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Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

Introduction Infections cause substantial morbidity and mortality in patients with acute myeloid leukemia (AML) and other high-grade myeloid neoplasms. The contemporary regimen of CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) has favorable hematologic outcomes compared to '7+3' (standard-dose cytarabine, anthracycline) in some studies but may be more myelosuppressive. The aim of this investigation was to determine and compare the incidence and spectrum of infections after CLAG-M and 7+3. Methods For this retrospective cohort study, we identified microbiologically documented moderate to severe infections (grade ≥2 infections; Blood and Marrow Transplant Clinical Trials Network Technical Manual of Procedures (BMT CTN MOP) guideline) after the first cycle of CLAG-M for newly-diagnosed (ND) or relapsed/refractory (R/R) AML or other high-grade myeloid neoplasms (≥10% blasts in marrow or peripheral blood) and compared these findings to adults receiving 7+3 for ND disease. We recorded infections for up to 90 days from the start of chemotherapy or until the start of a second cycle or death, whichever occurred first. We compared the cumulative incidence probability of time-to-first infection between cohorts using Gray's test with start of additional therapy and death as competing risk events. Infection rates, defined as average number of infections per 1000 patient days-at-risk, were compared between cohorts using Poisson regression. Results The study included 442 individuals consisting of 196 with ND disease and 131 with R/R disease receiving CLAG-M, and 115 with ND disease receiving 7+3 (Table 1). Fifty-four (28%), 65 (50%), and 19 (17%) individuals per cohort had one or more moderate to severe microbiologically documented infection, respectively. The absolute neutrophil count was Conclusions Moderate to severe microbiologically documented infections are common after the first cycle of chemotherapy for ND or R/R AML or other high-grade myeloid neoplasms. CLAG-M may be associated with more moderate to severe microbiologically documented infections than 7+3 for ND disease. Individuals with R/R disease are at the highest risk. Invasive fungal infections were relatively frequent but may be significantly reduced by mold-active azole prophylaxis. New approaches to improve neutrophil recovery and function may reduce infection risk. Figure 1 Figure 1. Disclosures Halpern: Abbvie: Consultancy; Tolero Pharmaceuticals: Research Funding; Agios: Consultancy; Gilead: Research Funding; Agios Pharmaceuticals: Research Funding; Bayer: Research Funding; Novartis: Research Funding; Imago Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Nohla Therapeutics: Research Funding; Pfizer: Research Funding. Delaney: Deverra Therapeutics: Current Employment, Other: Founder, CSO. Pergam: Chimerix, Inc: Research Funding; Global Life Technologies, Inc: Research Funding; Merck & Co.: Research Funding; Sanofi Aventis: Research Funding. Boeckh: Merck: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; GSK: Consultancy. Walter: BMS: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amphivena: Consultancy, Other: ownership interests; Selvita: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Hill: Gilead: Consultancy, Research Funding; Karius: Research Funding; Octapharma: Consultancy; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Allogene therapeutics: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; OptumHealth: Consultancy.

Introduction Herpes zoster (HZ) after hematopoietic cell transplant (HCT) is a well-known complication with a peak incidence during the first year post-HCT. Cord blood transplant (CBT) recipients are at increased risk for viral infections and historically have a cumulative incidence of HZ approaching 80% by 2.5 years in the context of short-term peri-HCT antiviral prophylaxis. In 2009, international guidelines for prevention of infections after HCT recommended maintaining HZ prophylaxis for at least 1 year after HCT. We retrospectively studied the impact of longer-term antiviral prophylaxis on the incidence of HZ after CBT. Methods Between 2006 and 2016, we performed 360 CBT at our Institution. Patients who were seronegative for varicella zoster virus (VZV) or received the live varicella vaccine (i.e. Varivax®) pre-CBT without a history of chickenpox or HZ were excluded. From 2006-2008, CBT recipients received acyclovir (ACV) 800 mg BID or valacyclovir (VACV) 500 mg BID for HSV and VZV prophylaxis. From 2008-2016, patients who were CMV seropositive received higher-dose prophylaxis with VACV 2g TID through day +100. Before 2009, institutional guidelines recommended to continue prophylaxis until the end of immunosuppression; after 2009, prophylaxis was recommended for at least 1 year and until 8 months after immunosuppression ends. For patients discharged from our center, data were collected through standardized questionnaires and medical records. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ after CBT, treating death and second HCT as competing risk events. Variables were evaluated for an association with development of HZ using Cox proportional hazards regression; those of biological interest and with a P value ≤ 0.3 in univariable analyses were considerate for multivariable model. Results The study cohort consisted of 227 CBT recipients with a median follow up of 25.4 months (interquartile range [IQR], 6.8 - 49). Follow up time was truncated at the time of death (n=113), second HCT (n=13) or last available records (n=32). Cohort characteristics are shown in Table 1. Among 1-year survivors, 91% were still receiving prophylaxis for a median duration of 20.6 months post-CBT (IQR, 14.1 - 29.4). HZ occurred in 44 patients (19%) at a median of 23.6 months (IQR, 16.1 - 30.3). Most patients (n=31/44, 70%) were not taking antiviral prophylaxis when HZ developed. The cumulative incidence of HZ by 1-year post-CBT was low (1.8%; 95% CI, 0.1%-4%) but increased starting from the second year and reached 26% (95% CI, 19%-33%) by 5 years (Figure 1). Disseminated HZ occurred in 5 cases (11%), and post-herpetic neuralgia occurred in 14 cases (31.8%). Of the 13 HZ episodes that occurred in patients reportedly taking antiviral prophylaxis, 6/13 had clear documentation of ongoing antiviral prophylaxis and 5/13 were still receiving immunosuppressive treatment for graft-versus-host disease (GvHD). All patients responded to antiviral treatment, which consisted of ACV (n=18), VACV (n=16), and famciclovir (n=1). In a multivariable analysis, patients who received myeloablative conditioning or had acute GvHD grades 2-4 had a higher risk of HZ, whereas the use of antiviral prophylaxis was associated with a lower risk of HZ (Table 2). Among 35 patients who discontinued prophylaxis before completing immunosuppressive therapy, 28.5% developed HZ. We found no association between CD4+ T cell counts at 1-year after-CBT and HZ risk. Conclusions In this cohort of 227 CBT recipients with up to 5 years of follow up, the cumulative incidence of HZ was 26% at 5 years, despite antiviral prophylaxis for >1 year in the majority of patients. Furthermore, these patients had high rates of post-herpetic neuralgia and disseminated VZV. Antiviral prophylaxis protected against HZ but there were breakthrough cases. Given that a high number of patients interrupted prophylaxis while still receiving immunosuppressants, adherence to antiviral prophylaxis should be emphasized by health care providers. Based on our findings, the lack of alternative prophylactic strategies at this time, and the safety of ACV/VACV, longer duration of prophylaxis should be considered, especially in patients with ongoing immunosuppression. Recent data demonstrating the safety and efficacy of the HZ subunit vaccine after autologous HCT support future study of HZ vaccination after allogeneic HCT. Disclosures Delaney: Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Boeckh:Chimerix: Research Funding; GSK: Other: Personal fees; GSK: Research Funding; Merck: Research Funding; Merck: Other: Personal fees; Clinigen: Other: Personal fees. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Hill:Takeda: Other: research support; Karius: Other: research support; Amplyx: Consultancy; Nohla Therapeutics: Consultancy, Other: research support.

Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease (P values < .01). Absolute lymphocyte count of

It is not known whether pandemic 2009 influenza A/H1N1 (2009 H1N1) leads to more serious disease than seasonal influenza in hematopoietic cell transplant (HCT) recipients. In a retrospective study in HCT recipients with virologically proven influenza virus infection, a total of 161 HCT recipients (18 2009 H1N1, 103 seasonal influenza A, and 40 seasonal influenza B) were analyzed. In multivariable analyses, more patients with 2009 H1N1 had lower respiratory tract disease (LRD), hypoxemia, and prolonged viral shedding compared with seasonal influenza A. Seasonal influenza A and B outcomes were similar. There was no difference in overall and influenza-associated mortality among influenza virus types. Both early and delayed administration of antiviral therapy was shown to be beneficial in terms of decreased rates of development of LRD, although earlier intervention appeared to be more effective. Profound lymphopenia and lack of early antiviral therapy were associated significantly with LRD, hypoxemia, and death. High-dose corticosteroid treatment (≥ 1 mg/kg) given at the time of influenza diagnosis was associated with a reduced risk for mechanical ventilation. Thus, our data suggest that infection with 2009 influenza A/H1N1 resulted in more severe respiratory disease in HCT recipients compared with seasonal influenza.

