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Immune reconstitution, vaccine responses, and rituximab use after ex-vivo CD34-selected myeloablative allogenic hematopoietic cell transplantation
Melica, G., Preston, E., Palazzo, M., Seier, K., Malard, F., Cho, C., Devlin, S. M., Maloy, M., Borrill, T., Maslak, P., et al
Bone marrow transplantation. 2024
Abstract
Myeloablative T cell depleted (CD34-selected) hematopoietic cell transplantation (HCT) is associated with less acute and chronic graft versus host disease (GVHD). We aimed to examine vaccine responses in relation to immune reconstitution and post HCT rituximab administration in this population. This single center retrospective study included 251 patients with hematological malignancies who received a first CD34-selected HCT between 2012 and 2015. Of 251 patients, 190 were alive 1 year after HCT. Among the entire population, 77 (30.7%) patients were vaccinated. After vaccine administration, 35/44 (80%), 30/75 (40%), 27/36 (75%), 33/65 (51%), 34/51 (51%), 22/28 (79%) and 20/34 (59%) of evaluable patients had protective antibody titers for haemophilus influenzae type B (Hib), Pneumococcus, Tetanus, Diphtheria, Pertussis, hepatitis A (HAV), and hepatitis B (HBV) respectively. Responders to the pneumococcal vaccine had a higher CD45RA T cell count than non responders, with 12/18 patients (66.7%) vs 11/32 (34.4%) p = 0.04. For pneumococcal vaccine, there was also a trend to higher total lymphocyte B cell count in responders vs non responders p = 0.06. Rituximab post HCT was given to 59/251 (23.5%) patients. No difference was found in immune reconstitution patterns for rituximab use between vaccine responders and not. Recipients of CD34-selected HCT may respond to vaccination, and T and B cell subsets could be useful to predict vaccine response.
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Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Bolaños-Meade, J., Hamadani, M., Wu, J., Al Malki, M. M., Martens, M. J., Runaas, L., Elmariah, H., Rezvani, A. R., Gooptu, M., Larkin, K. T., et al
The New England journal of medicine. 2023;388(25):2338-2348
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Editor's Choice
Abstract
BACKGROUND In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).
PICO Summary
Population
Adults with hematologic cancers undergoing HLA-matched related donor or a matched or 7/8 mismatched unrelated donor transplant, enrolled in an RCT in multiple centres in USA (n=431)
Intervention
Cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis, n=214)
Comparison
Tacrolimus-methotrexate (standard prophylaxis (standard prophylaxis, n=217)
Outcome
GVHD-free, relapse-free survival was significantly more common among patients in the experimental-prophylaxis group than among the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups.
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Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant
Prockop, S. E., Hasan, A., Doubrovina, E., Dahi, P. B., Rodriguez-Sanchez, I., Curry, M., Mauguen, A., Papanicolaou, G. A., Su, Y., Yao, J., et al
The Journal of clinical investigation. 2023;133(10)
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Editor's Choice
Abstract
BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.
PICO Summary
Population
Adults and children with cytomegalovirus (CMV) viremia or disease arising after HSCT, treated in a single centre in USA (n=67)
Intervention
Adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs).
Comparison
None
Outcome
T cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses Recipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.
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The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation
Elias, S., Brown, S., Devlin, S. M., Barker, J. N., Cho, C., Chung, D. J., Dahi, P. B., Giralt, S., Gyurkocza, B., Jakubowski, A. A., et al
British journal of haematology. 2023
Abstract
Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.
