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1.
J Infect Dis ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374872

RESUMO

BACKGROUND: We report on predictors of ADV viremia and correlation of ADV viral kinetics with mortality in ex-vivo T-cell depleted (TCD) HCT. METHODS: TCD HCT recipients from 1/1/2012 through 9/30/2018 were prospectively monitored for ADV in the plasma through Day (D)+100 post-transplant or for 16 weeks after the onset of ADV viremia. ADV viremia was defined as ≥2 consecutive viral loads (VL) ≥1000 copies/mL through D+100. Time-averaged area under the curve (AAUC) or peak ADV VL through 16 weeks after onset of ADV viremia were explored as predictors of mortality in Cox models. RESULTS: Of 586 patients (adult 81.7%), 51 (8.7%) developed ADV viremia by D+100. Age <18 years, recipient CMV seropositivity, absolute lymphocyte count <300 cells/µL at D+30, and acute graft-versus-host disease were predictors of ADV viremia in multivariate models. Fifteen. CONCLUSION: In TCD HCT, peak ADV VL and ADV AAUC correlated with mortality at D+180. Our data support the potential utility of ADV viral kinetics as endpoints in clinical trials of ADV therapies.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32315708

RESUMO

BACKGROUND: (Val)ganciclovir (vGCV) or Foscarnet (FCN) as preemptive therapy (PET) for CMV after allogeneic HCT are associated with myelosuppression and nephrotoxicity, respectively. We analyzed a cohort of CMV seropositive (R+) HCT recipients managed preemptively at a single center. The objectives of our study were to 1) quantify the frequencies of neutropenia and acute kidney injury (AKI) through Day +100 (D 100) post HCT and at PET discontinuation and 2) assess the impact of PET on neutropenia and AKI in multivariate models. METHODS: Retrospective cohort study of adult CMV (R+) recipients who underwent allo HCT at MSKCC from March 18, 2013 through December 31, 2017 and were managed with PET. Patients were grouped by receipt of PET (PET and No PET). Neutropenia and AKI were defined by CTCAEv4. Frequencies of toxicities by D100 were compared between relevant groups. The impact of PET on toxicities was examined in univariate and multivariate Poisson/negative binomial regression models. RESULTS: Of 368 CMV R+ HCT recipients, 208 (56.5%) received PET. Neutropenia by D 100 occurred in 41.8% and 28.6% patients in PET and No PET, respectively (p=0.0009). PET increased the risk of neutropenia (adjusted RR=1.81, 95% CI: 1.48-2.21; p<0.0001) in multivariate analyses. AKI by D 100 occurred in 12.0% and 7.8% patients in PET and No PET, respectively (p=0.19). PET increased the risk of AKI by 2.75-fold (95% CI: 1.71-4.42; p<0.0001). When PET recipients were grouped by first antiviral, neutropenia by D 100 occurred in 34.8% and 48.9% of vGCV and FCN recipients, respectively, (p=0.08), and AKI occurred in 13.0% and 34.0% of vGCV and FCN recipients, respectively (p=0.001). At discontinuation of vGCV or FCN, neutropenia was present in 11.2% versus 2.1% patients, respectively (p=0.08) and AKI was present in 1.9% of versus 12.8% patients respectively (p=0.005). CONCLUSIONS: Preemptive therapy for CMV increased the risk of neutropenia and AKI in the first 100 days post HCT by 1.8 fold and 2.8 fold, respectively. Our results underscore the need for safer antivirals for CMV management in HCT recipients.

4.
Leuk Lymphoma ; : 1-9, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32228298

RESUMO

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32286506

RESUMO

Contrary to tandem autologous transplant (auto-auto), autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers graft-versus-myeloma (GVM) effect but with higher toxicity. Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological randomization) and yielded conflicting results. A pooled analysis of multiple trials with extended follow up provides an opportunity to compare these strategies. We obtained individual patient data from participants of four trials comparing auto-auto vs. auto-allo after induction therapy. There were 899 patients in auto-auto and 439 in auto-allo. Median follow up of survivors was 118.5 months. Median overall survival (OS) was 78.0 months in auto-auto and 98.3 months in auto-allo (HR = 0.84, P = 0.02). OS was 36.4% vs. 44.1% at 10 years (P = 0.01) for auto-auto and auto-allo, respectively. Progression-free survival was also improved in auto-allo (HR = 0.84, P = 0.004). Risk of non-relapse mortality was higher in auto-allo (10 year 8.3% vs. 19.7%, P < 0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P < 0.001). Median post relapse survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR = 0.71, P < 0.001). This supports the existence of durable GVM effect enhancing myeloma control with subsequent therapies.