Background: DNA viral infections remain important causes of morbidity following cord blood transplantation (CBT). The cumulative incidence, risk factors, and kinetics of reactivation of multiple double-stranded (ds)DNA viruses after CBT are unknown. This lack of understanding limits development of strategies for broader prophylaxis. Methods: Weekly plasma samples through 100 days post-CBT were retrospectively tested by quantitative PCR for HHV-6B, HHV-6A, BK, adenovirus (ADV), and EBV; twice-weekly tests for CMV were performed prospectively. Children and adults with ≥1 year of follow up and availability of >60% of samples while alive, with Results: Cohort characteristics are presented in Table 1: 95% of patients had ≥1 virus. Detection rates were: CMV, 58%; HHV-6B, 74%; HHV-6A, 0%; BK, 62%; ADV, 10%; and EBV, 3% (Table 2). Detection of multiple viruses at any time and concurrently was frequent (Fig. 1); ≥3 viruses were detected in 39% of the cohort at any time and in 14% concurrently. The proportion of patients with detection of any and multiple viruses peaked by wk 4 and persisted through wk 14. Grade 3-4 acute GVHD increased risk for detection of ≥2 (aHR, 3.1; p=0.01) and ≥3 (aHR, 3.1; p=0.08) viruses. Median time to detection was similar for all viruses (3-4 wks) except EBV (7.6 wks; Table 2). Median time to peak viral load from first detection was longest for BK (7 wks) and shortest for HHV-6B (3 days). Despite preemptive therapy for CMV, median time to peak viral load was 3 weeks. Among patients with ≥5 samples tested, the median proportion of positive samples after first detection was Median viral loads after reactivation ranged from 2.3 (CMV) to 3.4 (BK) log10 copies/ml; CMV was mitigated by treatment. Max viral loads were significantly higher than first for all except EBV; mean differences ranged from 0.1 (EBV) to 1.6 (BK) log10 copies/ml (Table 2, Fig. 3). Viral load did not markedly differ if viruses were detected alone or concurrent with other viruses (Fig. 3). Conclusions: We demonstrate frequent and persistent detection of multiple dsDNA viruses through day 100 after CBT. BK demonstrated the greatest and most sustained expansion, whereas HHV-6B reached max levels soon after first detection. These findings provide the rationale to study the impact of multiple virus reactivations on organ disease, health care utilization, and mortality in larger cohorts. These data will be critical to design trials using novel, safer therapies (e.g. CMX001 [brincidofovir], multi-virus-specific T cells) for broad prevention of viral reactivation. Disclosures Hill: Chimerix, Inc.: Research Funding. Delaney:medac: Research Funding; Novartis: Other: Chair, DSMB; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Nichols:Chimerix, Inc.: Employment, Equity Ownership. Zerr:Chimerix, Inc.: Research Funding.

Background: Late cytomegalovirus (CMV) disease is a well-established complication in patients undergoing HCT and extended surveillance and preemptive therapy in high-risk patients is recommended by international guidelines. The objectives of this study were to describe the incidence, clinical characteristics and outcome of, and risk factors for the development of late CMV disease in day 100 survivors of allogeneic HCT who did and did not undergo viral load-guided preemptive therapy based on a pre-defined risk algorithm. Methods: We retrospectively analyzed medical records of 1526 HCT patients (donor or recipients seropositive), who received their first allogeneic HCT at FHCRC between 2001 and 2011 and survived to day 100. PCR-based surveillance was recommended for patients who had CMV viremia or disease before day 100 or had GVHD that required systemic treatment. Preemptive therapy was recommended for CMV DNA levels of >1000 copies per mL of plasma. We evaluated all CMV disease events occurring between day 100 and 2 years. Patients were categorized by their recommended surveillance status and, among those who were in the surveillance category, adherence to the testing schedule was examined. Cox proportional hazards models were used to evaluate the risk of late CMV disease and overall mortality. Candidate variables included risk status for PCR surveillance, CMV reactivation (before day 100 and after day 100 [as time dependent variable]), steroid use (≥ 1mg/kg/day) as well as other patient/donor and transplantation related factors; for mortality late CMV disease was also analyzed as a variable. Results: Among 1526 patients there were 118 cases of late CMV disease by 2 years (cumulative incidence 8% [95% CI- 7-9%]). The first manifestation of late CMV disease was pneumonia in 57 cases (48%), gastrointestinal disease (GI) in 54 cases (46%), and retinitis in 7 cases (6%). Fifteen percent of patients with late CMV disease (1% of cohort) had a subsequent event. Among first cases of late CMV disease 97 (82%) occurred between day 100 and 1 year and 21 (18%) occurred between 1 and 2 years after HCT. The median time to first late CMV disease was 192 days for pneumonia, 196 days for GI, and 230 days for retinitis. Extended CMV surveillance after day 100 was recommended for 1246 (82%) of patients. Late CMV disease occurred in 8.7% of patients for whom continued surveillance was recommended, compared to 2.9% of patients who were considered at low risk and were not advised to continue CMV testing. The median time to first late CMV disease event was 192 days post-transplant for the high risk group and 292 days for the low risk group. Among