Adult Hematopoietic Cell Transplantation Research Articles

Soluble C5b-9 As a Prognostic Biomarker for Thrombotic Microangiopathy at the Onset of Graft-Versus-Host Disease

Schmidt: Kypha Inc: Employment, Equity Ownership. Lee:Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.

Freesia Study Design: JNJ-53718678 in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Upper Respiratory Tract

Background Although Respiratory Syncytial Virus (RSV) is a commonly recognized respiratory pathogen that can cause upper respiratory tract infections (URTI) and severe lower respiratory tract infections (LRTI) in infants and young children, it can also affect immunocompromised (IC) patients. Hematopoietic cell transplantation (HCT) recipients are at high risk for severe disease caused by RSV. The progression of RSV from URTI to LRTI can cause significant morbidity, often leading to hospitalization, intensive care unit admissions for supportive care and results in mortality in 2-5% of RSV infected HCT recipients. At some clinical centers oral or intravenous ribavirin, intravenous immunoglobulin or anti-RSV-enriched antibody preparations are used to treat RSV infection. However, there are currently no approved direct-acting antiviral agents indicated for the prevention or treatment of RSV infection in IC adult patients. A recently conducted trial evaluating another RSV fusion inhibitor in HCT recipients demonstrated strong trends toward clinical benefit among patients who were early in their disease course and were severely immunocompromised. JNJ-53718678 (JNJ-8678) is a fusion protein inhibitor that was well tolerated and showed antiviral activity in a Phase 1b study of RSV-infected infants, and was well tolerated and demonstrated antiviral efficacy in healthy adult volunteers in a human viral challenge study. FREESIA will evaluate the clinical outcomes, antiviral activity, safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamics (PD) of JNJ-8678 in HCT recipients with RSV URTI who are at the highest risk for progression to LRTI. Study Design and Methods This is a randomized, double-blind, placebo-controlled, multi-center study to evaluate JNJ-8678 in adult and adolescent HCT recipients with RSV URTI. In the adult cohort, a sample size of approximately 249 patients is targeted. (Figure 1). Adult and adolescent HSCT recipients will be enrolled if they present for medical care with an absolute lymphocyte count <1,000 cells/μL, a PCR-based diagnosis of RSV infection, new onset of at least one respiratory symptom (nasal congestion, rhinorrhea, cough or pharyngitis) and/or worsening of one of these symptoms, if chronic due to an existing diagnosis, within 4 days prior to the anticipated start of dosing and no evidence of abnormalities consistent with LRTI on a chest X-ray. Eligible patients will be randomized 2:1 to receive orally either 500 mg JNJ-8678 once-daily (qd) or placebo qd for 21 days. The follow-up period will be 28 days in duration. The primary endpoint is the proportion of patients developing RSV LRTI, by external adjudication. Clinical course of RSV infection, antiviral activity, health-related quality of life, RSV viral sequencing and RSV viral kinetics will also be assessed. The PK/PD relationship of JNJ-8678 exposure with selected efficacy and safety parameters will be explored. Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical examination will be assessed. This study will begin recruitment globally in the northern hemisphere in November 2019. This study will clarify the role JNJ-8678 may play in the treatment of RSV in a broader IC population, potentially addressing a substantial unmet medical need. Disclosures Chemaly: Gilead: Research Funding; Gilead: Other: Personal fees; Chimerix: Research Funding; ReViral: Other: Personal fees; Oxford Immunotec: Other: Personal fees; Ansun: Other: Personal fees; Chimerix: Other: Personal fees; Oxford Immunotec: Research Funding; Merck: Research Funding; Ansun Pharmaceuticals: Research Funding; Janssen: Other: Personal fees; ADMA Biologics: Other: Personal fees; Merck: Other: Personal fees; Clinigen: Other: Personal fees; Ablynx: Other: Personal fees. Boeckh:Chimerix: Research Funding; GSK: Other: Personal fees; Merck: Research Funding; GSK: Research Funding; Clinigen: Other: Personal fees; Merck: Other: Personal fees. Weber:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Fleischhackl:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals: Employment. Stevens:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals: Employment. Michiels:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals: Employment. Rivas:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Chien:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals: Employment. Witek:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals: Employment.

Post-Transplant Work Status of Young Adult Survivors of Allogeneic Hematopoietic Cell Transplant: A Report from the Center for International Blood and Marrow Transplant Research (CIBMTR)

