RESUMO
Donor and recipient cytomegalovirus (CMV) serostatus correlate with transplant-related mortality that is associated with reduced survival following allogeneic stem cell transplant (SCT). Prior epidemiologic studies have suggested that CMV seronegative recipients (R-) receiving a CMV-seropositive graft (D+) experience inferior outcomes compared with other serostatus combinations, an observation that appears independent of viral reactivation. We therefore investigated the hypothesis that prior donor CMV exposure irreversibly modifies immunologic function after SCT. We identified a CD4+/CD57+/CD27- T-cell subset that was differentially expressed between D+ and D- transplants and validated results with 120 patient samples. This T-cell subset represents an average of 2.9% (D-/R-), 18% (D-/R+), 12% (D+/R-), and 19.6% (D+/R+) (P < .0001) of the total CD4+ T-cell compartment and stably persists for at least several years post-SCT. Even in the absence of CMV reactivation post-SCT, D+/R- transplants displayed a significant enrichment of these cells compared with D-/R- transplants (P = .0078). These are effector memory cells (CCR7-/CD45RA+/-) that express T-bet, Eomesodermin, granzyme B, secrete Th1 cytokines, and are enriched in CMV-specific T cells. These cells are associated with decreased T-cell receptor diversity (P < .0001) and reduced proportions of major histocompatibility class (MHC) II expressing classical monocytes (P < .0001), myeloid (P = .024), and plasmacytoid dendritic cells (P = .0014). These data describe a highly expanded CD4+ T-cell population and putative mechanisms by which prior donor or recipient CMV exposure may create a lasting immunologic imprint following SCT, providing a rationale for using D- grafts for R- transplant recipients.
Assuntos
Antígenos CD4/imunologia , Antígenos CD57/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células T de Memória/imunologia , Antígenos CD4/análise , Linfócitos T CD4-Positivos/imunologia , Antígenos CD57/análise , Células Cultivadas , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Doadores de Tecidos , Transplante Homólogo/efeitos adversosRESUMO
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.
Assuntos
Acetamidas/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acetamidas/administração & dosagem , Acetamidas/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento , Adulto Jovem , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation. Only half of patients with severe acute GVHD respond to first-line treatment with corticosteroids and, for several decades, there was no optimal second-line treatment of patients with corticosteroid-refractory acute GVHD. Ruxolitinib was recently approved for the treatment of corticosteroid-refractory acute GVHD in adult and pediatric patients 12 years and older. Thus, it is important to define the patient population that would now be considered as refractory to ruxolitinib vs ruxolitinib dependent. Here, we propose to define ruxolitinib-refractory acute GVHD as disease that shows: (1) progression of GVHD compared with baseline after at least 5 to 10 days of treatment with ruxolitinib, based either on objective increase in stage/grade, or new organ involvement; (2) lack of improvement in GVHD (partial response or better) compared with baseline after ≥14 days of treatment with ruxolitinib; or (3) loss of response, defined as objective worsening of GVHD determined by increase in stage, grade, or new organ involvement at any time after initial improvement. GVHD manifestations that persist without improvement in patients who had a grade ≥3 treatment-emergent and ruxolitinib-attributed adverse event that did not resolve within 7 days of discontinuing ruxolitinib would serve as a clinical indication for additional treatment. In addition, absence of complete response or very good partial response at day 28 after ruxolitinib could be considered as an eligibility criterion.