the 8 disease cases in patients in the low risk group, 4 cases (2 pneumonia, 2 GI) occurred in the first year and 4 (1 pneumonia, 3 GI) in the second year after HCT. In a multivariable Cox model steroid treatment after day 100 (HR=6.49; 95% CI 3.4-12.3, p Late CMV disease (HR=2.2; 95% CI 1.6-3, p An analysis of the adherence to PCR surveillance and viral load levels among breakthrough cases will be presented at the conference. Conclusions: Late CMV disease remains an important complication after HCT. Currently recommended risk stratification parameters for extended surveillance identify most patients at risk for late CMV disease, however, occasionally late CMV disease can occur in patients that were deemed at low risk at 3 months after HCT. Also, late CMV disease can occur beyond 1 year after HCT and disease recurrence is about 15%. Overall, both late CMV infection and disease continue to be independently associated with overall mortality in the preemptive therapy era. Refined strategies are needed to further reduce the late-occurring complications of CMV infection among HCT recipients. Disclosures Boeckh: Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

Background Parainfluenza virus (PIV) is a respiratory virus that infects approximately 10% of hematopoietic cell transplantation (HCT) recipients. A substantial proportion of patients with lower respiratory tract disease (LRD) present without prior upper respiratory tract infection (URI), but reasons for the lack of early detection are poorly understood. Since the definition of LRD differs among studies, we previously proposed a classification of LRD (possible, probable, and proven) that correlates with clinical outcomes (54thASH meeting; abstract #458). The classification demonstrated that patients with PIV detection in lungs (probable and proven LRD) had significantly worse survival than those with PIV detection in a nasopharyngeal (NP) sample alone (possible LRD and URI), with day 90 overall survival 50% vs. 90%, respectively. The purpose of the study was (1) to evaluate risk factors for progression to proven and probable LRD and (2) to determine factors associated with LRD without preceding URI. Patients and methods This retrospective cohort study included 391 HCT recipients with PIV infection transplanted between 1990 and 2011 at FHCRC. PIV detection was performed by conventional culture, direct fluorescent antibody testing, and/or polymerase chain reaction. Categories of PIV infection were defined according to site of PIV detection and radiography: URI: PIV detection in NP sample without new pulmonary infiltrates; possible LRD: detection in NP sample with new pulmonary infiltrates; probable LRD: detection in lung (BAL or biopsy) sample without new pulmonary infiltrates; and proven LRD: detection in lung sample with new pulmonary infiltrates. Patients diagnosed with LRD ≥ 2 days after URI diagnosis were considered to have progression to LRD. Risk factors for progression to proven/probable LRD were analyzed using Cox proportional hazards models, and comparisons between LRD cases with or without prior URI were performed by logistic regression models. Results Among 391 patients, 344 had a positive NP sample at diagnosis of PIV infection and 47 were diagnosed with a positive lung sample alone. Among 344 patients, 61 progressed to LRD and median time to progression was 7 days (range, 2–40). The cumulative incidence of progression by 30-days among patients who presented with URI was 19%; 5%, 4% and 11% of patients progressed to possible, probable and proven LRD, respectively, and 28% of patients with possible LRD further progressed to proven LRD. In a multivariate model among the 344 patients, bone marrow (BM) or cord blood (CB) as cell source (aHR, 3.1; 95% CI, 1.6-5.9, p < 0.001), lymphocyte count less than 100/µL at time of PIV infection (aHR, 2.7; 95% CI, 1.5-4.8, p = 0.001), steroid use greater than 1mg/kg/day before PIV infection (aHR, 2.1; 95% CI, 1.1-4.1, p = 0.035), and PIV type 3 (aHR, 10.0; 95% CI, 1.4-100, p = 0.021) were significantly associated with progression to proven/probable LRD. New pulmonary infiltrates in patients with upper respiratory viral detection (possible LRD) was also associated with progression to proven/probable LRD (aHR, 5.2; 95% CI, 2.8-9.5, p < 0.001). Among 56 patients with possible LRD, all patients who had BM or CB as cell source and high-dose steroids progressed to proven/probable LRD while patients receiving peripheral blood stem cells (PBSCs) with low or no steroid exposure rarely progressed. Among 94 proven/probable LRD cases, 47 presented with LRD without prior URI. PBSCs as cell source (aOR, 4.20; 95% CI, 1.7-10, p = 0.002) and inpatient status at diagnosis (aOR, 3.86; 95% CI, 1.5-9.7, p = 0.004) were significantly associated with progression to LRD without prior URI. Overall, 9 / 47 patients (19%) without virologically proven prior URI had NP tests that were negative or non-interpretable. Conclusion Progression from URI to proven/probable LRD occurs in 21% of PIV-infected patients. Risk factors for progression include PIV-3 subtype, high-dose steroids, BM or CB as cell source and lymphopenia. Progression rates are also high in patients with possible LRD. These data provide important information for clinical trial design as new antivirals are being developed. Strategies are needed to improve detection of PIV prior to progression. Disclosures: Seo: Ansun BioPharma: Research Funding. Boeckh:Ansun BioPharma: Research Funding.