Background: Return to full-time work after hematopoietic cell transplant (HCT) is an important indicator of health recovery and overall function of survivors. Because young adult (YA) HCT patients are at a critical personal and professional developmental phase at the time of their illness, they face unique challenges potentially impacting their ability to work post-HCT. We aimed to assess the post-HCT work status of YA patients undergoing allogeneic HCT and examine pre-HCT factors associated with their work status at the 1-year time-point post-HCT. Methods: Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we studied YA (18-39 years of age at HCT) survivors (alive ≥1-year post-HCT) of allogeneic HCT performed between 2008 and 2015 for malignant or non-malignant conditions. All conditioning regimens, stem cell sources, and donor types were included. Work status [full-time (FT), part-time (PT), unemployed, medical disability] was assessed at 6-months, 1-, 2-, and 3-years post-HCT. We performed a multivariable logistic regression to study the pre-HCT patient and disease related [patient age at HCT, sex, race/ ethnicity, pre-HCT education, pre-HCT work status, disease diagnosis, Karnofsky/ Lansky performance score, hematopoietic cell transplant comorbidity index (HCT-CI), marital status], and HCT-related (year of transplant, stem cell source, donor type, conditioning regimen) factors associated with post-HCT work status at the 1-year time-point [dichotomized as employed (in FT/PT work) vs unemployed (unemployed, medical disability)]. Results: A total of 1,365 allogeneic HCT recipients met the selection criteria. Median age at HCT was 30.8 years (range 18-39; interquartile range 9.3). Forty-four percent were females; 89% received HCT for malignant diseases (myeloid diseases: 62%, lymphoid diseases: 35%) and the remainder for non-malignant diseases (severe aplastic anemia, inherited abnormalities of erythrocyte differentiation/ function, and disorders of the immune system). Forty three percent received total body irradiation (TBI) based myeloablative conditioning regimens. Median follow-up time from HCT was 60.6 months (range: 12-121). From 6-months to 3-years post-HCT, the percentage of survivors employed FT (18% to 51%) and PT (7% to 11%) increased, and unemployed (38% to 18%) and on medical disability (37% to 20%) decreased (Figure 1). Of patients in FT work pre-HCT, 50% were either unemployed or had medical disability status at the 1-year time-point (Figure 2). Of those unemployed pre-HCT, 19% were working at 1-year post-HCT. In the multivariable logistic regression, survivors' pre-HCT work status was significantly associated with the post-HCT work status at 1-year time-point. Compared to patients working FT pre-HCT, patients who were unemployed and on medical disability were significantly less likely to be employed at 1-year post-HCT [pre-HCT unemployment: odds ratio (OR) of FT/PT employment 0.30; 95% confidence interval (CI) 0.20-0.48; pre-HCT medical disability: OR 0.46; 95% CI 0.30-0.71]. Females (OR 0.51; 95% CI 0.37-0.69) and patients with an HCT-CI score of 2 (OR 0.61; 95% CI 0.39-0.95), and ≥3 (OR 0.53; 95% CI 0.36-0.76) also had a lower likelihood of employment. Compared to patients with high school or lower education, patients with graduate school level education had significantly higher likelihood of employment (OR 2.53; 95% CI 1.72-3.71). Compared to patients treated with total body irradiation (TBI) based myeloablative conditioning, significantly higher odds of employment were seen in chemotherapy-based myeloablative conditioning (OR 1.81; 95% CI 1.28-2.56) (Table). Conclusions: In YA HCT survivors, the full-time and part-time work rates steadily improved post-HCT. Nonetheless, nearly 40% were still either unemployed or on medical disability even at 3 years post-HCT. Although there were limitations of the study including lack of post-HCT time-dependent covariates for the analysis and direct patient report for work status, our study findings provide an insight into the factors impinging on YA survivors' ability of returning to work and points to a need for return to work interventions. Disclosures Shaw: Therakos: Other: Speaker Engagement.

Risks and Benefits of Bronchoscopy during the First 100 Days Following Allogeneic Hematopoietic Cell Transplantation

BACKGROUND Pulmonary infiltrates are common after allogeneic hematopoietic cell transplantation (HCT) and can have infectious or non-infectious etiologies. Fiberoptic Bronchoscopy (FOB) with bronchoalveolar lavage (BAL) is frequently used to evaluate these patients. However, the diagnostic yield can be highly variable according to patient populations, and the impact on management is not well defined, especially in the era of modern antimicrobial therapies. The aim of this study was to investigate the diagnostic and therapeutic yield of FOB-BAL in adult patients with pulmonary infiltrates during the first 100 days following HCT. METHODS We retrospectively reviewed the medical records of adult HCT patients who underwent FOB-BAL during the first 100 days post HCT between January 2005 and December 2015 at Mayo Clinic, Rochester, MN. The interval from HCT to FOB was stratified into early (days 1-30) vs. late (days 31-100). The finding of progressively more hemorrhagic effluent and/or ≥ 20% hemosiderin-laden macrophages in BAL were considered diagnostic for diffuse alveolar hemorrhage (DAH). Univariate and multivariate logistic regression models were fit to identify clinical and transplant characteristics that may impact the diagnostic yield of FOB-BAL. RESULTS A total of 114 patients (median age 55 years), representing 12% of all HCT patients underwent FOB-BAL. Underlying diagnoses were AML in 36%, MDS in 16%, ALL in 16%, MPN in 12% , CLL in 7%, and other in 13%. Transplants were from matched related donor in 43%, matched unrelated donor in 40%, and other donor/matching status in 17%. FOB-BAL was performed during the early period in 61% and during the late period in 39% of patients. In the early period, FOB-BAL provided a specific diagnosis in 49% of patients (30% DAH and 19% infection). In the late period, FOB-BAL had a diagnostic yield of 55% (14% DAH and 36% infection) (Figure 1). The distribution of bacterial and viral infections identified via BAL were similar during the early period (39% and 38%, respectively), whereas more bacterial than viral infections were identified in the later period (56% vs. 19%, respectively) (Figure 2). Non-invasive testing for respiratory tract infection was performed in 34% of patients. These included nasopharyngeal swab for RSV/Influenza PCR in 16% (all negative), multiplex respiratory pathogen PCR in 5% (1 positive for coronavirus), and sputum culture in 21% (positive in 8 patients). This compares with the identification of an infectious pathogen via BAL in 36% of patients; bacterial in 16%, viral in 11%, and fungal in 10%. Transbronchoscopic lung biopsy biopsies were performed in 8 patients and provided diagnostic information in 3 patients (eosinophilic pneumonia, organizing pneumonia and diffuse alveolar damage each in 1 patient). Procedural complications occurred in 3 patients; 2 after transbronchoscopic lung biopsy (1 bleeding and 1 pneumothorax) and 1 during FOB-BAL (atrial fibrillation with rapid ventricular rate). In a multivariable logistic regression model, the underlying diagnosis, presence of acute respiratory failure, and early vs. later time period after HCT were independently affecting the diagnostic yield of FOB-BAL, with higher likelihood of DAH being diagnosed in patients with AML/MDS and during the early post-HCT period, and higher likelihood of DAH being diagnosed in patients with acute respiratory failure (Table 1). In 40% of patients, FOB-BAL findings lead to treatment changes. These included addition of antimicrobials in 24% and addition of corticosteroids in 22% (17% DAH, 2% idiopathic pneumonia syndrome, and 1% organizing pneumonia) (Figure 3). FOB findings lead to more antimicrobial modifications in the early than in the later period (32% vs. 18%, respectively). Overall survival was poor in all the three groups, although significantly better in patients with non-diagnostic FOB findings (median of 2, 3, and 11 months in patients with DAH, infection, or non-diagnostic FOB finings, respectively) (p = 0.03) (Figure 4). CONCLUSION FOB-BAL provides clinically useful information in the post-transplant period. BAL findings were diagnostic in 51% of patients, and led to management changes in 40% of patients. Transbronchoscopic lung biopsy is associated with higher rates of procedural complications. Further characterization of the underlying diagnosis in patients with non-diagnostic FOB-BAL findings remains an unmet clinical goal. Disclosures Sakemura: Humanigen: Patents & Royalties. Kenderian:Morphosys: Research Funding; Kite/Gilead: Research Funding; Lentigen: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Tolero: Research Funding; Novartis: Patents & Royalties, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Predictors of Loss to Follow-Up Among Pediatric and Adult Hematopoietic Cell Transplantation Survivors: A Report from the Center for International Blood and Marrow Transplant Research.

