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. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.

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. Herein, we analyzed serum levels of three prominent host disease status biomarkers C-reactive protein (CRP), haptoglobin (Hp), and annexin A1 (ANXA1) in IA patients during antifungal therapy. A total of 81 serial serum samples were collected at five or six different time points relative to IA diagnosis from 15 probable IA patients (10 acute leukemia [AL] and five hematopoietic stem cell transplantation [HSCT]). Of note, different biomarker profiles were observed in AL and HSCT patients, as not only levels of markers were significantly lower in HSCT patients but also more prominent interconnections among markers were observed in AL patients. Using a composite evaluation, patients were categorized as responders, nonresponders, and stable cases at last specimen. For AL responders, typical biomarker profiles were high initially but rapidly decreased for CRP and Hp post antifungal therapy, while low initial ANXA1 values were restored to normal levels after treatment. In contrast, CRP and Hp were persistently elevated whilst ANXA1 remained low throughout therapy in AL non-responders. As a pilot proof-of-concept study, our work demonstrates the great potential of using host biomarkers to monitor early therapeutic response in leukemia patients.

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. PCR-based approaches have shown promising potential in rapidly diagnosing mucormycosis. The spore coating protein homolog encoding CotH genes are uniquely and universally present among Mucorales. Thus, CotH genes are potential targets for the rapid diagnosis of mucormycosis. We infected mice with different Mucorales known to cause human mucormycosis and investigated whether CotH could be PCR amplified from biological fluids. Uninfected mice and those with aspergillosis were used to determine the specificity of the assay. CotH was detected as early as 24 h postinfection in plasma, urine, and bronchoalveolar lavage (BAL) samples from mice infected intratracheally with Rhizopus delemar, Rhizopus oryzae, Mucor circinelloides, Lichtheimia corymbifera, or Cunninghamella bertholletiae but not from samples taken from uninfected mice or mice infected with Aspergillus fumigatus Detection of CotH from urine samples was more reliable than from plasma or BAL fluid. Using the receiver operating characteristic method, the sensitivity and the specificity of the assay were found to be 90 and 100%, respectively. Finally, CotH was PCR amplified from urine samples of patients with proven mucormycosis. Thus, PCR amplification of CotH is a promising target for the development of a reliable, sensitive, and simple method of early diagnosis of mucormycosis.

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. We have provided our recommendations based on strength of evidence with the knowledge that ongoing clinical trials make this a dynamic field. Within this document, we discuss the decision to proceed with autologous HCT, factors to consider before proceeding to HCT, the role of tandem autologous HCT, post-HCT maintenance therapy, and the role of allogeneic HCT for patients with MM.

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. As a result, the Committee determined that clear standards or dosing guidelines are unable to be made for the obese population because Level I and II evidence are unavailable at this time. Instead, the Committee provides a current published literature review to serve as a platform for conditioning agent dose selection in the setting of obesity. A necessary goal should be to encourage future prospective trials in this patient population because further information is needed to enhance our knowledge of the pharmacokinetics and pharmacodynamics of conditioning agents in the setting of obesity.

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. Recently, plerixafor-containing strategies have been shown to significantly reduce mobilization failure rates, but the ideal method to maximize stem cell yields and minimize costs associated with collection has not yet been determined. A panel of experts convened to discuss the currently available data on autologous hematopoietic stem cell mobilization and transplantation and to devise guidelines to optimize mobilization strategies. Herein is a summary of their discussion and consensus.

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. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.

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. No studies have shown that survival is significantly affected by the method of mobilization, but some studies have suggested that cost and resource utilization may be different between different mobilization techniques. After the FDA approval of plerixafor with G-CSF to mobilize HSCs many transplant centers became concerned about the cost of HSC mobilization. A panel of experts was convened ant this paper reviews the current literature on the pharmacoeconomics of HSC mobilization.

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). Pharmacists have managed drug therapy in oncology patients with CPAs for decades; however, there are limited HSCT centers that employ this practice. Engaging in collaborative practice and billing agreements with credentialed pharmacists to manage therapeutic drug monitoring, chronic medical conditions, and supportive care in HSCT recipients may be cost-effective and enable physicians to spend more time on new or more complex patients. The goal of this paper is to provide a framework for implementation of a CPA and address how it may improve HSCT program capacity.

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. This report highlights the deliberations and recommendations of Year 2 and the associated symposium held in September 2011.