Introduction Mangement of AML typically calls for a bone marrow aspirate 7-10 days after completion of induction therapy with standard or high-dose cytarabine (HiDAC)-containing regimens (day 14 marrow). If this marrow contains >5-10% blasts, National Comprehensive Cancer Network guidelines recommend a second course of induction therapy. However, nearly 70% of patients who have persistent blasts in a day 14 marrow do not begin reinduction within 1 week. Additionally, at least in patients given higher doses of cytarabine as part of induction therapy, blast counts often continue to decrease between days 14 and 21, and many such patients will achieve complete remission (CR) without a second induction. These findings call into question the value of a day 14 marrow. Methods Our database contained 154 patients with newly diagnosed AML or MDS with 10-19% blasts seen in our hospital from 2008-2013. Patients lived at least 21 days after receiving induction therapy with regimens containing standard-dose cytarabine (114 patients, typically given “3+7” ) or high-dose cytarabine (40 patients). The treatments were not given on protocol, thus granting physicians discretion to determine when to examine the marrow. Marrow exams performed between days 10 and 17 after starting induction were considered a “day 14 marrow.” Response was assessed at least 21 days from the start of the initial induction course. Our goals were (1) to identify pretreatment factors (described below) associated with the decision to obtain a day 14 marrow and (2) to determine the influence obtaining a day 14 marrow had on the likelihood of CR on course 1, after accounting, by multivariable logistic regression, for age, cytogenetic risk (SWOG criteria), pretreatment blast % (morphologic count in marrow; peripheral blood if no marrow available), and type of AML (de novo vs. secondary). Results 116 of 154 patients (75%) had a day 14 marrow. Patients who had and did not have a day 14 marrow were similarly-aged (average 53 in both groups), had similar pretreatment blast percentages (52% vs 47%, respectively), and had a similar proportion with de novo AML (66% vs 68%). Patients who had a day 14 marrow more often received 3+7 (79% of standard-dose cytarabine patients had a day 14 marrow vs 65% of HiDAC, p=0.06). Only 60% of patients with favorable risk cytogenetics had a day 14 marrow vs 79% of patients with intermediate or unfavorable risk (p=0.03). Considering the 3+7 group separately, only a higher pretreatment blast count predicted the likelihood of a day 14 marrow (53% with a day 14 marrow vs 38% without, p=0.02). No factors were predictive in the HiDAC group. As expected, favorable cytogenetics were associated with a higher CR rate while age, pretreatment blast %, and de novo vs secondary AML did not influence CR. After accounting for these covariates, there was no difference in the rate of CR between patients who did and did not have a day 14 marrow (66% vs 74%, p=0.61). The same was true when standard and high-dose cytarabine were analyzed separately (p=0.80 and 0.26, respectively). 18 patients with a day 14 marrow had resistant disease and received a second induction course; of these, two achieved CR. Likewise, two patients without a day 14 marrow were reinduced for resistant disease, and one entered CR. While the response to the second induction was not included in the analysis, results would not be expected to vary significantly given the CR rates with the second course. Conclusions These results suggest that while patients are more likely to have a day 14 marrow if they have intermediate- or poor-risk cytogenetics and receive 3+7, the decision to obtain a day 14 marrow does not lead to a higher CR rate. Disclosures: No relevant conflicts of interest to declare.

Background Multiplex PCR assays now allow the concomitant testing of multiple respiratory viral pathogens, including viruses previously difficult to detect with traditional diagnostic methods. We present a systematic assessment of respiratory viral shedding patterns, rates of progression from upper (URI) to lower respiratory tract disease (LRD) and association of viruses with clinical disease in a large prospective cohort of allogeneic HCT recipients. Patients and Methods Between 2005 and 2011, 471 allogeneic HCT recipients were followed prospectively with PCR testing of serial nasal wash and throat swab samples and a standardized symptom survey (12 respiratory and 4 systemic symptom questions) for 1 year after HCT (day 0-100: weekly symptom survey and PCR; day 101-365, weekly symptom survey and PCR every 3 months and whenever URI symptoms occurred). Bronchoalveolar lavage testing was done when lower respiratory symptoms and/or