Follow-up is integral for hematopoietic cell transplantation (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of and predictors for being lost to follow-up. Two-year survivors of first allogeneic HCT (10,367 adults and 3865 children) or autologous HCT (7291 adults and 467 children) for malignant/nonmalignant disorders between 2002 and 2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. The 10-year cumulative incidence of being lost to follow-up was 13% (95% confidence interval [CI], 12% to 14%) in adult allogeneic HCT survivors, 15% (95% CI, 14% to 16%) in adult autologous HCT survivors, 25% (95% CI, 24% to 27%) in pediatric allogeneic HCT survivors, and 24% (95% CI, 20% to 29%) in pediatric autologous HCT survivors. Factors associated with being lost to follow-up include younger age, nonmalignant disease, public/no insurance (reference: private), residence farther from the tranplantation center, and being unmarried in adult allogeneic HCT survivors; older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) in adult autologous HCT survivors; older age, public/no insurance (reference: private), and nonmalignant disease in pediatric allogeneic HCT survivors; and older age in pediatric autologous HCT survivors. Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.

Feasible outcome of blinatumomab followed by allogeneic hematopoietic cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage.

In adult patients with relapsed or refractory (R/R) Philadelphia chromosome‐negative (Ph‐negative) B‐cell presursor acute lymphoblastic leukemia (BCP‐ALL), complete remission (CR) and overall survival (OS) rates are poor. We analyzed treatment outcomes and prognostic factors for 32 adult patients with R/R Ph‐negative BCP‐ALL who received blinatumomab at first salvage. Patients who achieved CR proceeded to allogeneic hematopoietic cell transplantation (allo‐HCT). At the time of blinatumomab treatment, 11 patients (34.3%) were primary refractory, 10 (31.4%) had relapsed with first CR duration (CRD1) ≥12 months, and 11 (34.3%) had relapsed with CRD1 <12 months. After the first blinatumomab cycle, 22 (68.8%) achieved CR. At the end of the second cycle, 20 of the 22 patients remained in persistent CR, and 1 patient achieved new CR. The overall minimal residual disease negativity rate was 75% among evaluable patients with persistent CR. Patients with CRD1 <12 months were associated with poorer response to blinatumomab. Twenty (62.5%) of 32 patients underwent allo‐HCT in blinatumomab‐induced CR. After a median follow‐up of 15.2 months, the 1‐year OS rates for all patients and patients receiving allo‐HCT in CR were 55.5% (median OS, 18.2 months) and 70.7%, respectively. Patients with CRD1 <12 months, extramedullary disease (EMD), and high peripheral blood blasts were associated with poorer OS. Blinatumomab is effective for achieving good quality CR and bridging to allo‐HCT for adult patients with R/R Ph‐negative BCP‐ALL in first salvage. The role of blinatumomab in patients with CRD1 <12 months, EMD, or high tumor burden should be evaluated in future trials.