6.
Leukemia ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32203138

RESUMO

Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6-3.6; p = 0.44). Median (95% CI) OS was 5.36 (4.27-7.95) months for combination therapy versus 7.26 (6.47-8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79-1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee's recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.

7.
Blood ; 135(13): 981-983, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32219351
8.
J Palliat Med ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32216649

RESUMO

Context and Objectives: The myriad of benefits of early palliative care (PC) integration in oncology are well established, and emerging evidence suggests that PC improves symptom burden, mood, and quality of life for hematopoietic cell transplant (HCT) recipients. Specific impact of PC consultation on outcomes of older allogeneic HCT (allo-HCT) recipients, a historically high-risk population vulnerable to transplant-related complications and mortality, has not been explored. Design and Methods: In this single institution, retrospective analysis of 527 first allo-HCT recipients aged ≥60 years, we characterized 75 patients who had received post-HCT PC consultation and its association with geriatric vulnerabilities identified by pre-HCT geriatric assessment. We also examined end-of-life care outcomes among patients who died within one-year of allo-hematopoietic cell transplantation. Results: In multivariate analysis, higher disease risk, female gender, and, importantly, pre-HCT functional limitation (hazard ratio 2.35, 95% confidence interval, 1.35-4.09, p = 0.003) were associated with post-HCT PC utilization. Within one-year of hematopoietic cell transplantation, 127 patients died; among those, recipients of early PC consultation had significantly higher rates of hospice enrollment (25% vs. 9%, p = 0.019) and lower rates of hospital death (71% vs. 90%, p = 0.013), intensive care unit admission (44% vs. 75%, p = 0.001), and high-intensity medical care in last 30 days of life (46% vs. 77%, p = 0.001). Conclusions: Our results highlight important pre-HCT risk factors associated with increased PC needs posthematopoietic cell transplantation and benefits of PC involvement for older allo-HCT recipients at the end of life. Prospective studies should examine the optimal timing of PC consultation and its multidimensional benefits for older allo-HCT patients.

9.
Br J Haematol ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135029

RESUMO

Radiotherapy is potentially an important salvage strategy post-chimeric antigen receptor T cell therapy (CART), but limited data exist. We reviewed 14 patients treated with salvage radiation post-CART progression (SRT). Most received SRT for first post-CART relapse (71%) to sites previously PET-avid pre-CART (79%). Median overall survival (OS) post-SRT was 10 months. Post-SRT, six localized relapses achieved 100% response (3 = complete, 3 = partial), with improved freedom from subsequent relapse (P = 0·001) and OS (P = 0·004) compared to advanced stage relapses. Three were bridged to allogeneic transplantation; at analysis, all were alive/NED. SRT has diverse utility and can integrate with novel agents or transplantation to attempt durable remissions.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32165328

RESUMO

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32088367

RESUMO

Isavuconazole is a broad-spectrum triazole approved for treatment of invasive fungal infections (IFIs). In this open-label, single-arm study, we evaluated isavuconazole for antifungal prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Adult patients admitted for first HCT received micafungin 150 mg i.v. daily from admission through day +7 (D+7) post-transplantation (±2 days) followed by isavuconazole prophylaxis (i.v./p.o. 372 mg every 8 hours for 6 doses and then 372 mg daily) through maximum D+98 post-HCT. Patients were followed through D+182. The primary endpoint was prophylaxis failure, defined as discontinuation of prophylaxis for proven/probable IFI; systemic antifungal therapy for >14 days for suspected IFI; toxicity leading to discontinuation; or an adverse event. Between June 2017 and October 2018, 99 patients were enrolled in the study, of whom 95 were included in our analysis. The median patient age was 57 years (interquartile range [IQR], 50 to 66 years). Sixty-four (67%) patients received peripheral blood, 17(18%) received bone marrow, and 14 (15%) received a cord blood allograft for acute leukemia (55%), lymphoma (17%), myelodysplastic syndrome (16%), or another hematologic disease (14%). One-third (n = 31; 33%) of patients underwent CD34+-selected HCT. Isavuconazole prophylaxis was given for a median of 90 days (IQR, 87 to 91 days). Ten patients (10.7%) met the primary endpoint. Candidemia occurred in 3 patients (3.1%), 1 of whom had grade III skin acute graft-versus-host disease (GVHD). Toxicity leading to discontinuation occurred in 7 patients (7.4%). The most common toxicity was liver function abnormalities in 5 patients, including grade 1 transaminitis in 2 patients and grade 3 hyperbilirubinemia in 3 patients. Four patients (4.2%) had early discontinuation of isavuconazole for reasons not meeting the primary study endpoint. Six patients died during the study period, including 3 during prophylaxis and 3 during follow-up. No deaths were attributed to isavuconazole. The majority (85%) of allogeneic HCT recipients completed isavuconazole prophylaxis according to protocol. The rate of breakthrough candidemia was 3.1%, and there were no invasive mold infections. Our data support the utility of isavuconazole for antifungal prophylaxis after HCT.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32070723

