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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. [ABSTRACT FROM AUTHOR]

To examine activity of ibrutinib in steroid-refractory chronic GVHD (SR-cGVHD) after FDA approval, we conducted a multicenter retrospective study. Data were standardly collected (N=270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), GI (26%), lung (27%), liver (19%), genital (7%), other (4.4%). NIH severity was mild in 5.7%, moderate 42%, severe 53%. 39% had overlap subtype. KPS was ≥ 80% in 72%. Median prednisone (mg/kg) was 0.21 (0-2.27). Ibrutinib was started at median of 18.2 months after cGVHD onset and in earlier lines of therapy (2nd line: 26%, 3rd: 30%, 4th: 21%, 5th: 9.6%, 6th: 10%, 7th or higher: 1.2%)). Among evaluable subjects, the 6 month NIH overall response rate (CR/PR) was 45% (PR 42%, CR 3%). Median duration of response was 15 months (range 1-46). Liver involvement had association with 6 month ORR (multivariate (MVA) OR 5.49 (95% CI 2.3-14.2, p <0.001). Best overall response was 56%, with most (86%) achieving by 1-3 months. With median follow up for survivors of 30.5 months, FFS was 59% (53-65%) at 6 months and 41% (36-48%) at 12 months. On MVA, increased age (HR 1.01, 95% CI 1.0-1.02, p=0.033), higher baseline prednisone (HR 1.92, 1.09-3.38, p=0.032), and lung involvement (HR 1.58, 1.1-2.28, p=0.016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation., (Copyright © 2024 American Society of Hematology.)

Background: Chronic graft-versus-host disease (GVHD) is a leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying response to treatment. The goal of the Predicting the Quality of Response to Specific Treatments (PQRST) in chronic GVHD study is to identify predictors of treatment response. This report describing the study design seeks to raise awareness and invite collaborations with investigators who wish to access clinical data and research samples from this study., Methods: This is a prospective, observational cohort study involving data collection from patients who are beginning first-, second-, or third-line systemic therapy for chronic GVHD with defined agents. Evaluable participants will have baseline assessments and research samples prior to starting the index therapy, and 1 month after starting treatment. Response assessments occur at 3 and 6 months after start of treatment, or if a new systemic therapy is started before 6 months. Target enrollment is approximately 200 patients at 8 institutions, with at least 6 months of follow up to determine response to index therapy., Results: Enrollment started in July 2020 and was delayed due to the COVID-19 pandemic; as of 3/1/2024, 137 evaluable participants have been enrolled., Discussion: The Chronic GVHD Consortium "PQRST" is a large longitudinal cohort study that aims to investigate predictors of treatment response by identifying biologically and clinically defined patient subgroups. We welcome investigators to collaborate in the use of these data., Trial Registration: NCT04431479., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. BKH has been an advisory board member for Nkarta, Sanofi, Incyte, Rigel, Maat; participated in consultancy with ACI Group, received speaker fees from Therakos/Mallinkrodt; and is on the data safety monitoring committee for Angiocrine; and adjudication committee with CSL Behring. JP has been a consultant and advisory board member for Syndax, CTI Biopharma, Amgen, Regeneron, Incyte. He has received clinical trial support from Novartis, Amgen, Takeda, Janssen, Johnson and Johnson, Pharmacyclics, Abbvie, CTI Biopharma, and Bristol Myers Squibb. NF has served on an Incyte Advisory Board. CLK has served on advisory boards for Horizon Therapeutics and Incyte. CJL received honoraria and/or consultancy and/or research funding from Incyte, Sanofi, Fresenius Kabi, BMS, Kite, and Kadmon. CC has received consulting fees/honoraria from Sanofi, InhibRx, Cellarity, Astellas, Rigel, Novartis, Incyte; and consulting fees/equity from Cimeio, Oxford Immune Algorithmics, OrcaBio; and serves on the data safety monitoring board of Allovir and Angiocrine. SJL has received consulting fees from Mallinckrodt, Equillium, Kadmon, Novartis and Incyte; research funding from AstraZeneca, Incyte, Kadmon, Pfizer, Sanofi, and Syndax, and drug supply from Janssen. She is on Incyte and Sanofi clinical trial steering committees. PC, NEJ, RM, GC: nothing to declare., (Copyright © 2024. Published by Elsevier Inc.)