Assuntos
Corticosteroides/uso terapêutico , Resistência a Medicamentos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Terapia de Salvação , Terapias em Estudo , Doença Aguda , Adolescente , Adulto , Criança , Progressão da Doença , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Nitrilas , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas , Terapia de Salvação/métodos , Terapia de Salvação/tendências , Terapias em Estudo/métodos , Terapias em Estudo/tendências , Falha de Tratamento , Adulto JovemRESUMO
Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pirazóis/uso terapêutico , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirimidinas , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Clinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Prednisona/uso terapêutico , Sirolimo/uso terapêutico , Doença Aguda , Adolescente , Adulto , Idoso , Antineoplásicos Hormonais , Transplante de Medula Óssea/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
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.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Fatores de Risco , Condicionamento Pré-TransplanteRESUMO
Immunomodulatory drugs (IMiDs) have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic backbone at all phases of therapy. Although well-tolerated, IMiDs increase rates of venous thromboembolism (VTE). In this phase IV, single-arm pilot study, fifty patients with MM on IMiDs received apixaban 2·5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for six months. The primary safety outcomes were rates of major haemorrhage and clinically relevant non-major haemorrhage over six months. The primary efficacy outcome was the rate of symptomatic VTE over six months. IMiDs used were lenalidomide (58%) or pomalidomide (42%). During the six-month evaluation period, no patients experienced major haemorrhage or VTE. Three patients experienced clinically relevant, non-major haemorrhage which was managed medically, and all were able to resume apixaban. One patient stopped therapy shortly after initiation due to an allergic reaction to apixaban. No patients experienced stroke, myocardial infarction, or death. In this pilot study, low-dose apixaban was safe and well-tolerated as a primary prevention therapy of VTE for patients with MM receiving IMiDs. Further studies are needed to validate low-dose apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs.
Assuntos
Inibidores do Fator Xa/uso terapêutico , Fatores Imunológicos/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Trombofilia/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle , Idoso , Comorbidade , Quimioterapia de Consolidação , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/epidemiologia , Hemorragia/etiologia , Humanos , Fatores Imunológicos/uso terapêutico , Lenalidomida/efeitos adversos , Lenalidomida/uso terapêutico , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Projetos Piloto , Estudo de Prova de Conceito , Estudos Prospectivos , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Trombofilia/etiologia , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia , Trombose Venosa/prevenção & controleRESUMO
Despite the Centers for Medicare and Medicaid Services' recent approval to increase payments for inpatient-delivered chimeric antigen receptor T-cell therapy (CAR-T) for adult lymphoma, reimbursement remains far below the costs of the product and overall treatment of the therapy. We surveyed 92 CAR-T-certified centers in the U.S. to assess the perceived financial viability and related challenges for treating adult patients with lymphoma. Of 92 certified CAR-T centers in the U.S., 20 (22%) directors or chief medical officers responded. More than three quarters of facilities reported treating patients in an inpatient setting, and 60% reported that the majority of their patients were covered under commercial/private insurance. The financial viability rating across centers (median: 62; interquartile range: 48-69; scale 1-100) signals that economic sustainability of institutional programs for adult lymphoma is a concern. These dynamics may limit access to CAR-T for Medicare beneficiaries and lead to greater outpatient use of the therapy, which may limit access for medically complex patients.
Assuntos
Medicare , Neoplasias , Adulto , Idoso , Centers for Medicare and Medicaid Services, U.S. , Custos e Análise de Custo , Humanos , Imunoterapia Adotiva , Neoplasias/terapia , Estados UnidosRESUMO
OBJECTIVE: To describe upper dermal microvasculature of healthy human skin in terms of density and size of cutaneous blood vessels, leukocyte velocity, and leukocyte interactions with the endothelium. METHODS: We used a reflectance confocal microscope, the VivaScope 1500, to acquire videos of individual cell motion. RESULTS: We found no rolling leukocytes in the upper microvasculature of ten healthy subjects. We observed "paused" leukocytes, that is, leukocytes that temporarily stop, coinciding with the simultaneous stopping of the rest of the blood flow. We imaged more paused (median: 1.0 per subject) and adherent (1.5) leukocytes in the forearm than in the chest (median 0 paused and 0 adherent per subject) per 5 minutes of videos per body site. Leukocytes were paused for a median of 7 seconds in the forearm and 3 seconds in the chest, and we found no correlation between this parameter and the blood vessel or leukocyte size. We visualized blood flow change direction. Flowing leukocyte velocities followed a lognormal distribution and were on average higher in the chest (117 µm/s) than in the forearm (66 µm/s). CONCLUSION: The proposed method and reported values in healthy skin provide new insights into intact human skin microcirculation.
