Cytomegalovirus (CMV)-Specific Polyfunctional T-Cell Responses after Letermovir (LET) Prophylaxis in Hematopoietic Cell Transplantation (HCT)

Cytomegalovirus (CMV)-Specific Polyfunctional T-Cell Responses after Letermovir (LET) Prophylaxis in Hematopoietic Cell Transplantation (HCT)

S68 Abstracts / Biol Blood Marrow Transplant 26 (2020) S8 S74 limited data on the use of these instruments in the HCT population. We evaluated these...

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Abstracts / Biol Blood Marrow Transplant 26 (2020) S8 S74

limited data on the use of these instruments in the HCT population. We evaluated these PRO measures in HCT recipients and their association with post-HCT outcomes. We identified 292 adult pts undergoing first allogeneic HCT from 2015-2018. Of those, 257 had at least one PRO assessment and were included in this analysis. Time intervals evaluated were: pre-HCT (within 3 months [mos]), 0-6 mos, 6-12 mos, 1-2 years (yrs), and 2-5 yrs post HCT. PHQ-9 assesses depression and categorized as minimal (score 0-4), mild (5-9), moderate (10-14), moderately severe (15-19), and severe (2027). Higher DT scores indicate more distress and categorized as mild (0-3), moderate (4-7), severe (8-10). Lower scores on PROMIS indicate poorer PH or MH respectively. We evaluated PRO data descriptively for each time interval. Pre-HCT scores were analyzed for association with grade 2-4 acute graft-versus-host disease (GVHD), relapse, non-relapse mortality (NRM), and survival. Figure 1 shows boxplots for mean PHQ-9 and DT scores pre- and post-HCT. Mean scores for the PHQ-9 ranged from 1.1 § 2.4 (SD) occurring >2 yrs post-HCT to 2.4 § 3.0 preHCT. Mean DT scores were overall low, with highest distress (2.0 § 2.2) seen pre-HCT. Mean scores for PH and MH were similar at each time intervals, with means ranging 4748 for PH and 49-51 for MH. Higher PHQ-9 pre-HCT was associated with higher NRM (HR 1.21, 95% CI 1.09-1.34, P<0.001) and worse overall mortality (HR 1.12, 95% CI 1.02-1.23, P=0.016). Higher PROMIS PH and MH scores were associated with lower NRM (HR 0.49, 95% CI 0.260.94, P=0.031 and HR 0.28, 95% CI 0.14-0.56, P<0.001), respectively. DT scores had no associations with any outcome. Pts who developed acute GVHD had significantly higher PHQ-9 scores (mean 2.8 vs 1.9, P=0.014), PROMIS-PH (mean 45 vs 49, P=0.029) and MH scores (mean 47 vs 52, P=0.011) relative to those who did not have acute GVHD. PROs such as the PHQ-9, DT, and PROMIS have important clinical utility in allogeneic HCT recipients. Routine clinical use of these assessments not only help identify pts with high levels of distress or depression in real-time, they also demonstrate prognostic value for post-HCT survival outcomes.

90 Prevalence and Biobehavioral Predictors of Early and LongTerm Fatigue Following Hematopoietic Stem Cell Transplantation Erin S. Costanzo PhD1, Jennifer M. Knight MD, MS2, Christopher L. Coe PhD3, Peiman Hematti MD4, Mark B. Juckett MD4. 1 Psychiatry, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI; 2 Psychiatry, Medicine, Medical College of Wisconsin, Milwaukee, WI; 3 Harlow Center for Biological Psychology, University of WisconsinMadison, Madison, WI; 4 Medicine, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI Fatigue is a commonly reported quality of life concern after hematopoietic stem cell transplant (HSCT). Fatigue severity, duration, and interference with daily activities were evaluated at post-transplant milestones during acute recovery and through 6 years post-HSCT. We also investigated whether disease and treatment factors (allogeneic or autologous graft, diagnosis, treatment regimen), inflammation, and psychological symptoms during the peri-transplant period predicted early and long-term fatigue. Participants were 433 (191 allogeneic, 242 autologous) HSCT recipients who completed measures of fatigue (FSI), depression and anxiety (IDAS) pre-HSCT, and 1, 3, and 6 months, and 1, 3, and 6 years post-HSCT. A