1001. Feasibility and Outcomes of a Pre-Transplant Antibiotic Allergy Evaluation Program for Allogeneic Hematopoietic Cell Transplant (HCT) Candidates

BackgroundAntibiotic allergies impact the management of hematopoietic cell transplant (HCT) patients who are often prescribed antibiotics for infection prophylaxis and treatment. We evaluated the feasibility and outcomes of an antibiotic allergy evaluation program prior to allogeneic HCT.MethodsIn August 2017, we implemented a program to expedite allergy clinic referrals for adult allogeneic HCT candidates who reported an antibiotic allergy at their initial pre-transplant evaluation visit (PTEV). Allergy labels and clinical data including outcomes of allergy evaluation were prospectively collected for patients with PTEVs between 8/10/17 and November 15/18. The use of selected antibiotics was collected in the 100 days following HCT among patients with a reported β-lactam allergy (BLA). Choice of prophylactic agent for Pneumocystis jiroveci among patients with reported sulfa allergies was assessed among HCT recipients after engraftment.ResultsOf 276 allogeneic HCT candidates, 109 (39.5%) reported >= 1 antibiotic allergy (Table 1). Of the 109, 69 (63%) were referred for allergy evaluation; 83% (57/69) of those referred were evaluated at a median of 14 days after PTEV, and a median of 18 days before transplant. Among evaluated patients, 45 (79%) had >= 1 antibiotic allergy de-labeled including 74% (28/38) of those with BLA (Figure 1). Of the 10 patients whose BLAs could not be delabeled, 1 had a possible immediate IgE-mediated reaction, 5 had a delayed type IV hypersensitivity, and 4 had other reactions or required additional testing. Post-transplant antibiotic use among evaluated vs. nonevaluated patients reporting BLA is shown in Figure 2. Among 31 patients with reported sulfa allergies who underwent HCT, those who were evaluated received TMP-SMX rather than alternative prophylaxis more often (48%; 11/23) than those who were not evaluated (25%; 2/8). 10 (43%) of 23 evaluated patients were delabeled; 7 of 10 delabeled patients received TMP-SMX.ConclusionAntibiotic allergies are frequently reported among HCT candidates. Pre-transplant antibiotic allergy evaluation was feasible, led to de-labeling of the majority of reported allergies, and may alter antibiotic prescribing and increase the use of preferred agents following transplant. Disclosures All authors: No reported disclosures.

1761. A Single-Center Experience with Cidofovir for the Treatment of Double-Stranded (ds) DNA Viruses in Hematopoietic Cell Transplant (HCT) Recipients

BackgroundCidofovir (CDV), a nucleotide analog antiviral, is active against multiple dsDNA viruses relevant in HCT recipients. Despite a broad spectrum of activity, CDV utility is limited due to nephrotoxicity. We describe our experience with CDV in a large contemporary cohort from a single Institution.MethodsRetrospective review of adult HCT recipients who received CDV for any indication from 2011 to 2017. Initiation and duration of CDV treatment were at physicians’ discretion. CDV exposure and indications, Serum Creatinine (SCr) and outcomes were extracted from medical records and hospital databases.ResultsOf 1,235 HCT recipients, 54 (4.4%) received ≥1 dose of CDV. Stem cell source was peripheral blood in 39 (72%) patients, cord blood in 13 (24%) and marrow in 2(4%); 42 (78%) patients received CD34+ selected HCT. At CDV initiation, 23 (43%) patients had active GvHD and 16 (30%) received systemic steroids. CDV was started a median of 85.5 days (range 14–335) post HCT, given for a median of 3 doses (range 1–13) for a median of 2 weeks (range 1–17). Indications were adenovirus (ADV) infection in 35 patients, CMV in 19, BK virus in 21 and HHV6 in 3 patients. Nineteen (35%) patients had >1 dsDNA virus. Forty-one (76%) patients received CDV (3–5 mg/kg) once weekly, mainly for ADV or CMV, and 13 received CDV (≤1 mg/kg) once to thrice weekly, mostly for BK hemorrhagic cystitis (N = 12). Baseline sCr was mean 0.88 mg/dL (standard deviation [SD] = 0.37) at CDV initiation, mean 1.07 mg/dL at end of treatment (EOT) (SD = 0.57, N = 48, P = 0.004) and mean 1.23 mg/dL at EOT + 2 weeks (SD = 0.72, n = 28, P = 0.027). At EOT, 13 patients (24%) had acute kidney injury (AKI, ≥1.5-fold increase from baseline sCr). Of those, 12 (92%) received concomitant nephrotoxic drugs. AKI was attributed to other etiologies by treating physician in six patients. Of 51 patients with follow-up at EOT, 29 (57%) had clinical response to CDV treatment. Nineteen (35%) patients died ≤ 4 weeks from last CDV dose.Conclusion24% of highly immunocompromised HCT patients experienced AKI following CDV treatment for dsDNA viruses. The co-administration of nephrotoxic medications and the direct effect of infection limit our ability to assess the relative impact of CDV on renal function. Our data underscores the need for safer treatment options for HCT patients with life-threatening infections with dsDNA viruses. Disclosures All authors: No reported disclosures.

Autologous hematopoietic cell transplantation for acute myeloid leukemia in adults: 25years of experience in Japan.

Autologous hematopoietic cell transplantation (HCT) has not gained universal popularity in the treatment of acute myeloid leukemia (AML), and its status remains unclear. To determine the implementation status and outcomes of autologous HCT for adults with AML in Japan, we analyzed data from 1,174 patients (including 446 with acute promyelocytic leukemia [APL]) who underwent autologous HCT between 1992 and 2016 consecutively reported to the Japanese nationwide transplantation registry. The annual number of transplantations peaked at 82 cases in 1997, and has recently remained at around 40 cases. The percentage of APL has increased sharply since 2004, and currently exceeds 70%. While most non-APL patients underwent autologous HCT during first complete remission (CR), transplantation during second CR has become mainstream for APL patients since the early 2000s. The 5-year survival, relapse, and non-relapse mortality rates were 55.3%, 42.1%, and 8.6% for non-APL patients, and 87.6%, 12.9%, and 3.4% for APL patients, respectively. Patients transplanted in the later period showed better survival than those transplanted in the earlier period, both for non-APL (P < 0.001) and APL (P = 0.036). These results clearly show the various changes in transplantation practice and post-transplant outcomes in Japan over the past 25years.