Assuntos
Microcirculação/fisiologia , Pele/irrigação sanguínea , Adolescente , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Masculino , Microscopia Confocal , Microscopia de Vídeo , Pessoa de Meia-IdadeRESUMO
For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Terapia de Salvação , Sulfonamidas/administração & dosagem , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
BACKGROUND: Haploidentical bone marrow transplant (haplo-BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo-BMT for SCD. METHODS: A multi-institution learning collaborative was developed in the context of a phase II clinical trial of a non-myeloablative, related haplo-BMT with post-transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available. RESULTS: Median age was 14.8 years. Out of 23, 18 participants received pre-conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo-BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event-free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV-6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post-transplant lymphoproliferative disease. CONCLUSION: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo-BMT with post-transplant cyclophosphamide for SCD.
Assuntos
Anemia Falciforme/complicações , Transplante de Medula Óssea/efeitos adversos , Ciclofosfamida/administração & dosagem , Reconstituição Imune , Imunossupressores/administração & dosagem , Ativação Viral , Adolescente , Adulto , Criança , Ensaios Clínicos Fase II como Assunto , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro , Humanos , Estudos Prospectivos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Haploidêntico/efeitos adversos , Adulto JovemRESUMO
Assessments of overall improvement and worsening of chronic graft-versus-host disease (GVHD) manifestations by the algorithm recommended by National Institutes of Health (NIH) response criteria do not align closely with those reported by providers, particularly when patients have mixed responses with improvement in some manifestations but worsening in others. To elucidate the changes that influence provider assessment of response, we used logistic regression to generate an overall change index based on specific manifestations of chronic GVHD measured at baseline and 6 months later. We hypothesized that this overall change index would correlate strongly with overall improvement as determined by providers. The analysis included 488 patients from 2 prospective observational studies who were randomly assigned in a 3:2 ratio to discovery and replication cohorts. Changes in bilirubin and scores of the lower gastrointestinal tract, mouth, joint/fascia, lung, and skin were correlated with provider-assessed improvement, suggesting that the main NIH response measures capture relevant information. Conversely, changes in the eye, esophagus, and upper gastrointestinal tract did not correlate with provider-assessed response, suggesting that these scales could be modified or dropped from the NIH response assessment. The area under the receiver operator characteristic curve in the replication cohort was 0.72, indicating that the scoring algorithm for overall change based on NIH response measures is not well calibrated with provider-assessed response.
Assuntos
Algoritmos , Doença Enxerto-Hospedeiro , Pessoal de Saúde , Transplante de Células-Tronco Hematopoéticas , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Especificidade de Órgãos , Estudos Prospectivos , Estados UnidosRESUMO
New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; Pâ¯=â¯.005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P = .648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (Pâ¯=â¯.047) and decreased peripheral/skeletal muscle uptake (Pâ¯=â¯.031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P = .039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT.