subset (n = 210) provided blood samples during the first 6 months post-HSCT for determination of circulating cytokine levels (IL-6, TNFa, IL-10). The majority of participants reported clinically significant fatigue at 1 (83.9%), 3 (68.4%), and 6 months (64.7%) post-HSCT. Mixed effects regression models evaluated predictors of fatigue during early recovery. Allogeneic HSCT recipients showed a slower recovery, reporting more fatigue than autologous HSCT recipients at 3 and 6 months post-HSCT, but comparable fatigue at other points (interaction z=2.99, p=0.003). No other disease or treatment factors predicted fatigue. After covarying for transplant type and patient age, higher IL-6, TNFa and IL-10 levels (all p<0.05), as well as more severe anxiety and depression symptoms (all p<0.001), were strongly associated with more severe fatigue during the 6 months following HSCT. Fixed effects models indicated that, for individual participants, changes in cytokine levels or psychological symptoms were associated with corresponding changes in fatigue (all p<0.01). Most surviving participants continued to experience persistent fatigue at 1 (62.3%), 3 (68.0%), and 6 years (63.8%) post-HSCT. Only anxiety and depression symptoms during the peri-transplant period consistently predicted fatigue severity at the long-term assessments (most p<0.05). This pattern of results was similar for fatigue duration and interference. Findings highlight fatigue as a persistent sequela of HSCT though 6 years post-transplant, with little improvement beyond 3-6 months post-transplant. Allogeneic transplant and inflammatory responses appear to be risk factors for fatigue during early recovery, whereas depression and anxiety during the peri-transplant period are more sensitive predictors of long-term fatigue.

ORAL ABSTRACT - SESSION M - INFECTION AND IMMUNITY

91 Cytomegalovirus (CMV)-Specific Polyfunctional T-Cell Responses after Letermovir (LET) Prophylaxis in Hematopoietic Cell Transplantation (HCT) Danniel Zamora MD1,2, Brenda Akoto1, Hu Xie MS3, Richard Kiener PhD4, Bradley C. Edmison1, Terry Stevens-Ayers MS3, Ralf Wagner PhD5, Marco Mielcarek MD, PhD6,7, Wendy M Leisenring PhD3, Stephen De Rosa MD1,8, Michael Boeckh MD, PhD1,2. 1 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 2 Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA; 3 Fred Hutchinson Cancer Research Center, Seattle, WA; 4 Regensburg University, Regensburg, Germany; 5 Institute of Medical Microbiology and Hygiene, University Medical Center Regensburg, Regensburg, Germany; 6 Division of Medical Oncology, University of Washington, Seattle, WA; 7 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 8 Department of Laboratory Medicine, University of Washington, Seattle, WA Introduction: In a randomized, placebo-controlled trial, prophylaxis with LET decreased clinically significant CMV infection after allogeneic HCT; however, there was an increase of CMV infection after discontinuation of prophylaxis at day 100 (NEJM 2017; 377:2433). Objective: To determine the influence of LET prophylaxis on CMV-specific immune reconstitution after HCT as a possible