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Characteristics of Distress and Support Group Participation in Caregivers of Older Allogeneic Hematopoietic Cell Transplantation Patients: A Single Institution Retrospective Review
Elko, T. A., Brown, S., Lobaugh, S., Devlin, S., Jakubowski, A. A., Perales, M. A., Maloy, M. A., Applebaum, A. J., Giralt, S. A., Levy, L., et al
Journal of the advanced practitioner in oncology. 2023;14(2):127-137
Abstract
Older patients with hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplant (allo-HCT). However, older patients often have increased comorbidities and thus may require an increased level of post-transplant care. These factors can contribute to increased caregiver distress, which has been associated with worsened health outcomes for caregivers and patients. To examine predictors of caregiver distress and support group participation in caregivers of older allo-HCT patients, we retrospectively reviewed charts of 208 patients aged 60 and older who underwent their first allo-HCT at our institution from 2014 through 2016. We systematically characterized and identified the incidence of caregiver distress and attendance in a caregiver support group from the start of conditioning through 1 year post allo-HCT. Evidence of caregiver distress and support group participation was recorded by reviewing clinical and/or social work documentation. We found that 20 caregivers (10%) endorsed stress and 44 caregivers (21%) attended our support group at least once. A patient's prior history of psychiatric diagnosis (p = .046) or the use of potentially inappropriate medications for older adults (p = .046) was found to be associated with caregiver stress. Caregivers who were spouses or partners of patients (p = .048) or caregivers of married patients were more likely to attend the support group (p = .007). While limited by retrospective design and likely underreporting, this study reveals factors associated with caregiver distress in the older allo-HCT caregiver population. This information can help providers identify caregivers at risk for distress and improve caregiver resources, which may improve both caregiver and patient outcomes.
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Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
Westin, J. R., Locke, F. L., Dickinson, M., Ghobadi, A., Elsawy, M., van Meerten, T., Miklos, D. B., Ulrickson, M. L., Perales, M. A., Farooq, U., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;:Of1-of12
Abstract
PURPOSE Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. PATIENTS AND METHODS Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). RESULTS Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years. CONCLUSIONS Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.
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Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma
Westin, J. R., Oluwole, O. O., Kersten, M. J., Miklos, D. B., Perales, M. A., Ghobadi, A., Rapoport, A. P., Sureda, A., Jacobson, C. A., Farooq, U., et al
The New England journal of medicine. 2023
Abstract
BACKGROUND In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes. METHODS In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization. RESULTS A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival. CONCLUSIONS At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
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ASTCT Clinical practice recommendations for transplant and cellular therapies in diffuse large B-cell lymphoma
Epperla, N., Kumar, A., Abutalib, S. A., Awan, F. T., Chen, Y. B., Gopal, A. K., Holter-Chakrabarty, J., Kekre, N., Lee, C. J., Lekakis, L., et al
Transplantation and cellular therapy. 2023
Abstract
Autologous hematopoietic cell transplantation (auto-HCT) has long remained the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B-cell lymphoma (DLBCL). However, the advent of chimeric antigen receptor (CAR) T-cell therapy has caused a paradigm shift in the management of R/R DLBCL patients, especially with the recent approval of CD19-directed CAR T-cell therapy in the second line setting in high-risk groups (primary refractory and early relapse [≤12 months]). Consensus on the contemporary role, optimal timing, and sequencing of HCT and cellular therapies in DLBCL is lacking. Therefore, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines undertook this project to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 20 consensus statements with a few key statements as follows: 1) in the first-line setting, there is no role of auto-HCT consolidation for those achieving complete remission (CR) following R-CHOP or similar therapy in non-double hit/triple hit cases (DHL/THL) and in DHL/THL cases receiving intensive induction therapies, but auto-HCT may be considered in eligible patients receiving R-CHOP or similar therapies in DHL/THL cases. 2) Auto-HCT consolidation with thiotepa-based conditioning is standard-of-care for eligible patients with primary central nervous system achieving CR with first-line therapy. 3) In the primary refractory and early relapse setting, the preferred option is CAR T-cell therapy, while in late relapse (>12 months), consolidation with auto-HCT is recommended in those achieving chemosensitivity to salvage therapy (CR or partial response), and CAR T-cell therapy is recommended in those not achieving remission. These clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R DLBCL.