Assuntos
Diabetes Mellitus/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Transplante HomólogoRESUMO
Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema and superficial and deep sclerosis in 8 anatomic sites in patients with incident disease (ie, new cGVHD diagnosis within 3 months of study entry) receiving systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at the time of cGVHD diagnosis was more common than has been suggested by previous studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (46% and 16%, respectively, of the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (nâ¯=â¯71; 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (nâ¯=â¯4; 2%). Deep sclerosis did not occur in this region, and instead was most likely to occur on the upper extremities (nâ¯=â¯14; 8%) and lower extremities (nâ¯=â¯14; 8%). More than one-half of patients with erythema (nâ¯=â¯107; 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared with less than one-third of those with sclerosis (nâ¯=â¯16; 30.2%).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasias , Dermatopatias , Adulto , Aloenxertos , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/patologia , Neoplasias/terapia , Estudos Prospectivos , Dermatopatias/epidemiologia , Dermatopatias/etiologia , Dermatopatias/patologiaRESUMO
Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a median follow-up of 26 months (range, .53 to 36.7 months), best overall response rate in the all treated population was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs. Six of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. Eleven of 18 patients (61%) who had sclerosis at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42 patients (64%) reached a corticosteroid dose of <.15 mg/kg/day during the study; 8 discontinued corticosteroid treatment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of the original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (nâ¯=â¯6), fatigue (nâ¯=â¯5), and diarrhea (nâ¯=â¯4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (nâ¯=â¯12). AEs leading to discontinuation occurred in 18 patients (43%). At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Doença Crônica , Feminino , Humanos , Masculino , Piperidinas , Pirazóis/farmacologia , Pirimidinas/farmacologia , Fatores de TempoRESUMO
In clinical trials of chronic graft-versus-host disease (cGVHD), the need to start a new systemic treatment is considered a treatment failure. A composite endpoint called "failure-free survival" (FFS), where events are initiation of a new systemic cGVHD treatment, recurrent malignancy, and death, has been suggested as a possible long-term indicator of success. The goal of the current study was to identify changes in cGVHD manifestations from baseline to 6 months that could accurately predict subsequent longer-term FFS, thereby making it possible to assess outcomes earlier than would otherwise be possible. We used data from 2 prospective, multicenter, observational studies to develop the cGVHD-FFS index. The cGVHD-FFS index was calculated at 6 months, a typical timepoint for assessment of the primary endpoint of phase II cGVHD trials. Subsequent FFS was only 45% within the next 2 years. We found that changes in the scores for the eyes, joint/fascia, and mouth ulcers from baseline to 6 months were associated with subsequent FFS, but the prognostic accuracy of these changes was not adequate for use in trials. Biomarker studies might help to identify criteria that improve prediction of long-term clinical outcomes in patients with cGVHD.
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Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group.
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Emprego , Doença Enxerto-Hospedeiro/economia , Cobertura do Seguro , Classe Social , Doença Crônica , Estudos Transversais , Feminino , Doença Enxerto-Hospedeiro/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Pacientes , Inquéritos e QuestionáriosRESUMO
Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.
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Doença Enxerto-Hospedeiro/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Corticosteroides/uso terapêutico , Adulto , Tirosina Quinase da Agamaglobulinemia , Idoso , Biomarcadores/metabolismo , Doença Crônica , Demografia , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/sangue , Proteínas Tirosina Quinases/metabolismo , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Índice de Gravidade de Doença , Falha de Tratamento , Adulto JovemRESUMO
No gold standard has been established as a primary endpoint in trials of initial treatment of chronic graft-versus-host disease (GVHD), and evidence showing the association of any proposed primary endpoint with clinical benefit has not been conclusively demonstrated. To address this gap, we analyzed outcomes in a cohort of 328 patients enrolled in a prospective, multicenter, observational study within 3 months after diagnosis of chronic GVHD. Complete and partial response, stable disease, and progressive disease were defined according to the 2014 National Institutes of Health Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease. Success was defined as complete or partial response with no secondary systemic treatment or recurrent malignancy at 1 year after enrollment. Success was observed in fewer than 20% of the patients. The burden of disease manifestations at 1 year was lower for patients in this category than for those with stable or progressive disease. Systemic treatment ended earlier, and subsequent mortality was lower among patients with complete or partial response than among those with stable or progressive disease and those who had received secondary systemic treatment. We conclude that survival with a complete or partial response and no previous secondary systemic treatment or recurrent malignancy at 1 year after initial systemic therapy is associated with clinical benefit, a critical characteristic for consideration as a primary endpoint in a pivotal clinical trial. This prospective observational study was registered at www.clinicaltrials.gov as #NCT00637689.
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Determinação de Ponto Final , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Adulto , Idoso , Inibidores de Calcineurina/uso terapêutico , Doença Crônica , Progressão da Doença , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fotoferese , Prednisona/uso terapêutico , Estudos Prospectivos , Recidiva , Rituximab/uso terapêutico , Índice de Gravidade de Doença , Sirolimo/uso terapêutico , Análise de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Estados UnidosRESUMO
Given the limited treatment options for relapsed lymphoma post-allogeneic hematopoietic cell transplantation (post-allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post-allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post-allo-HCT and prior to anti-PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti-PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post-allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.