Infectious complications in children and adults with hematological malignancies

AbstractInfections are the main cause of morbidity and mortality in pediatric hematology and oncology (PHO) and hematopoietic cell transplantation (HCT) settings in children and adults. The analysis of incidence and outcome of bacterial, fungal, and viral infections in Polish PHO/ HCT centers was performed over a period of 72 months (2012–2017). The summary of infections in 5628 patients with newly diagnosed malignancy and 971 HCTs is presented in this paper. Additionally, data of 650 pediatric HCTs from 2012 to 2015 were compared with the data of 3200 HCTs in adults. The risk of any infection per patient was higher in HCT vs PHO patients (2062/971 vs 7115/5628; 2.1 vs 1.3; HR=1.7, p&lt;0.0001). The incidence of bacterial infections was 34,2±0,6% in PHO vs 41,5±1,6% in HCT patients, and the outcome was better in PHO patients: 97,9±0,2% vs 91,8±1,0%. The incidence of patients with fungal infection was 8,8±0,4% vs 21,2±1,3%, and the outcome was better in PHO patients: 95,9±0,7% vs 85,8±2,3%. Incidence of viral infections was 5,0±1,0% in PHO setting, including part of previously transplanted patients, and 47,8±2,2% in HCT setting (60,9±2,3% allo-HCT; 5,6±1,3% auto-HCT). In children, the incidence was higher for bacterial (36.0% vs 27.6%), fungal (25.3% vs 6.3%), and viral (56.3% vs 29.3% allo-HCT; 6.6% vs 0.8% auto-HCT) infections than in adults (p&lt;0.0001), and the outcome was better for bacterial (95.5% vs 91.4%), fungal (88.0% vs 74.9%), and viral (98.6% vs 92.3%) infections. In conclusion, the presented large studies have determined the incidence of infectious complications and their outcomes in HCT and PHO centers in Poland.

Histologic and clinical cross-sectional study of chronic hair loss in patients with cutaneous chronic graft-versus-host disease

While scalp alopecia represents a distinctive feature of chronic graft-versus-host disease (cGVHD), little is known about the clinical and histologic presentation of hair loss. We sought to classify the clinical presentations and histologic findings of chronic hair loss in patients with cutaneous cGVHD. A prospective cohort of 17 adult hematopoietic cell transplantation (HCT) recipients with cutaneous cGVHD was enrolled. Dermatologic examinations were performed, and punch biopsy specimens of the scalp were obtained. Biopsy specimens were analyzed with hematoxylin-eosin and immunohistochemical stains in all cases and fluorescence in situ hybridization analyses in specific cases. Clinically, 4 patterns of hair loss were described-patchy nonscarring (41.2%), diffuse nonscarring (11.8%), diffuse sclerotic (11.8%), and patchy sclerotic (5.9%). The location of the inflammatory infiltrate on hematoxylin-eosin-stained specimens correlated with the hair loss pattern patients had clinically, with cell populations around the bulb and bulge in nonscarring and sclerotic cases, respectively. Fluorescence in situ hybridization studies in female cGVHD patients with male donors demonstrated green Y chromosomes limited to the area of the hair follicle affected by inflammatory cells. This study describes the various clinical and histologic subtypes of long-standing alopecia in adult cGVHD patients and suggests that this alopecia may be a direct manifestation of cGVHD of the hair follicle.

Antimicrobial de-escalation in adult hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin.

The optimal duration of empiric antimicrobial therapy in febrile neutropenia of unknown origin is unclear. This study evaluated outcomes in autologous and allogeneic hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin who received early de-escalation of broad-spectrum antimicrobials prior to hematopoietic recovery versus those who continued broad-spectrum antimicrobials until hematopoietic recovery. A single-center, retrospective study assessed hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin. Patients were categorized into either cohort 1, representing early de-escalation prior to hematopoietic recovery, or cohort 2, representing continuation of broad-spectrum antimicrobials until hematopoietic recovery. A total of 107 patients were included (22.4% in cohort 1 and 77.6% in cohort 2). Most patients (87.5%) in cohort 1 underwent haploidentical hematopoietic cell transplantation, whereas 84.3% of patients in cohort 2 received autologous hematopoietic cell transplantation. There were no significant differences in rates of recurrent fever (4.2% versus 7.2%, in cohorts 1 and 2, respectively, adjusted odds ratio = 0.84, P = 0.85), re-escalation (4.2% versus 4.8%, adjusted odds ratio = 1.57, P = 0.64), and Clostridioides difficile-associated infections (4.2% versus 2.4%, adjusted odds ratio = 2.27, P = 0.43). No patient experienced in-hospital mortality, intensive care unit admission, or bacteremia. Hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin in which broad-spectrum antimicrobials were de-escalated prior to hematopoietic recovery did not experience adverse outcomes. These results concur with recently published studies and the Fourth European Conference on Infections in Leukemia guidelines. An early de-escalation approach in haploidentical hematopoietic cell transplantation recipients specifically appears safe and may result in a reduction in antimicrobial utilization.

Incidence and Outcomes of Bacterial Bloodstream Infections during Acute Graft-versus-Host Disease Involving the Gastrointestinal Tract after Hematopoietic Cell Transplantation.