Physical frailty as a sign of accelerated aging is not well characterized in breast cancer (BC) and hematopoietic cell transplant (HCT) survivors and its correlation with outcomes and quality of life (QOL) is not defined. We conducted a prospective study to determine the prevalence of frailty in adult BC and HCT survivors, examine its impact on QOL, and determine its association with p16 INK4a , a molecular biomarker for biological aging. The study included 59 BC and 65 HCT survivors. Median age was 60 years (range 27-81), 68.5% were female and 49.2% were 18-59 vs. 51.8% ≥60 years old. A total of 71 (57.3%) were "fit" (frailty score 0) vs. 53 (42.7%) were pre-frailty/frail (frailty scores ≥1), and of the latter 17 (32.1%) were BC and 36 (67.9%) HCT patients. On multivariate analysis, patients >60 years were twice as likely to be frail (OR 2.04, 95% CI, 0.96-4.33; p=0.07), HCT were more likely to be frail compared to BC patients, and female HCT had 2.43 (95% CI, 0.92-6.40) and male HCT patients had 3.25 (95% CI, 1.37-7.72) times higher risk of frail; p=0.02. Frailty was associated with significant decline in QOL, measured by Medical Outcomes Study (MOS) Short Form 36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS), and FACT (Functional Assessment of Cancer Therapy) scores. p16 INK4a expression was higher in those who were frail, older than 60, and with higher expression in frail vs. fit patients who are 18-59 years. Our study highlights the high prevalence of frailty in survivors with detrimental effects on physical and overall wellbeing, and supports an association between frailty and the senescence marker p16 INK4a .

Abstract: Socioeconomic status (SES) and race/ethnicity have been associated with the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HCT). Certain aspects of graft-versus-host disease (GVHD) management, such as the need for long-term care, prolonged immunosuppressive treatment, and close follow-up for complications, may exacerbate disparities. Adults (≥18 years) reported to the Center for International Blood and Marrow Transplant Research who underwent a first allo-HCT for acute leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm between 2008 and 2018 were included. End points for those developing GVHD included overall survival (OS), transplant-related mortality (TRM), and disease relapse. Models were adjusted for patient- and transplant-related variables. A 2-sided P value < .01 was considered significant. Among the 14 825 allo-HCT recipients, 6259 (42.2%) and 6675 (45.0%) patients developed acute GVHD (aGVHD) and chronic GVHD (cGVHD), respectively. Among patients with aGVHD, non-Hispanic Black patients had increased TRM and overall mortality compared with non-Hispanic White patients; this association disappeared when severity of aGVHD was included in the model. Lower SES was associated with increased risk of disease relapse but not OS or TRM. In patients who developed cGVHD, race and ethnicity were not associated with OS, TRM, or disease relapse. However, the highest quartile of annual household income (≥$80 000) had improved OS and reduced TRM compared with the lowest quartile, after adjusting for race and ethnicity. In summary, race/ethnicity and SES are associated with outcomes after GVHD. Optimizing the health care resources available to low SES patients and strategies to minimize the risk of severe GVHD in non-Hispanic Black patients may improve long-term outcomes., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Frailty is a phenotype of decreased physiologic reserve associated with increased risk of toxicities and nonrelapse mortality (NRM) in hematopoietic cell transplant (HCT) recipients. The incidence, predictors, and adverse effects of pre-HCT frailty are not well known. We evaluated the association of pre-HCT frailty, defined using Fried's criteria, with age and baseline characteristics in patients ≥18 years undergoing autologous (auto) or allogeneic (allo) HCT for hematological malignancies. Assessments were performed as part of routine pre-HCT evaluations and then retrospectively analyzed. We additionally investigated the association of mental health distress indicators with frailty and the association between frailty and transplant outcomes including NRM and overall survival (OS) plus healthcare utilization. Patients undergoing HCT for hematological malignancies were analyzed (total n = 300; 162 auto, 138 allo). The overall prevalence of frailty was 18%, 21.7% among alloHCT, and 14.8% among autoHCT recipients, with similar distributions of frailty domains. Logistic regression analysis of the overall cohort revealed that older age was associated with an increased risk of frailty (odds ratio [OR] 1.37, 95% confidence interval [CI] [1.02-1.82]; P = 0.04). AlloHCT (OR 