scholarly journals Impact of Changes of the 2020 Consensus Definitions of Invasive Aspergillosis on Clinical Trial Design: Unintended Consequences for Prevention Trials?

2021 ◽  
Vol 8 (10) ◽  
Author(s):  
John R Wingard ◽  
Barbara D Alexander ◽  
Lindsey R Baden ◽  
Min Chen ◽  
Michele W Sugrue ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Invasive Aspergillosis ◽  
Hematologic Malignancy ◽  
Antifungal Prophylaxis ◽  
Unintended Consequences ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Revised Definitions ◽  
The Impact ◽  
New Criteria

Abstract Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.

scholarly journals Antifungal Resistance and Predictors of Response in Patients with Hematologic Malignancy

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S85-S85
Author(s):  
Shiuan (Shannon) Wey ◽  
Jane Kriengkauykiat ◽  
Ayla Chan ◽  
Bernard Tegtmeier ◽  
James Ito ◽  
...  
Keyword(s):  
Treatment Response ◽  
Amphotericin B ◽  
Hematologic Malignancy ◽  
Antifungal Susceptibility ◽  
Hematologic Malignancies ◽  
Antifungal Prophylaxis ◽  
Cell Transplant ◽  
Research Support ◽  
Hematopoietic Cell Transplant ◽  
The Past

Abstract Background Invasive aspergillosis (IA) causes significant morbidity and mortality in patients with hematologic malignancies (HM). Azole resistance has emerged as a therapeutic challenge in managing IA. The aim of this study was to investigate Aspergillus susceptibility to antifungals over the past decade among HM patients, and correlate susceptibility to clinical outcomes. Methods All Aspergillusisolates banked from 2002 to 2014 isolated from HM patients with probable/proven IA were tested for antifungal susceptibility. Patients with hematopoietic cell transplant, duplicate and non-viable isolates were excluded. Data were collected on demographics and clinical factors that could affect the treatment response, antifungal susceptibility (MICs/MECs), and treatment response at 14, 30, and 90 days. Results Forty patients were identified. MICs for amphotericin B slightly increased over the past decade (R = 0.32, P = 0.09), but were stable for voriconazole (R = −0.08, P = 0.61). The MIC50 during the first 3 years (2002–2004) and last 3 years (2012–2014) for amphotericin B were 0.5 and 1 mg/l, and for voriconazole 0.5 and 1. Mean age 56 years, 48% male, 82% had active HM and 45% had received chemotherapy within 14 days of IA. 50% were neutropenic and 30% had circulating blasts. Forty percent were on antifungal prophylaxis. Seventy-five percent of isolates were A. fumigatus. Fourteen responded to treatment (TR) and 26 were non-responders (NTR), and they did not differ in baseline characteristics. However, neutropenia (14% TR vs. 58%, NTR, P < 0.017) and circulating blasts (0% TR vs. 35% NTR, P < 0.02) at 14 days differed. The MIC50 for voriconazole was 0.5 mg/l in both groups, and for amphotericin B was 0.25 in TR vs. 1 mg/l in NTR. Fourteen-day response correlated with 90-day response (R = 0.74, P < 0.01) which validated the use of 14-day response for clinical outcome. All responders on amphotericin B at 14, 30, and 90 days had isolates with MIC < 1, whereas no apparent MIC-response correlation was found for voriconazole. Conclusion Although not statistically significant, a trend of increasing Aspergillus amphotericin B MICs was observed over the past decade. Neutropenia and persistent disease correlated with treatment failure. Clinical response was not affected by the azole or polyene MICs. Disclosures J. Ito, Astellas: Speaker’s Bureau, Speaker honorarium. S. Dadwal, Merck: Investigator, Research support. GlaxoSmithKline: Investigator, Research support. Ansun Biopharma: Investigator, Research support. Oxford Immunotec: Investigator, Research support. Gilead Sciences: Investigator, Research support

Approaches to the Management of Invasive Fungal Infections in Hematologic Malignancy and Hematopoietic Cell Transplantation

2009 ◽  
Vol 27 (20) ◽  
pp. 3398-3409 ◽  
Author(s):  
Mauricette Michallet ◽  
James I. Ito
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Fungal Infections ◽  
Hematologic Malignancy ◽  
Treatment Strategies ◽  
Underlying Disease ◽  
Antifungal Prophylaxis ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Increased Risk

Patients with hematologic malignancy and hematopoietic cell transplant (HCT) recipients are at increased risk for invasive fungal infection (IFI) as a result of immunosuppression or organ damage stemming from their underlying disease, its treatment, or both. Such IFIs can cause significant morbidity and mortality, and the diagnosis and treatment of infected patients frequently are clinically challenging. This article discusses the epidemiology and risk factors for IFI in patients with hematologic malignancy and HCT recipients. The pros and cons of available antifungal agents are discussed, and evolving treatment strategies and recent prophylaxis guidelines from various professional organizations are reviewed. Finally, recommendations are offered for antifungal prophylaxis according to risk group.