RESUMO

Telehealth involves the use of telecommunication and information technology for the delivery of clinical care and may be a mechanism to alleviate the burden of visits faced by patients undergoing hematopoietic cell transplantation (HCT). Few studies have evaluated the feasibility and acceptability of telehealth visits in the care of HCT patients. We conducted 27 telehealth visits with 25 patients undergoing HCT using a videoconferencing system that allows for real-time, 2-way interactions and administered satisfaction surveys to patients and providers. Of the 25 patients included in the study, 20 (80%) and 5 (20%) were undergoing autologous and allogeneic HCT, respectively. The telehealth visits were distributed as follows: 3 inpatient visits upon admission for HCT; 11 inpatient visits between 2 and 14 days post-HCT; 4 inpatient visits prior to discharge after HCT; 8 outpatient, post-HCT follow-up visits; and 1 handoff to a community oncologist. Out of a total of 54 provider assessments, 7 providers (13%) were unable to complete some part of the physical examination, but no provider reported being unable to manage patients' symptoms through telehealth. Eighty-one percent of patients were either satisfied or very satisfied with the telemedicine session. Overall satisfaction was higher among patients than providers (mean scores 4.12 versus 2.64; scale 1 to 5, with 1 = very poor to 5 = excellent). Technological barriers resulting in delays and suboptimal physical examination were largely responsible for provider dissatisfaction. The use of telehealth to deliver comprehensive follow-up care to HCT patients is feasible across different HCT types but is dependent upon quality of data streaming and videoconferencing technologies.

13.
N Engl J Med ; 382(9): 822-834, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32101664

RESUMO

BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).


Assuntos
Microbioma Gastrointestinal , Transplante de Células-Tronco Hematopoéticas/mortalidade , Adulto , Biodiversidade , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Análise de Sobrevida , Transplante Homólogo/mortalidade
18.
Blood Adv ; 4(4): 676-686, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32084260

RESUMO

Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell-related toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n = 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n = 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99% and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed.

20.
Blood Adv ; 4(1): 191-202, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31935291

RESUMO

Quality of immune reconstitution after cord blood transplantation (CBT) without antithymocyte globulin (ATG) in adults is not established. We analyzed immune recovery in 106 engrafted adult CBT recipients (median age 50 years [range 22-70]) transplanted for hematologic malignancies with cyclosporine/mycophenolate mofetil immunoprophylaxis and no ATG. Patients were treated predominantly for acute leukemia (66%), and almost all (96%) underwent myeloablation. Recovery of CD4+ T cells was faster than CD8+ T cells with median CD4+ T-cell counts exceeding 200/mm3 at 4 months. Early post-CBT, effector memory (EM), and central memory cells were the most common CD4+ subsets, whereas effector and EM were the most common CD8+ T-cell subsets. Naive T-cell subsets increased gradually after 6 to 9 months post-CBT. A higher engrafting CB unit infused viable CD3+ cell dose was associated with improved CD4+ and CD4+CD45RA+ T-cell recovery. Cytomegalovirus reactivation by day 60 was associated with an expansion of total, EM, and effector CD8+ T cells, but lower CD4+ T-cell counts. Acute graft-versus-host disease (aGVHD) did not significantly compromise T-cell reconstitution. In serial landmark analyses, higher CD4+ T-cell counts and phytohemagglutinin responses were associated with reduced overall mortality. In contrast, CD8+ T-cell counts were not significant. Recovery of natural killer and B cells was prompt, reaching medians of 252/mm3 and 150/mm3 by 4 months, respectively, although B-cell recovery was delayed by aGVHD. Neither subset was significantly associated with mortality. ATG-free adult CBT is associated with robust thymus-independent CD4+ T-cell recovery, and CD4+ recovery reduced mortality risk.

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