radiographic changes occurred. PCR testing for RSV, human metapneumovirus (HMPV), parainfluenza virus (PIV) 1-4, influenza (A, B), adenovirus (ADV), human bocavirus (HBoV), human coronaviruses (HCoV, OC43, 229E, NL63, HKU1), and human rhinoviruses (HRhV) were performed in real time on all upper and lower respiratory tract samples. Viral load was quantified when possible. Results From 471 patients, a total of 7,091 samples (median 15, range 1-50 per patient) were tested and 12,709 symptom surveys (median 22, range 1-57 per patient) were collected. Overall, 70% of patients had at least one respiratory virus infection documented during follow-up. 48% of the infections resolved within one week, mostly without treatment (exceptions: all patients with influenza virus and some with RSV received treatment according accepted treatment guidelines). The most common viruses detected were HRhV (32.7%) and HCoV (19.7%), followed by PIV, ADV, RSV, influenza, HMPV and HBoV (Table). Most infectious episodes detected by PCR were associated with respiratory symptoms but completely asymptomatic episodes occurred with HRhV, HCoV, ADV and occasionally with influenza and PIV (Table). Only one patient with RSV infection was completely asymptomatic. Rates of progression from URI to LRD varied from 36% (HMPV) to 5.9% (HBoV) (Table). The time to progression to lower tract disease also varied widely, with the shortest median time observed with RSV and influenza (Table). Only 13% of patients presented initially with LRD (no prior upper respiratory tract viral detection). Conclusion In this prospective surveillance study of HCT recipients, we found that (1) asymptomatic infection may occur with HRhV, HCoV, ADV and occasionally with influenza and PIV, but is otherwise rare; (2) progression rates from URI to LRD differ substantially among viruses, with highest rates observed with HMPV and RSV; (3) the proportion of patients presenting initially with LRD was very rare in this surveillance study; and (4), viral shedding may be prolonged, especially for HRhV, HCoV, PIV-3 and influenza A. These results suggest that close monitoring of respiratory viruses in HCT patients may identify patients at risk for experiencing progression to LRD. Disclosures: Boeckh: Gilead: Consultancy; GSK: Consultancy, Research Funding; Chimeix Inc.: Consultancy, Research Funding; Genentech: Consultancy; Ansun: Research Funding. Chien:Gilead Sciences: Employment. Englund:GSK: Consultancy; Chimerix Inc.: Research Funding; Gilead: Research Funding.

Abstract 1418 Introduction: Presence of minimal residual disease (MRD) after induction therapy predicts risk of relapse in AML (San Miguel JF et al 2001). Furthermore, achievement of complete remission (CR) rather than CR with incomplete platelet recovery (CRp) (defined using standard morphologic criteria) after induction therapy is independently associated with shorter relapse-free survival (Walter RB et al 2010). These results suggest a correlation between peripheral blood count recovery at the time of morphologic remission and MRD; however, this has not been documented. Here we address this question and examine whether response and MRD have independent effects on relapse. Patients and methods: We retrospectively analyzed data from 340 adults with AML who achieved CR, CRp or CRi (CR with incomplete peripheral count recovery; cellular marrow with Results: Among the 340 patients, 23% of the 247 with CR, 37% of the 65 with CRp and 50% of the 28 with CRi had MRD (p =0.002). Amounts of MRD differed among the 3 groups (p=0.015) and in particular was higher with CRi median 2.6 (interquartile range [IQR] 1.3–3.4), than with CRp median 0.7 (IQR 0.3–1.3) and CR median 0.7 (IQR 0.3–2.4). By univariable Cox proportional regression analysis with death before relapse considered a competing risk, patients with MRD were more likely to relapse than patients without MRD regardless of whether MRD was considered as 0 vs. > 0 (hazard ratio [HR] 1.85; 95% CI 1.25–2.72; p=0.002) or as a numerical variable (HR 1.15 for each 1% increase; 95% CI 1.06–1.25; p 0 (HR 1.50; 95% CI 1.00–2.23; p=0.047), response (CR vs. CRp and CRi: HR 2.11; 95% CI 1.40–3.17; p Conclusion: CRp and CRi are associated with increased frequency of MRD (0 vs. >0) in comparison to CR while CRi is characterized by higher levels of MRD than CRp or CR. This indicates that failure of blood count recovery is often due to persistent AML rather than toxic effects on normal progenitors and thus should often call for further therapy rather than delay. Clinical response, MRD and cytogenetic factors are independent predictors for relapse in AML patients achieving remission. Disclosures: No relevant conflicts of interest to declare.