scholarly journals The Hematopoietic Cell Transplant Pharmacist: A Call to Action

Pharmacy ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 3 ◽  
Author(s):  
Amber Clemmons
Keyword(s):  
Cellular Therapy ◽  
Pharmacy Practice ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Call To Action ◽  
American Society ◽  
State Of The Science ◽  
Available Information ◽  
The Impact

Recently, the required training and credentials for as well as the various roles of the hematopoietic cell transplant (HCT) pharmacist have been endorsed by the leading organizations in cellular therapy, the American Society of Transplant and Cellular Therapy and the European Society of Blood and Bone Marrow Transplantation. While these documents establish the roles a HCT pharmacist can fulfill within the multi-disciplinary team, few reports have evaluated the impact of the HCT pharmacist on clinical, financial, or quality outcomes. Further, a paucity of information has been reported on types of practice models, such as the use of collaborative practice agreements, or described effective methods to overcome the barriers to the increased utilization of HCT pharmacists. Herein, a brief summary of available information is provided to aid readers in understanding the state of the science for pharmacists practicing in this specialty with the goal to stimulate further research to justify the roles of HCT pharmacists and the correlation of such research to various outcome measures. Practitioners are encouraged to build upon this existing knowledge to create the novel integration and elevation of pharmacy practice to improve outcomes for patients, providers, and payors.

scholarly journals The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia

2019 ◽  
Vol 3 (4) ◽  
pp. 670-680 ◽  
Author(s):  
Moshe Yeshurun ◽  
Daniel Weisdorf ◽  
Jacob M. Rowe ◽  
Martin S. Tallman ◽  
Mei-Jie Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lower Risk ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Low Grade ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Graft Versus Leukemia ◽  
The Impact ◽  
Risk Of Relapse

Abstract Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.

scholarly journals Impact of donor age and kinship on clinical outcomes after T-cell–replete haploidentical transplantation with PT-Cy

2020 ◽  
Vol 4 (16) ◽  
pp. 3900-3912 ◽  
Author(s):  
Jacopo Mariotti ◽  
Anna Maria Raiola ◽  
Andrea Evangelista ◽  
Angelo Michele Carella ◽  
Massimo Martino ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Clinical Outcomes ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Cell Transplant ◽  
Donor Age ◽  
Hematopoietic Cell Transplant ◽  
The Impact ◽  
Risk Of Relapse

Abstract Donor selection contributes to improve clinical outcomes of T-cell–replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.

scholarly journals Role of Human Bocavirus Respiratory Tract Infection in Hematopoietic Cell Transplant Recipients

2020 ◽  
Author(s):  
Chikara Ogimi ◽  
Emily T Martin ◽  
Hu Xie ◽  
Angela P Campbell ◽  
Alpana Waghmare ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Hematopoietic Cell ◽  
Respiratory Pathogen ◽  
Human Bocavirus ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Cell Transplant ◽  
Tract Infections ◽  
The Impact

Abstract Background Limited data exist regarding the impact of human bocavirus (BoV) in hematopoietic cell transplant (HCT) recipients. Methods In a longitudinal surveillance study among allogeneic HCT recipients, pre-HCT and weekly post-HCT nasal washes and symptom surveys were collected through day 100, then at least every 3 months through 1 year post-HCT at the Fred Hutchinson Cancer Research Center (2005–2010). Samples were tested by multiplex semiquantitative polymerase chain reaction (PCR) for 12 viruses. Plasma samples from BoV + subjects were analyzed by PCR. Separately, we conducted a retrospective review of HCT recipients with BoV detected in lower respiratory tract specimens. Results Among 51 children and 420 adults in the prospective cohort, 21 distinct BoV respiratory tract infections (RTIs) were observed by 1 year post-HCT in 19 patients. Younger age and exposure to children were risk factors for BoV acquisition. Univariable models among patients with BoV RTI showed higher peak viral load in nasal samples (P = .04) and presence of respiratory copathogens (P = .03) were associated with presence of respiratory symptoms, but BoV plasma detection was not. Only watery eyes and rhinorrhea were associated with BoV RTI in adjusted models. With additional chart review, we identified 6 HCT recipients with BoV detected in lower respiratory tract specimens (incidence rate of 0.4% [9/2509] per sample tested). Although all cases presented with hypoxemia, 4 had respiratory copathogens or concomitant conditions that contributed to respiratory compromise. Conclusions BoV RTI is infrequent in transplant recipients and associated with mild symptoms. Our studies did not demonstrate convincing evidence that BoV is a serious respiratory pathogen.

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