Abstracts / Biol Blood Marrow Transplant 26 (2020) S8 S74

mechanism for the observed effect, we compared CMV T-cell responses in a prospective cohort of allogeneic HCT recipients who received LET prophylaxis to CMV T-cell responses in historical controls transplanted prior to the introduction of LET. Methods: We included CMV-seropositive adult patients given LET prophylaxis after first allogeneic HCT; controls received PCR-guided preemptive CMV-directed therapy prior to the introduction of LET (2010-17). PBMC samples collected »3 months post-HCT were cryopreserved and then analyzed for intracellular expression of TNF-a, IL-2, IFN-g, CD107a, and Granzyme B in CD4 and CD8 T cells. Samples stimulated with CMV peptide mixes (pp65 and IE-1) and staphylococcal enterotoxin B (SEB) served as positive controls. Clinical data including baseline characteristics were obtained from medical records. Polyfunctional T-cell responses were defined as those expressing IFN-g plus at least one additional cytokine. Univariable Wilcoxon ranksum tests were used to compare differences between LET patients and controls and multivariate linear regression analysis was performed to adjust comparisons for other factors affecting immune reconstitution, such as donor CMV serostatus, lymphopenia, and GVHD severity. Results: Forty-two patients given LET and 95 controls were evaluated; patient characteristics were similar between groups. Polyfunctional CD8 T-cell responses at 3 months were lower in LET patients under all testing conditions while CD4 Tcell responses were decreased after stimulation with IE-1 only (Figures 1-3). After adjusting for CMV donor status, lymphopenia, GVHD and underlying disease, polyfunctional CD8 (Mean difference -5.736, 95% Confidence interval [CI] -11.17, -0.301, p= 0.039) and CD4 (Mean difference -0.138, 95% CI -0.257, -0.019, p= 0.023) T-cell responses to IE-1 remained significantly decreased in patients given LET prophylaxis compared to controls. Conclusion: LET prophylaxis appeared to be associated with a delayed CMV-specific cellular immune response. Our study provides a potential mechanism for the observed increase of clinically significant CMV events after discontinuation of LET prophylaxis. Studies are ongoing to evaluate correlations of the observed CMV-specific immunodeficiency with post-day 100 CMV events. Measuring CMV-specific T cell responses at the conclusion of LET prophylaxis could identify patients who might benefit from extended surveillance or prolonged prophylaxis.

Figure 1. IE-1 Polyfunctional T-cell Responses.

Figure 2. pp65 Polyfunctional T-cell Responses.

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Figure 3. SEB PolyfunctionaI T-cell Responses.

92 Incidence and Impact of Cytomegalovirus Infection in Haploidentical and Matched-Related Donors Receiving Post-Transplant Cyclophosphamide (PTCy): A CIBMTR Analysis Scott R Goldsmith MD1, Ephraim J. Fuchs MD, MBA2, Asad Bashey MD, PhD3, Stefan O. Ciurea MD4, Anurag K Singh MD5, Siddhartha Ganguly MD, FACP5, Randy Taplitz MD6, Carolyn Mulroney MD7, Richard T. Maziarz MD8, Soyoung Kim PhD9, Min Chen MS10, Roy F. Chemaly MD, MPH, FIDSA, FACP11, Krishna V. Komanduri MD12, Miguel Perales MD13, Rizwan Romee MD14, Marcie L. Riches MD15. 1 Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO; 2 The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD; 3 The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA; 4 Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX; 5 Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood, KS; 6 Medicine, University of California, San Diego, La Jolla, CA; 7 BMT, University of California, San Diego, Carlsbad, CA; 8 Knight Cancer Institute, Oregon Health & Science University, Portland, OR; 9 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI; 10 Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; 11 Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX; 12 Adult Stem Cell Transplant Program, University of Miami Hospital and Clinics, Sylvester Comprehensive Cancer Center, Miami, FL; 13 Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY; 14 Division of Transplant and Cellular Therapies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 15 University of North Carolina, Chapel Hill, NC Single-institution studies suggest increased incidence of CMV infection (DNAemia/organ disease) in recipients of haploidentical grafts with PTCy (HaploCy). It is unclear what factors confer the increased risk. Given increased use of PTCy in matchedsibling donor transplant (SibCy), we examined the impact of donor type and PTCy on transplant outcomes by donor(D)/ recipient(R) CMV serostatus and reported CMV DNAemia by day 180. Patients reported to the CIBMTR with AML/ALL/MDS receiving HaploCy (n = 757), SibCy (n=403), or Sib with calcineurin inhibitor and methotrexate/mycophenolate mofetil (SibCNI, n=1605) between 2012 and 2017 were examined (Table 1). Too few MUD with PTCy were reported to include MUD cohorts. Cumulative incidences of CMV DNAemia by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26) for