Despite the association of acute graft-versus-host disease (aGVHD) and bacterial bloodstream infections (BSIs) in hematopoietic cell transplant (HCT) recipients, relatively little is known about BSIs, specifically during gastrointestinal (GI) tract aGVHD (aGHVD-GI). The purpose of this study was to evaluate the incidence, risk factors, and mortality of BSIs complicating aGVHD-GI. This was a retrospective review of adult HCT recipients with grades I to IV aGVHD-GI between January 2009 and October 2017 at Oregon Health and Sciences University. BSIs occurring within 30 days of onset of aGVHD-GI were included. BSIs were categorized as "clinical" or "surveillance" based on chart review. A subgroup analysis of patients with grade IV aGVHD-GI examined potential BSI risk factors and cumulative survival at 30 and 45 days after onset of aGVHD-GI. Included were 229 patients. There were 45 unique BSIs in 39 patients (17%): 31 clinical (68.9%) and 14 surveillance (32.1%). The median time from aGVHD-GI onset to BSI was 18.5 days. BSIs were significantly more common during grade IV aGVHD-GI compared with grades I, II, or III. Fifty-two organisms were isolated during BSIs: 23 (44.2%) gram-positive and 29 (55.8%) gram-negative. Sixteen BSIs (36%) occurred during antibiotic exposure, and those were more likely to be caused by multidrug-resistant organisms. Prior BSI occurring between the time of HCT and onset of aGVHD-GI and receipt of etanercept for steroid-refractory aGVHD-GI were independently associated with BSI. Eight patients, all with grade IV aGVHD, representing 30.8% of patients with BSI in this subgroup, experienced infection-associated mortality. Cumulative survival at days 30 and 45 after onset of grade IV aGVHD-GI was similar among patients with and without BSI. BSI is a common complication of grade IV aGVHD-GI, resulting in significant infection-associated mortality. Interventions targeting those at highest risk may be warranted.

Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients.

Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking. We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period. One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses. Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis.

Preliminary Outcomes of Letermovir Use for Cytomegalovirus Prophylaxis: A Retrospective Assessment at a Single Center

Introduction Cytomegalovirus (CMV) is associated with significant morbidity and mortality in the hematopoietic cell transplant (HCT) population. In the absence of prophylaxis, reactivation occurs in upwards of 80% of seropositive allogeneic HCT recipients and primary infections in roughly 15% of CMV-mismatched HCTs. Agents used to prevent clinically significant CMV (csCMV) including ganciclovir and foscarnet can be associated with toxicities including renal dysfunction and myelosuppression. Letermovir is a novel antiviral targeting the viral terminase complex and has demonstrated efficacy in preventing csCMV in adult CMV seropositive allogeneic HCT recipients with minimal associated toxicities. Objectives To describe a single center experience of the use of letermovir as primary and secondary prophylaxis in adult allogeneic HCT recipients. Methods This retrospective analysis assessed 25 adult HCT patients receiving letermovir for primary or secondary prophylaxis between January 1, 2018 and September 24, 2018. Primary prophylaxis per hospital protocol was given through approximately d+100 in CMV seropositive recipients and also allowed in CMV seronegative recipients with seropositive donors. csCMV was defined as CMV viremia necessitating preemptive therapy or CMV disease. Patients were evaluated for development of csCMV on letermovir prophylaxis, early cessation of prophylaxis due to perceived toxicities, and development of csCMV post-cessation of primary prophylaxis. Results Twenty-two patients received letermovir for primary CMV prophylaxis. The primary underlying disease was AML (7/22, 32%). CMV serostatus was as follows: D-/R+ (9/22, 41%), D+/R+ (9/22, 41%), D+/R- (4/22, 18%). Letermovir was initiated ata median of 5.5 days post-transplant. Median letermovir duration was 95 days post-transplant. Early cessation due to perceived toxicities occurred in 41% (7/22) of patients. Reasons for early discontinuation were ongoing cytopenias (4/7, 44%) and nausea (3/7, 33%). No csCMV developed during therapy. In patients completing the intended primary prophylaxis (n = 10), thus far no patients have developed csCMV within a median duration of 150 days post letermovir cessation. Three patients received letermovir for secondary prophylaxis. All were CMV seropositive and high risk on basis of haploidentical donors (2/3, 67%) and use of cord blood (1/3, 33%). Therapy was initiated a median of 57 days post-transplant with no patients developing csCMV on therapy. Conclusions Letermovir was an effective antiviral in both primary and secondary CMV prophylaxis and was generally well tolerated. Side effects directly related to letermovir were difficult to assess in this complex patient population. Close monitoring is required following cessation of primary prophylaxis. Prospective studies defining the optimal duration for letermovir prophylaxis are needed.

The Role of Measurable Residual Disease (MRD) at Time of Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia Transplanted after Myeloablative Conditioning. A Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. Therefore, in this retrospective multicenter study we explored if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in recipients of myeloablative TBI-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18-72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. In 1816 of these patients no disease was detectable before transplantation and in 964 patients MRD was detectable (MRD positivity). Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02-1.39), 1.26 (1.1-1.44), 1.51 (1.26-1.8). TBI was associated with a better OS, LFS and RI with HR of 0.75 (0.62-0.90), 0.70 (0.60-0.82) and 0.60 (0.49-0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS (HR 1.26, 1.05-1.51) and LFS (HR 1.3,1.1-1.53), and higher RI (HR 1.53, 1.23-1.9) in the TBI group, and with higher RI (HR 1.58, 1.13-2.21) in the chemotherapy group. There was no significant association between MRD and other outcomes in this last cohort. TBI based conditioning was associated with improved OS, LFS, and RI in both MRD negative and MRD positive patients (figure). In this large study we confirmed that patients who are MRD negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI based conditioning in myeloablative setting.