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. RECENT FINDINGS: The use of antibiotic prophylaxis in pediatric leukemia, myelodysplastic syndromes, and hematopoietic stem cell transplant populations has been evaluated in recent studies. Several centers have noted increased rates of antibiotic resistance in patients receiving prophylaxis. SUMMARY: Several single-center studies have emphasized the concern for the emergence of antibiotic resistance associated with the routine use of fluoroquinolone prophylaxis. The potential for antibiotic resistance continues to be worrisome and warrants further ongoing studies.

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. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.

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. For patients with IPA, only the first BAL sample linked to the IPA episode was analyzed. Eighty samples were associated with proven, 12 with probable, and 32 with possible invasive fungal infections (IFI), and 37 were associated with no IFI. Among patients with IFIs, 4 had proven, 11 probable, and 32 possible IPA. Using BAL GM ≥ 0.5 (cutoff for serum GM) and ≥ 0.85 (optimal cutoff identified by receiver-operating characteristic curve), the sensitivity in diagnosing proven or probable IPA was 73% (11/15) and 67% (10/15), respectively, and specificity was 89% (33/37) and 95% (35/37). At these cutoffs, positive and negative predictive values were 73% (11/15) and 83% (10/12), and 89% (33/37) and 87% (35/40), respectively. BAL GM was more sensitive than cytology (0%, 0/14), BAL culture (27%, 4/15), transbronchial biopsy (40%, 2/5), or serum GM (67%, 10/15) for diagnosing IPA. BAL GM was ≥ 0.85 and ≥ 0.5 in 86% (6/7) and 100% (7/7) of patients with proven or probable IPA who received a mold-active agent for ≤ 3 days. BAL GM added sensitivity to serum GM and other means of diagnosing IPA, and was not impacted by short courses of mold-active agents.

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. Costs, HRU, and all-cause mortality in the 100-day and 365-day periods after HCT were compared between patients with aGVHD and those without aGVHD. The impact of aGVHD severity and gastrointestinal (GI) involvement on mortality, HRU, and economic burden was also evaluated. Medical costs and total hospital length of stay (LOS) were retrieved from administrative data that allocate costs to services based on departmental input for resource use and were adjusted to 2018 dollars. The Wilcoxon rank-sum test was used to compare the number of inpatient days and total costs. Multivariable linear regression was fitted on log-transformed costs. Compared with patients without aGVHD, those with aGVHD had a significantly greater median hospital LOS (28 days versus 22 days) and higher rates of intensive care unit (ICU) admission (13% versus 6%) and rehospitalization (59% versus 38%) during the first 100 days post-HCT. The presence of grade I-II aGVHD significantly prolonged the hospital LOS by a median of 3 days and increased the readmission rate by 18%, whereas grade III-IV aGVHD was associated with a nearly 30% increase in the readmission rate and a doubling of inpatient LOS, ICU admission rate, and mortality in the first 100 days post-HCT. Compared with the absence of aGVHD, lower GI involvement in aGVHD was also associated with increased risk of readmission (30%) and twice as many inpatient days, doubling the likelihood of ICU admission and mortality over the first 100 days. Similar findings were observed over days 101 to 365 post-HCT. The mean cost attributable to aGVHD regardless of grade was $60,923 in the first 100 days post-HCT. This cost varied by grade. The mean aGVHD- attributable costs were $18,071 for grade I, $36,115 for grade II and $120,929 for grade III/IV aGVHD and $114,668 for aGVHD involving the lower GI tract. In the 101- to 365-day period, the mean attributable aGVHD cost regardless of grade was $17,527. This cost also varied by grade. There were no additional aGVHD-attributable costs for grade I, but the mean aGVHD-attributable costs were $9743 for grade II, $62,220 for grade III/IV, and $55,724 for aGVHD with lower GI involvement compared with the controls without aGVHD. High-grade aGVHD and GI involvement in aGVHD, especially lower GI aGVHD, is associated with a considerably increased mortality and healthcare economic burden. Therefore, it is imperative that new therapeutic strategies be developed for this patient population.

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. 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.