2.03, CI [1.07-3.84]; P = .03), and patient health questionnaire-9 (PHQ-9) (health depression) score ≥10 (OR 6.28, CI 1.93-20.43; P < .01) were each independently associated with pre-HCT frailty. In alloHCT patients, older age (OR 1.44, CI [1.00-2.06]; P = .05) was the only significant risk factor for pre-HCT frailty, while for autoHCT patients, only a higher PHQ-9 score was associated with frailty (OR 6.43, CI [1.34-30.82]; P = .02). For the whole cohort OS at 1 year was lower in frail recipients at 83% (95% CI, 70-91%) versus 92% (95% CI, 88-95%) in nonfrail (P = .04); with multivariate analysis showing higher risk of death in the frail group (hazard ratio [HR] 2.31, CI 0.97-5.46; P = .06). In the alloHCT cohort, multivariate analysis showed greater 1-year mortality in frail recipients (HR 2.55, CI [0.99-6.56]; P = .053). In the alloHCT recipients, we observed a 1-year NRM of 20% in frail patients versus 9% in nonfrail, and multivariate analysis showed a marginally higher risk of NRM in the frail group (HR 2.70, CI 0.90-8.10; P = .08). Frailty was not associated with higher risk of relapse in alloHCT or autoHCT recipients. Frail alloHCT patients experienced a longer initial hospital stay following HCT compared to nonfrail recipients (P < .01). We observed a high prevalence of pre-HCT frailty across all age groups, and identify older age is a risk factor for frailty, particularly in alloHCT recipients. Frailty is associated with a greater risk of NRM and lower survival which needs investigation in a larger cohort. Frailty associates with greater HCT complexity suggesting a need for early assessments and targeted interventions for this vulnerable population. Our findings suggest the utility of frailty and mental distress screening along with multidisciplinary interventions in pre-HCT to limit the morbidity of HCT., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Our phase I graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib, (recommended phase II dose: 100mg po BID day 0 to +70) plus sirolimus and tacrolimus (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits IL-6 receptor activity and pathogenic Th1/Th17 differentiation in preclinical models and the phase I trial. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT. This single-arm phase II trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed %pSTAT3+ CD4+ T cells at day +21 (primary endpoint: %pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II-IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n=28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary endpoint, reducing %pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of Tregs to Th1 and Th17 cells with PAC/SIR/TAC at RP2D PAC compared to dose level 1 PAC. The cumulative incidence of grade II-IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46 v 43%). While PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention., (Copyright © 2024 American Society of Hematology.)

Post-transplantation cyclophosphamide (PTCy) following hematopoietic cell transplantation (HCT) has emerged as standard of care for graft-versus-host disease (GVHD) prevention in adult patients without increasing malignant relapse. We previously defined acute GVHD (aGVHD) treatment response categories as corticosteroid-sensitive (SS), -dependent (SD), or -resistant (SR) based on response to first-line corticosteroids and reported their clinical outcomes following non-PTCy-based prophylaxis. More than one-third of patients developed aGVHD necessitating systemic therapy. Cases were predominantly SR, with a 14% overall incidence of SR aGVHD. The incidence and clinical outcomes of these 3 distinct aGVHD treatment response groups following PTCy-based prophylaxis have not been well described. The objective of this retrospective single-institution cohort study was to assess the incidence and clinical outcomes of SS, SD, and SR aGVHD following HCT with PTCy-based prophylaxis using a prophylactic regimen of PTCy, tacrolimus, and mycophenolate mofetil (MMF). We included 196 consecutive adult and pediatric patients undergoing allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota between 2017 and 2021. Patients received PTCy on days +3 and +4 plus tacrolimus and MMF prophylaxis. Bone marrow and peripheral blood stem cell graft sources and related and unrelated donors were included. Recipients received myeloablative or reduced-intensity conditioning regimens. Of the 196 allografts, 54 (28%) developed aGVHD before day +180, with a median time to onset of 50 days (interquartile range, 34 to 71 days). Of those, 32 patients (16% overall) developed maximum grade II-III aGVHD necessitating systemic corticosteroids, with the following response: 13 SS (41%), 10 SD (31%), and 9 SR (28%). The overall incidence of SR