Abstract 458 Background: Parainfluenza virus (PIV) is one of the most common respiratory viruses causing respiratory symptoms after hematopoietic cell transplantation (HCT); 20–30% of HCT recipients with PIV infection have lower respiratory tract disease (LRTD), associated with high mortality. Although previous studies have reported the outcome and risk factors of PIV LRTD, the definition of PIV LRTD differs in various reports, ranging from patients with radiographically and virologically confirmed cases to cases with only lower respiratory tract symptoms and viral detection from the upper respiratory tract. Here we examined the impact of various manifestations of LRTD, antiviral treatment, and patient and transplant factors on clinical outcome. Patients and methods: This retrospective cohort study included HCT recipients with PIV infection transplanted between 12/1990 and 11/2011 at the FHCRC. PIV infection was defined by detection of PIV in any sample using culture, direct fluorescent antibody testing, and/or polymerase chain reaction. Upper respiratory tract infection (URTI) was defined by PIV detection in nasopharyngeal swab/wash, or sputum without new pulmonary infiltrates. LRTD was divided into 3 groups: possible (new pulmonary infiltrates plus URTI), probable (PIV detection in BAL or biopsy without new pulmonary infiltrates), and proven (new pulmonary infiltrates plus PIV detection in BAL or biopsy). Risk factors for overall mortality were analyzed using Cox proportional hazards models. Results: In 372 patients with PIV infection, median age was 44 years (range, 0–75), and median time to PIV infection after HCT was 69 days (range, 1–2566). Thirty-five (9%) patients had a secondary episode of PIV infection. URTI only, possible, probable, and proven LRTI occurred in 273 (73%), 39 (10%), 7 (2%), and 53 (14%) patients, respectively. In 28 (47%) proven and probable LRTD cases, PIV was first detected in upper respiratory samples a median of 7 days (range, 1–40) prior to detection in BAL or biopsy. Among patients with LRTD, the probability of 90-day survival after PIV LRTD was 47% in proven cases, 57% in probable, and 90% in possible (p < .001; Figure). Comparison between probabilities of 90-day survival after PIV infection in patients with URTI and possible LRTD showed no difference (92% in URTI vs. 90% in possible LRTD, p = 0.67). Cox proportional hazard analysis also showed that proven/probable LRTD resulted in significantly worse survival than URTI (HR, 8.6; 95% CI, 5.0–14.6, p Conclusions: The outcome of PIV LRTD with viral detection in BAL or biopsy (proven/probable LRTD) was worse compared with that of PIV LRTD with detection in nasopharyngeal samples alone (possible LRTD). Moreover, the outcome of possible LRTD was comparable to that of URTI. Thus, future outcome analyses should consider these disease entities separately. High-dose steroid use was associated with poor survival and neither ribavirin nor IVIG use appeared to be effective in improving overall survival of probable/proven PIV LRTD. Reduction of steroid dose might improve outcome, but further studies are needed to test this hypothesis. New drugs with anti-PIV activity (e.g. DAS181) should be evaluated in this patient population. Disclosures: No relevant conflicts of interest to declare.

2598 Background: After initial induction chemotherapy for acute myeloid leukemia (AML), it is commonplace that reinduction or intensified therapy is not indicated if the bone marrow has 1000/μl and platelet count >100,000/μl per standard criteria (Cheson BD, et al. J Clin Oncol. 1990;8(5):813-9), might still occur and that the lack of blood count recovery may not bear prognostic significance. However, the time to CR after the first induction has been shown to be inversely related to subsequent duration of disease-free survival (DFS) and survival (OS), independent of age, treatment, and cytogenetics (Estey EH, et al. Blood. 2000;95(1):72-7). Additionally, the level of ANC and platelet recovery at time of CR is prognostic, with significantly better DFS among patients with higher counts (Yanada M, et al. Leuk Res. 2008;32(10):1505-9). Newly-diagnosed AML patients often present with below normal neutrophil and platelet counts, suggesting that persistence of such cytopenias after induction may be a clinical indicator of minimal residual disease (MRD) in the marrow. We therefore examined whether blood count recovery affected the probability of subsequent CR in patients with 30,000 was associated with significantly lower incidence of CR, OR 0.26 (0.1–0.8, p=0.02), and was independent of cytogenetic risk, antecedent hematologic disorder, and induction regimen, and (b) there was a suggested association between earlier count recovery and CR (>28 days vs. day 21–28), OR 0.31 (0.1–1.0, p=0.051). Conclusion: Persistence of low peripheral blood counts, despite the presence of 42 | 3,2 (67%) | | 1,1 (100%) | 2,1 (50%) | 1,1 (100%) | 1,1 (100%) | | 4,3 (75%) | | Totals | 36,16 (44%) | 29,19 (66%) | 20,19 (95%) | 40,21 (53%) | 26,20 (77%) | 5,3 (60%) | 14,10 (71%) | 85,54 (64%) | Disclosures: Becker: Sanofi: Research Funding.