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. Drug treatment simulations based on unique patient-specific disease networks were used to generate treatment predictions. To evaluate the accuracy of the genomics-informed computational platform, we conducted a pilot prospective clinical study (NCT02435550) enrolling confirmed MDS and AML patients. Blinded to the empirically prescribed treatment regimen for each patient, genomic data from 50 evaluable patients were analyzed by CBM to predict patient-specific treatment responses. CBM accurately predicted treatment responses in 55 of 61 (90%) simulations, with 33 of 61 true positives, 22 of 61 true negatives, 3 of 61 false positives, and 3 of 61 false negatives, resulting in a sensitivity of 94%, a specificity of 88%, and an accuracy of 90%. Laboratory validation further confirmed the accuracy of CBM-predicted activated protein networks in 17 of 19 (89%) samples from 11 patients. Somatic mutations in the TET2, IDH1/2, ASXL1, and EZH2 genes were discovered to be highly informative of MDS response to hypomethylating agents. In sum, analyses of patient cancer genomics using the CBM platform can be used to predict precision treatment responses in MDS and AML patients.

Pharmacoeconomic analysis of caspofungin versus liposomal amphotericin B as empirical antifungal therapy for neutropenic fever.

PURPOSE: An analysis was conducted that evaluated and compared the cost differences between caspofungin and liposomal amphotericin B when the medications were used as empirical antifungal therapy for persistent fever during neutropenia. METHODS: Rates of drug use and impaired renal function (IRF) were based on data from published studies. IRF was defined as a doubling of the serum creatinine level or, if the creatinine level was elevated at enrollment, an increase of at least 1 mg/dL. The estimates of the costs for drug acquisition and treating IRF were derived using published data and applied to compare caspofungin with liposomal amphotericin B. Sensitivity analyses were performed by varying the IRF and relative acquisition costs to assess the effect of these factors on the cost differences. RESULTS: The acquisition costs per patient were 6942 dollars for liposomal amphotericin B and 3996 dollars for caspofungin. The estimated cost per patient from IRF was 3173 dollars for liposomal amphotericin B and 793 dollars for caspofungin. Combining drug acquisition and IRF costs, the overall treatment cost per patient for caspofungin was 5326 dollars less than for liposomal amphotericin B. In sensitivity analyses of drug costs, the price of liposomal amphotericin B would have to be 23.95 dollars per vial for the overall treatment costs to be equal. CONCLUSION: Comparison of cost estimates derived from published data revealed that a combined estimate of acquisition costs and costs related to the treatment of IRF was lower for caspofungin than for liposomal amphotericin B for empirically treating patients with neutropenic fever.

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. We conducted a single center, retrospective study of 166 AML patients who underwent HCT. Thirty-eight of one hundred sixty-six (23%) patients in complete remission (CR) or CR with incomplete count recovery (CRi) had MRD detectable by MFC, CG, or FISH. MRD was more frequently seen in patients with poor risk karyotype at diagnosis (P = 0.011). MRD-negative patients (MRDneg) had significantly longer overall survival (OS) and relapse-free survival than patients who were MRD positive (MRDpos) (P = 0.002 and 0.013, respectively). In patients with MRDpos prior to HCT, the presence of acute graft vs. host disease (GVHD) (grade ≥ 2) or chronic GVHD significantly improved progression free survival (PFS) (hazard ratio (HR) = 0.053 (95% confidence interval (CI): 0.01-0.279), P = 0.0005) and OS (HR = 0.211 (95% CI: 0.081-0.547), P = 0.0014).

New strategies of antifungal therapy in hematopoietic stem cell transplant recipients and patients with hematological malignancies.

Invasive fungal infections (IFIs) are associated with considerable morbidity and mortality among high-risk individuals. Outcomes for IFI historically have been suboptimal and associated with a high mortality rate, hence global prophylaxis strategies have been applied to at-risk populations. Among certain populations, fluconazole prophylaxis has reduced systemic and superficial infections caused by Candida species. Newer azoles are currently being evaluated as prophylaxis and have the potential to provide protection against mould pathogens that are more troublesome to treat once they occur. Global prophylaxis strategies have the shortcoming of subjecting patients to therapy that ultimately will not need it. Targeted prophylaxis has the advantage of treating only patients at highest risk using some parameter of greater host susceptibility. Prophylaxis strategies are most suitable in patients at the highest risk for IFI. For patient groups whose risk is somewhat lower or when suspicion of IFI occurs in patients receiving prophylaxis, empirical antifungal therapy is often employed following a predefined period of fever. Again this approach subjects many non-infected patients to unnecessary and toxic therapy. A more refined approach such as presumptive or pre-emptive therapy whereby treatment is only initiated upon positive identification of a surrogate marker of infection in combination with clinical and radiological signs will subject fewer patients to toxic and expensive treatments.