are at an increased risk for subsequent cancer including acute myeloid leukemia (AML). Treatment of AML following solid transplantation represents a clinical challenge as most patients have significant comorbidities at the time of AML diagnosis. In this study, we evaluated the treatment and outcomes of patients who developed AML following solid organ transplantation at our institution and reviewed the literature on outcomes for these patients. The study cohort consisted of 14 patients (median age 66 years, range 52-77 years) with newly diagnosed AML following solid organ transplantation. The median interval time between solid organ transplantation and AML diagnosis was 72 months (range 15-368 months). Seven patients received standard induction chemotherapy, four patients received intermediate type therapy, and the remaining three patients were deemed not fit for therapy and received palliative and supportive care. Six of the 11 treated patients (55%) achieved complete remission (CR). The median overall survival (OS) for all patients was 6 months. The median OS for the patients who achieved complete remission after therapy was 17 months and 2 months for the remaining patients. Despite initial CR, relapse rates are still high, suggesting that alternative strategies for post-remission therapies are warranted.
Asunto(s)
Leucemia Mieloide Aguda/etiología , Trasplante de Órganos , Complicaciones Posoperatorias , Anciano , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/terapia , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Consensus Project Ancillary and Supportive Care Guidelines recommend annual assessment of bone mineral density (BMD) to monitor bone health. The study of osteoporosis in patients with cGVHD has been limited to small numbers of patients, and the guidelines are based on experience with other chronic diseases and expert opinion. We hypothesized that the prevalence of osteoporosis is high in a cohort of 258 patients with moderate to severe cGVHD because of prolonged exposure to risk factors for osteoporosis after allogeneic hematopoietic stem cell transplantation. We defined osteoporosis using BMD criteria (T-score ≤-2.5) at 3 anatomic sites-the femoral neck (FN), lumbar spine (LS), and total hip (TH)-and characterized risk factors through univariate and multivariate analyses. We found that low body weight (FN, P < .0001; LS, P = .0002; TH, P < .0001), malnutrition (FN, P = .0002; LS, P = .03; TH, P = .0076), higher platelet count (FN, P = .0065; TH, P = .0025), higher average National Institutes of Health organ score (FN, P = .038), higher prednisone dose (LS, P = .032), lower complement component 3 (LS, P = .0073), and physical inactivity (FN, P = .01) were associated with osteoporosis in at least 1 site. T-scores were significantly lower in the FN compared with the LS or TH (P < .0001 for both). The prevalence of osteoporosis and osteopenia was high (17% and 60%, respectively), supporting current recommendations for frequent monitoring of BMD. The association of higher platelet count in patients with cGVHD and osteoporosis has not been reported previously and represents a new area of interest in the study of osteoporosis after allogeneic hematopoietic stem cell transplantation.
Asunto(s)
Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Osteoporosis/etiología , Adulto , Anciano , Densidad Ósea , Enfermedad Crónica , Estudios de Cohortes , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/diagnóstico , Recuento de Plaquetas , Guías de Práctica Clínica como Asunto , Factores de Riesgo , Trasplante Homólogo , Adulto JovenRESUMEN
Pulmonary nodules (PNs) develop frequently in patients with acute myeloid leukemia (AML). They are of infectious or inflammatory origin. They pose potential challenges to successful hematopoietic progenitor cell (HPC) transplant as they may be niches for infection reactivation or sites susceptible to subsequent infections. We retrospectively analyzed the outcome of 20 AML patients with multiple PNs who underwent allogeneic HPC transplants (12 related, 8 unrelated). There were 13 males and seven females (median age 52 yrs). Nine patients were in CR1, seven in CR2, and four with residual disease. The median times from appearance of PNs and from last positive CT scans to transplant were three and two months, respectively. The median time from pretransplant CT scans to transplant was one month. Multiple PNs were still reported in 5/20 of the pretransplant scans. The PNs in all five patients did not worsen after transplant. Four patients (one with positive pretransplant CT scan) died within the first 100 d after transplant, but none from primary pulmonary pathology. The median survival of this group of patients was 350 d. Our results, therefore, suggest that multiple PNs of uncertain etiology in patients with AML do not impact adversely on the outcome of allogeneic HPC transplant.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Nódulo Pulmonar Solitario , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Nódulo Pulmonar Solitario/mortalidad , Nódulo Pulmonar Solitario/patología , Nódulo Pulmonar Solitario/terapia , Tasa de SupervivenciaRESUMEN
Clostridium difficile infections (CDI) remain the leading cause of infectious diarrhea among hospitalized patients in this country. Patients with hematologic malignancies, especially those who undergo hematopoietic progenitor cell transplants are particularly at risk for developing CDI. One hundred and forty seven consecutive allogeneic hematopoietic progenitor cell transplants were analyzed for peri-transplant Clostridium difficile infections (PT-CDI). Sixteen patients (11%) developed PT-CDI (Median time = 7 days after transplant). The probability for developing PT-CDI during the peri-transplant period was 12.3%. History of CDI was strongly associated with the development of PT-CDI (P = 0.008) (OR = 5.48) (P = 0.017). These patients also developed PT-CDI much earlier than in those without a history (median 1 day vs. 8 days, P = 0.03). The probability for developing PT-CDI for those with a history was 39%. There was a trend toward significance (P = 0.065) between matched related donor grafts and the development of PT-CDI (OR = 0.245) (P = 0.08). Age, sex, diagnosis, transplant preparative regimens, Graft-versus-host disease (GVHD) prophylaxis, grade 3/4 acute GVHD, or use of antimicrobials within 8 weeks of transplant were not associated with PT-CDI. Non-CDI-related deaths occurred in one patient in the PT-CDI group and nine in the group without PT-CDI. In the remaining 139 patients, the length of hospital stay for those with PT-CDI was significantly longer than those without (mean 27 days vs. 22 days; P = 0.02).