Abstract 2596 Background: Patients with acute myeloid leukemia (AML) receiving induction or salvage chemotherapy often undergo bone marrow evaluation around day 14 to determine early treatment response and guide decision-making regarding need for immediate re-induction therapy. However, the parameters that define whether or not to initiate such therapy are seemingly not always objective. Thus we sought to define what factors influence physicians' decisions to pursue a second course of induction chemotherapy in AML. Methods: We retrospectively reviewed 211 patients with newly diagnosed, relapsed, or refractory AML who received induction chemotherapy at the University of Washington /Fred Hutchinson Cancer Research Center from January 2008 to May 2012. 178 had a marrow aspirate and/or biopsy between days 13 to 17 after start of chemotherapy and were included in our “day 14” analysis. Bone marrows were assessed both morphologically and by multi-parameter flow cytometry (MFC). We used the Wilcoxon signed rank test and Fisher exact test to compare patient age, pre-treatment cytogenetics (SWOG criteria), newly diagnosed vs. relapsed or refractory AML, day 14 marrow cellularity, day 14 blast count by morphology or MFC, and induction regimen given on the first course (ara-C-containing vs. not) among patients who did and did not receive a second course of induction chemotherapy within 1 week of the “day 14” marrow. The second course could either be the same or different than the first course. Results: 81% of the 178 patients had fewer than 10% blasts by morphology and MFC on day 14. None of these patients received course 2 within 1 week. 34 patients (19%) had greater than 10% blasts on the day 14 marrow by morphology or flow cytometry, of whom 18 (53%; 95% confidence interval 36–70%) received course 2 prior to day 21 and 16 (47%; 95% CI 30–64%) patients did not. As the decision of whether or not to begin course 2 within 1 week varied once blasts counts were >10%, we analyzed the 34 patients with >10% blasts between day 13–17 to assess what factors influenced the decision to begin a second course of treatment. The median age in those who received and did not receive course 2 within 1 week was 60 and 50.5, respectively (p=0.269). The fraction of newly diagnosed AML (as opposed to relapsed or refractory disease) in the two groups was 83% and 69%, respectively (p=0.429). The blast count by morphology was 69.5% in those who did vs. 24.4% in those who did not receive a second course within 1 week of the day 14 marrow (p=0.001) and by flow cytometry were 63% and 10%, respectively (p Conclusions: Although day 14 blast percentages were significantly higher among patients who received a second course of induction chemotherapy within 1 week of the day 14 marrow, 47% of patients with >10% blasts in a day 14 marrow and 56% who received a higher intensity regimen on course 1 did not begin a second course during the next week despite National Comprehensive Cancer Network (NCCN) guidelines that they do. We are studying whether this reflects objective patient and marrow characteristics, such as change in blast count from pre-treatment to day 14 marrow, or other more subjective factors in clinical practice. Disclosures: Becker: Sanofi: Research Funding.

Abstract 678 Background: Umbilical cord blood transplant (UCBT) recipients are high risk for cytomegalovirus (CMV) complications due to delayed and insufficient immune reconstitution. Since CMV viral load has been shown to be associated with the development of disease, an intensified prevention strategy was adopted at the FHCRC (Seattle, WA) which consists of pre-transplant ganciclovir (from day -8 to day -2), and high-dose acyclovir ([HDA] 2 gm valacyclovir 3 times daily) with preemptive bi-weekly monitoring for CMV DNA in serum from day 0 until day +100. Methods: We set out to compare rates of CMV reactivation and disease through day +100 in high-risk CMV seropositive UCBT recipients who received either the intensified strategy (G+HDA) or standard dose of acyclovir/valacyclovir (SDA, acyclovir 800 mg or valacyclovir 500 mg twice daily). All patients underwent weekly plasma testing for CMV by polymerase chain reaction (PCR). Our primary outcomes of interest were any CMV reactivation or disease by day 100. Risk factors for CMV reactivation were assessed using a multivariate Cox proportional hazards model. Results: Of the 105 UCBT recipients transplanted at the FHCRC between 1/2006 and 12/2009, 61 (58%) were CMV seropositive and eligible for inclusion in the cohort. In total, 31/61 (51%) received SDA and 30 (49%) G+HDA. The median patient age was lower in the SDA group 21.3 (interquartile range [IQR] 14.8–46.7) years and 30.1 (IQR 10.1–41.8) for G+HDA group, but other demographic factors were similar. Overall, the cumulative incidence of CMV reactivation was significantly lower in the G+HDA group (60% vs. 96.7; p=0.001 [Gray's test]) (Figure 1). In patients receiving G+HDA, the median time to first positive CMV PCR occurred later (27 days [IQR 11–35]) when compared to those given SDA prophylaxis (17 days [IQR 8–25]) (p=0.26). Additionally, the G+HDA group had significantly lower initial (71 copies/mL [IQR 47–110] vs. 235 [IQR 63–760], p=0.006) and maximum PCR viral loads (VL) (170 copies/ml [IQR 88–310] vs. 3200 [1400-11000], p Conclusions: Our study demonstrates that G+HDA was effective in preventing CMV complications in UCBT recipients. This intensified prevention strategy was associated with a decreased rate of CMV reactivation and appeared to significantly alter CMV replication dynamics. Importantly, the increased valacyclovir exposure did not alter the risk for developing either renal or hematologic toxicity. Disclosures: No relevant conflicts of interest to declare.