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EASIX score predicts inferior survival after allogeneic hematopoietic cell transplantation
Sanchez-Escamilla, M., Flynn, J., Devlin, S., Maloy, M., Fatmi, S. A., Tomas, A. A., Escribano-Serrat, S., Ponce, D., Sauter, C. S., Giralt, S. A., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
The Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses common clinical laboratory values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at the onset of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We hypothesized that EASIX calculated at different time points pre- and post- HCT may predict NRM and OS, and that EASIX calculated at onset of GVHD may predict response to steroids. We evaluated the EASIX score pre- and post-HCT in 152 patients with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) alloHCT with uniform GVHD prophylaxis. In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher NRM (HR = 1.64, p = 0.009) and lower OS (HR = 1.33, p = 0.046). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65, p < 0.001; and HR = 1.65, p < 0.001) and decreased OS (HR = 1.27, p = 0.018; and HR = 1.49, p < 0.001), independent of HCT-CI, disease and conditioning regimen. Our study shows that high EASIX scores at various time points pre- and post-HCT are significantly associated with poorer overall outcomes. EASIX provides an independent and easily accessible tool to predict outcomes that can be complementary to other measures of risk stratification for patients undergoing HCT.
PICO Summary
Population
Adults with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) allogeneic HSCT with uniform GVHD prophylaxis, from a single centre in USA (n=152)
Intervention
Evaluation of the EASIX score pre-transplant between day -30 and day -10
Comparison
Evaluation of the EASIX score post-transplant at day 30 and day 100
Outcome
In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher non-relapse mortality (Hazard ratio (HR) = 1.64) and lower overall survival (HR = 1.33). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65; and HR = 1.65) and decreased OS (HR = 1.27; and HR = 1.49), independent of HCT-CI, disease and conditioning regimen.
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Incidence and impact of fungal infections in post-transplant Cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis and haploidentical hematopoietic cell transplantation: A CIBMTR analysis
Papanicolaou, G. A., Chen, M., He, N., Martens, M. J., Kim, S., Batista, M. V., Bhatt, N. S., Hematti, P., Hill, J. A., Liu, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Fungal infections (FI) after allogeneic hematopoietic cell transplant (HCT) are associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft versus host disease (GVHD), and viral infections are risk factors for FI. OBJECTIVES The objectives of this CIBMTR registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants receiving either calcineurin inhibitor (CNI)-based or PTCy-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplant outcomes. STUDY DESIGN Patients who received their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndromes and received related haploidentical transplant with PTCy (HaploCy, N = 757) or Sib transplant with PTCy (SibCy, N = 403) or CNI (SibCNI, N = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as a cumulative incidence with death as the competing risk. The association of FI on overall survival (OS), non-relapse mortality (NRM), chronic GVHD, and relapse at 2 years post HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model. RESULTS By Day 180 post HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI developed ≥1 FI (<0.001). The cumulative incidence (99% confidence interval) of yeast FI was 5.2% (3.3-7.3), 2.2% (0.7-4.5), and 1.9% (1.1-2.9) (p=.001), and mold FI was 2.9% (1.5-4.7). 3.7% (91.7-6.6) and 1.7% (1.0-2.6) (p=0.040) for HaploCy, SibCy, and SibCNI, respectively. FI were associated with an increased risk of death with an adjusted hazard ratio [HR] (99% confidence interval) of 4.06 (2.2-7.6); 4.7(2.0-11.0) and 3.4 (1.8-6.4) for HaploCy; SibCy and SibCNI compared with SibCNI without FI, respectively (p<.0001; for all). Similar associations were noted for transplant-related mortality. FI did not impact relapse or chronic GVHD. CONCLUSIONS Rates of FI by Day 180 ranged between 1.9-5.2% for yeast and 1.7%-3.7% for molds across the 3 cohorts. Use of PTCy was associated with higher rates of yeast infections only in Haplo HCT and mold infections in Haplo and Sib HCT. Presence of FI by Day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor or PTCy. While rates of FI were low with PTCy, FI were associated with increased risk of death, underscoring the need for improved management strategies.