Oral Brincidofovir Decreased HHV-6 Viremia in Hematopoietic Cell Transplant Recipients: Results from the Suppress Study

Introduction Human herpesvirus 6B (HHV-6) is detected in plasma in ∼40% of allogeneic hematopoietic cell transplant (HCT) recipients and ∼75% of cord blood recipients. HHV-6 viremia, particularly at levels >104 copies/mL, is associated with increased risk for HHV-6 encephalitis. Ganciclovir and foscarnet have antiviral activity against HHV-6, but studies of pre-emptive or prophylactic treatment have not been successful in preventing HHV-6 encephalitis. Prophylaxis for HHV-6 has never been studied in a randomized trial. Brincidofovir (BCV, CMX001) has potent in vitro activity against HHV-6 (EC50=0.007 µM), and unlike cidofovir, has good CNS penetration. Objectives In vivo activity of BCV against HHV-6 has not been demonstrated. We tested plasma from participants in the SUPPRESS clinical trial to explore the potential of BCV to prevent HHV-6 viremia. Methods SUPPRESS was a randomized, double-blind, placebo (PBO)-controlled trial of oral BCV for cytomegalovirus (CMV) prophylaxis after allo-HCT. 452 adult CMV-seropositive HCT recipients without CMV viremia at screening were randomized 2:1 to receive BCV or PBO twice-weekly until week 14 post-HCT. We selected subjects who were randomized within 2 weeks of allo-HCT, who did not have HHV-6 viremia at baseline, and who received at least 6 doses of BCV or PBO within the first 3 weeks of randomization for HHV-6 testing. Plasma samples from the first six weeks post-HCT were tested for HHV-6 with quantitative PCR (Viracor Eurofins, Lee's Summit, MO). We compared HHV-6 viremia between subjects who received BCV and those who received PBO using the Kaplan-Meier method, log rank test, and Cox proportional hazards model. Results 92 subjects in the BCV group and 61 in the PBO group met criteria for inclusion: 64% were male, 84% were white, and median age was 57 years (range: 18-76). 6% of subjects received cord blood grafts, 5% had haploidentical donors, and 8% had mismatched donors. 41% had ex vivo T-cell depletion or received serotherapy with antithymocyte globulin or alemtuzumab. Baseline characteristics were balanced between groups. 15% of BCV subjects vs. 31% of PBO subjects had detectable HHV-6 viremia within 6 weeks after HCT. The cumulative incidence of HHV-6 viremia was significantly lower in BCV subjects (Figure 1). Two subjects (2%) in the BCV group had HHV-6 viremia >103 copies/mL compared to 7 (11%) in the PBO group (Figure 2). In the study overall, no subjects in the BCV group and one in the PBO group developed HHV-6 encephalitis. Conclusion BCV reduced the incidence of detectable HHV-6 viremia in HCT recipients enrolled in a randomized, placebo-controlled clinical trial. BCV prophylaxis could prevent the morbidity and mortality associated with HHV-6 in HCT recipients.

Limited Utility of Outpatient Surveillance Blood Cultures in Hematopoietic Cell Transplant Recipients on High-Dose Steroids for Treatment of Acute Graft-versus-Host-Disease.

Steroids used to treat acute graft-versus-host-disease (GVHD) are believed to blunt clinical symptoms of infection. We aimed to assess the value of weekly surveillance blood cultures (SBCs) drawn in an outpatient setting from hematopoietic cell transplant (HCT) patients receiving high-dose steroids. We hypothesized that most positive outpatient surveillance cultures would be low-pathogenicity, gram-positive organisms and would lead to excess vancomycin therapy. We conducted a retrospective review of blood cultures collected from a cohort of adult HCT patients enrolled in a clinical trial of acute GVHD therapy with high-dose steroids (prednisone-equivalent doses ≥ .5 mg/kg/day) between April 2009 and May 2013. SBCs were defined as those collected weekly from central venous catheters in the outpatient setting while patients were receiving high-dose steroids. Cultures obtained as part of a symptom workup or as follow-up for documented bacteremia were excluded. Clinical data were collected using center databases supplemented by medical record review. One hundred twenty-seven HCT recipients were eligible for inclusion in the study. A total of 1015 SBCs were obtained, with a median of 8 cultures (interquartile range, 5 to 10) per patient. Forty-two organisms were isolated from 36 of 1015 cultures (3.5%) in 30 unique patients, or 1 positive culture per 28 blood cultures drawn. The most frequently detected organisms were coagulase-negative Staphylococci (25/1015 [2.5%]). Gram-negative organisms were rare (4/1015 [.4%]. Antibiotics were administered to most patients with positive surveillance cultures (33/36 [92%]). Six were admitted to the hospital for treatment; none needed intensive care or died from their bacteremia. Vancomycin was the most frequently administered antibiotic, comprising 256 of 376 total days (68%) of antibiotic received by the cohort with a median duration of 10 days ((interquartile range, 7 to 14). Weekly outpatient SBCs obtained from asymptomatic patients on high-dose glucocorticoids for treatment of acute GVHD after allogeneic HCT were infrequently positive, and most organisms were low-pathogenicity organisms. SBCs also led to excess antibiotic exposure and costs, suggesting benefits of such ambulatory screening may be of limited value in this setting.

