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

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.

Severity of Acute Graft-versus-Host Disease and Associated Healthcare Resource Utilization, Cost, and Outcomes.

Acute graft-versus-host disease (aGVHD) contributes to poor outcomes and increased healthcare resource utilization (HRU) after allogeneic hematopoietic stem cell transplantation (HCT). However, HRU and the economic burden of aGVHD based on severity of the disease is not well characterized. Our study cohort comprised 290 adults who underwent allogeneic HCT between 2010 and 2018.

A genomics-informed computational biology platform prospectively predicts treatment responses in AML and MDS patients.

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are generally older and have more comorbidities. Therefore, identifying personalized treatment options for each patient early and accurately is essential. To address this, we developed a computational biology modeling (CBM) and digital drug simulation platform that relies on somatic gene mutations and gene CNVs found in malignant cells of individual patients.

Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation.

We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively.

PCR-Based Approach Targeting Mucorales-Specific Gene Family for Diagnosis of Mucormycosis.

Mucormycosis is an aggressive, life-threatening infection caused by fungi in the order Mucorales. The current diagnosis of mucormycosis relies on mycological cultures, radiology and histopathology. These methods lack sensitivity and are most definitive later in the course of infection, resulting in the prevention of timely intervention.

Applying host disease status biomarkers to therapeutic response monitoring in invasive aspergillosis patients.

One critical factor impeding successful management of invasive aspergillosis (IA) is the lack of reliable biomarkers to assess therapeutic response. We hypothesized that changes in certain host biomarkers reflect the nature of infection status and disease progression. Upon primary IA diagnosis, these disease status biomarkers can be monitored to track response to antifungal therapy and provide early markers that prognosticate likelihood of response.

Minimal residual disease by either flow cytometry or cytogenetics prior to an allogeneic hematopoietic stem cell transplant is associated with poor outcome in acute myeloid leukemia.

Relapsed acute myeloid leukemia (AML) is a significant challenge after allogeneic hematopoietic cell transplant (HCT). Multiparameter flow cytometry (MFC), conventional cytogenetics (CG), and fluorescence in situ hybridization (FISH) are routinely performed on bone marrow specimens prior to HCT to assess disease status. We questioned the extent by which pre-HCT evidence of minimal residual disease (MRD) detected by these standard assays, corresponded with post-HCT relapse.

A new model to predict remission status in AML patients based on day 14 bone marrow biopsy.

Although bone marrow evaluation on day 14 after initiation of induction chemotherapy (D14 BM) is a widely accepted practice in patients with acute myeloid leukemia (AML), it has suboptimal predictive value for predicting complete remission. We retrospectively analyzed pretreatment characteristics and post-induction response in a cohort of AML patients to determine if adding clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation. Among 297 patients treated for AML at the single institution 183 patients (61%) had leukemia-positive D14 BM.

Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from the American Society for Blood and Marrow Transplantation.

Therapeutic strategies for multiple myeloma (MM) have changed dramatically over the past decade. Thus, the role of hematopoietic stem cell transplantation (HCT) must be considered in the context of this evolution. In this evidence-based review, we have critically analyzed the data from the most recent clinical trials to better understand how to incorporate HCT and when HCT is indicated.

Tandem Autologous Stem Cell Transplantation for Multiple Myeloma Patients Based on Response to Their First Transplant-A Prospective Phase II Study.

In this prospective phase II clinical trial, multiple myeloma (MM) patients were randomized to receive a second (tandem) autologous stem cell transplantation (ASCT) based on whether they achieved a partial response or worse (≤PR) following initial ASCT (ASCT1). Patients who achieved a very good partial response or better (≥VGPR) had salvage ASCT at relapse. Seventy-five patients received conditioning therapy and ASCT1.

Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation.

Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness.

Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee.

Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the current published literature on the dosing of pharmacologic agents used for HCT preparative regimens with specific focus on the obese patient population. The review found that dose adjustments for obesity have, to date, been based empirically or extrapolated from published data in the nontransplantation patient population.

Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations.

Autologous hematopoietic stem cell transplantation (aHSCT) is a well-established treatment for malignancies such as multiple myeloma (MM) and lymphomas. Various changes in the field over the past decade, including the frequent use of tandem aHSCT in MM, the advent of novel therapies for the treatment of MM and lymphoma, and the addition of new stem cell mobilization techniques, have led to the need to reassess current stem cell mobilization strategies. Mobilization failures with traditional strategies are common and result in delays in treatment and increased cost and resource utilization.

Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants.

Purpose: The cost-effectiveness of voriconazole versus fluconazole prophylaxis against fungal infections in hematopoietic cell transplant (HCT) recipients is investigated.

Methods: A decision-analytic model was developed to estimate the drug costs associated with planned or supplemental prophylaxis and empirical therapy and the costs of treating suspected or documented invasive fungal infections (IFIs) in HCT recipients. Published clinical trial data on 599 patients who received 100-180 days of prophylactic therapy with voriconazole or fluconazole were used to model specified IFI-prevention and mortality outcomes; 6-month, 12-month, and lifetime incremental cost-effectiveness ratios (ICERs) were estimated, with a bootstrap analysis performed to reffect the uncertainty of the clinical trial data.

Pharmacoeconomics of hematopoietic stem cell mobilization: an overview of current evidence and gaps in the literature.

Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have been used to mobilize HSCs. Studies have shown that the efficiency of HSC mobilization and collection may vary when different methods of mobilization are used.

Utilization of collaborative practice agreements between physicians and pharmacists as a mechanism to increase capacity to care for hematopoietic stem cell transplant recipients.

Survival after hematopoietic stem cell transplantation (HSCT) has improved and the number of allogeneic HSCTs performed annually in the United States is expected to reach 10,000 by 2015. The National Marrow Donor Program created the System Capacity Initiative to formulate mechanisms to care for the growing number of HSCT recipients. One proposed method to increase capacity is utilization of pharmacists to manage drug therapy via collaborative practice agreements (CPAs).

Hematopoietic cell transplantation in 2020: summary of year 2 recommendations of the National Marrow Donor Program's System Capacity Initiative.

The National Marrow Donor Program, in partnership with the American Society for Blood and Marrow Transplantation, sponsored and organized a series of symposia to identify complex issues affecting the delivery of hematopoietic cell transplantation (HCT) and to collaboratively develop options for solutions. "Hematopoietic Cell Transplantation in 2020: A System Capacity Initiative" used a deliberative process model to engage professional organizations, experts, transplant centers, and stakeholders in a national collaborative effort. Year 2 efforts emphasized data analysis and identification of innovative ideas to increase HCT system efficiency, address future capacity requirements, and ensure adequate reimbursement for HCT programs to meet the projected need for HCT.

Use of antibacterial prophylaxis in patients with chemotherapy-induced neutropenia.

Purpose Of Review: Antibiotic prophylaxis has been found to have multiple benefits in patients receiving intensive chemotherapy at high risk for infection. Interest continues in identifying what additional groups of high-risk patients might potentially benefit from its use. However, concerns about the potential emergence of antibiotic resistance have led to multiple recent studies exploring this issue.

Galactomannan testing in bronchoalveolar lavage fluid facilitates the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies and stem cell transplant recipients.

Invasive pulmonary aspergillosis (IPA) is a major cause of mortality in patients with stem cell transplants and hematologic malignancies. Timely diagnosis of IPA improves survival but is difficult to make. We evaluated the effectiveness of bronchoalveolar lavage (BAL) galactomannan (GM) in diagnosing IPA in these populations by retrospectively reviewing records of 67 consecutive patients, in whom 89 BAL GM tests were performed.

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation.

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients.

Adequacy of published oncology randomized controlled trials to provide therapeutic details needed for clinical application.

Background: Randomized controlled trials (RCTs) improve clinical care through evidence-based results. Guidelines exist for RCT result reporting, but specific details of therapeutic administration promote clinical application and reproduction of the trial design. We assess the reporting methodology in RCTs published in major oncology journals.

Use of bronchoalveolar lavage to detect galactomannan for diagnosis of pulmonary aspergillosis among nonimmunocompromised hosts.

Pulmonary aspergillosis in nonimmunocompromised hosts, although rare, is being increasingly recognized. The diagnosis of pulmonary aspergillosis is difficult, since the recovery of Aspergillus from respiratory samples cannot differentiate colonization from invasion. We assessed the role of bronchoalveolar lavage (BAL) in detecting galactomannan (GM) for diagnosing pulmonary aspergillosis in 73 nonimmunocompromised patients with pulmonary infiltrates for whom the test was ordered.