56+ Cell Reconstitution Kinetics in HLA Matched Unrelated Donor Allografts: What Doesn't Kill You Makes You Stronger

Introduction Patients who receive HLA matched allogeneic hematopoietic cell transplant (HCT) from donors with killer immunoglobulin-like receptor (KIR) haplotype B have improved survival, decreased acute GVHD, and less CMV reactivation when compared with those transplanted with KIR haplotype A donors. However, the effect of NK cell (CD56+) reconstitution kinetics on clinical outcomes in patients with different KIR haplotypes is not well studied. Objectives Compare CD 56+ cell reconstitution kinetics in HCT patients with donor KIR Haplotypes A and B and its effect on clinical outcomes. Methods We assessed absolute NK and T cell counts at days +30, +60 and +100 in 10/10 allele level HLA matched unrelated HCT recipients with known donor KIR typing. KIR haplotype B was assigned when KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 or KIR3DS1 were present in the donor, and haplotype A in their absence. We also evaluated potential impact of NK cell and T cell count recovery on key post transplant outcomes in these patients. Results The study population consisted of 60 adult HCT patients with a median age of 52 years; 55% had lymphoid and 45% had myeloid disease; 57% received a reduced intensity conditioning regimen; 82% underwent T cell depletion with ATG; 88% received GCSF mobilized PBSCT. Recipients of donor haplotype A had a median absolute CD56+ cell count of 210mL−1 (±156) on day (d) +30; 189 (±225) on d+60, and 160 (±120) on d+100; recipients of haplotype B had median absolute CD56 cell counts of 286 (±276) on d+30, 196 (±194) on d+60, and 165 (±124) on d+100 (P=N.S. for haplotype B vs. A). As a whole, median CD56+ cell counts peaked at d+30 post HCT, a phenomenon more pronounced in haplotype B (fig. 1), and then declined at d+60 and d+100. There was no correlation between CD56 and CD3 at d+60. Survival was superior in patients who had CD56+ cell count > median for the entire cohort (227 µL−1) on d+60 (p= .039) (fig. 2); ROC-AUC analysis confirmed the deleterious effect of low NK cell counts, with a higher mortality rate observed in those with CD56+ cell count of Conclusions The magnitude of NK cells reconstitution at d+60 may override the effect of KIR Haplotype on survival in patients with myeloid and lymphoid malignancies, as well as play an important role in controlling viral reactivation. Our data demonstrates that poor NK cell recovery does not necessarily imply delayed T cell reconstitution; suggesting that the adverse survival effect may be NK cell mediated. Ongoing work is examining relationship between NK- and T-cell reconstitution as well as KIR-KIR ligand interactions, and clinical outcomes.

Efficacy and Pharmacoeconomic Impact of Letermovir for CMV Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients

Cytomegalovirus (CMV) seropositivity and early CMV reactivation after hematopoietic-cell transplantation (HCT) remain associated with increased mortality. Those at high risk include CMV seropositive recipient/donor pairs (CMV R+ or D+) and those on escalated immunosuppression (prednisone ≥ 20mg/kg) for graft versus host disease (GVHD). Historically, our institutional CMV reactivation rate (RR) was 63% in our high risk cohort, similar to national average. Prophylaxis with letermovir, a new CMV-antiviral therapy, significantly reduced the incidence of CMV reactivation and viremia in a prospective trial (Marty FM, et al. NEJM 2017). The purpose of this study was to assess CMV reactivation, defined as CMV viral load > 500 IU/mL, with letermovir prophylaxis and its pharmacoeconomic impact in an outpatient transplant program. This was a retrospective review of adult HCT patients receiving letermovir from December 2017-August 2018 at Vanderbilt University Medical Center. Use of letermovir was standardized at a program level. Therapy was used in high risk patients, undergoing HCT with matched-unrelated donor (MUD), cord blood donor or haploidentical donor transplants with no active CMV reactivation prior to initiation and no anti-CMV treatment post-HCT. Primary endpoint compared CMV RR to historical controls utilizing a two-sided t-test. Secondary outcomes evaluated logistics and cost impact. 30 patients met entry criteria (26 CMV R+, 21 D+), RR was significantly lower than our historical control (20% vs 63%; p = 0.0003). Median time to reactivation was 38 days post-HCT (29-58). 4 of the 6 patients with reactivation received induction therapy with ganciclovir (50%), valganciclovir (25%), or letermovir (25%, peak viral load 740 IU/mL) for ∼40 days (31-52). All were CMV R-/D+ with AML and received HCT from MUD (75%) or haploidentical donors (25%). The remaining 2 patients (CMV R+/D+) had low level reactivation (137-500 IU/mL) and continued letermovir through day 100 without additional CMV treatment. Patients started letermovir by day 14 post-HCT (5-65) with a median 83 days (7-158) of prophylaxis. 3 patients received letermovir as secondary prophylaxis due to prior CMV reactivation or escalated immunosuppression for GVHD. Of those patients, reactivation occurred in 1 patient (AML MUD transplant; CMV D-/R+) who had 2 reactivations while on foscarnet therapy. No letermovir resistance was observed. Letermovir copay was between $10 and $360/month. 76% of prescriptions required prior authorization, 19% monetary grant, 18% patient assistance. Majority had private insurance (49%) and Medicare/Medicaid (36%) with a median of 3 days for approval and 5 days from prescription submission to patient medication pick-up. Primary prophylaxis with letermovir is associated with significantly lower RR compared to historical controls and is financially feasible with dedicated pharmacy services.