aGVHD was 4.6%. Only 12 patients (6%) developed maximum grade III aGVHD, and none had grade IV aGVHD. The 2-year overall survival analyzed from 80 days after initiation of systemic treatment was similar in the SS and SD groups (77 and 75%, respectively), comparable to those without aGVHD (81%), and was lowest in the SR group (20%), with GVHD the primary cause of death. Nonrelapse mortality was highest in the SR group. MN high-risk and higher GVHD grade at onset were risk factors for developing SR aGVHD. Overall, we report a low incidence (16%) of aGVHD requiring systemic corticosteroids with PTCy-based prophylaxis. aGVHD cases were predominantly SS aGVHD, with lower incidences of SD and SR aGVHD. Our findings suggest that PTCy-based prophylaxis reduces the rate of treatment-resistant aGVHD. Patients with SR aGVHD had the worst clinical outcomes and poorest survival. Those with SS and SD aGVHD had similar clinical outcomes, both better than seen with SR aGVHD., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Abstract: Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Response to treatment of chronic graft-versus-host disease (cGVHD) may help predict prognosis and outcomes. We hypothesized that the response of cGVHD to treatment and the ability to taper immunosuppression define distinct treatment response categories that differ in terms of risk factors and prognosis. Our aim was to determine specific clinical characteristics and outcomes associated with 3 distinct cGVHD treatment response groups based on the response to and duration of immunosuppressive therapy (IST) as treatment-sensitive (TS), treatment-resistant (TR), and treatment-dependent (TD) cGVHD. This retrospective single-institution cohort study included 1142 consecutive adult and pediatric recipients of allogeneic hematopoietic cell transplantation (HCT) performed for malignant and nonmalignant disorders at the University of Minnesota between 2008 and 2016. All donor, graft, conditioning regimen, and GVHD prophylaxis strategies were included, but only patients who commenced systemic treatment within 30 days of cGVHD diagnosis were included. A total of 185 patients who developed cGVHD necessitating IST within 30 days of cGVHD diagnosis were included in this analysis. At 1 year after cGVHD onset, 13% of the patients were TS, 27% were TD, and 60% were TR (including 14% deceased), whereas at 2 years after cGVHD onset, 29% were TS, 5% were TD, and 66% were TR (including 22% deceased). In a landmark analysis starting at 1 year after cGVHD onset, 5-year failure-free survival (FFS) and overall survival (OS) were lowest in the TR group (FFS, 38%; OS, 70%), with comparable outcomes in the TD (74% and 82%, respectively) and TS (79% for both) groups. Compared to no cGVHD, TR cGVHD was associated with worse OS at 5 years after cGVHD (hazard ratio, 2.09 versus no cGVHD; 95% confidence interval, 1.3 to 3.3; P < .01). Our findings suggest that refining cGVHD classification into 3 treatment response states defines important predictors of early and late clinical outcomes and identifies patients needing more effective treatment., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Importance: Chronic graft-vs-host disease (GVHD) is associated with impaired quality of life and symptom burden. The independent association of skin involvement with patient-reported outcomes (PROs) and their utility as a clinical prognostic marker remain unknown. Identification of patients with cutaneous chronic GVHD and impaired PROs could assist in initial risk stratification and treatment selection., Objective: To compare the association of sclerotic and epidermal-type chronic GVHD with longitudinal PROs and to evaluate whether PROs can identify patients with cutaneous chronic GVHD at high risk for death., Design, Setting, and Participants: This multicenter prospective cohort study involved patients from the Chronic GVHD Consortium of 9 US medical centers, enrolled between August 2007 and April 2012, and followed up until December 2020. Participants included adults 18 years and older with a diagnosis of chronic GVHD requiring systemic immunosuppression and with skin involvement during the study period., Main Outcomes and Measures: Patient-reported symptom burden was assessed using the Lee Symptom Scale (LSS) skin subscale with higher scores indicating worse outcomes. Quality of life was measured using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) instrument with lower scores indicating worse outcomes. Nonrelapse mortality, overall survival, and their association with PROs at diagnosis were also assessed., Results: Among 436 patients with cutaneous chronic GVHD (median [IQR] age at transplant, 51 [41.5-56.6] years; 261 [59.9%] male), 229 patients had epidermal-type chronic GVHD (52.5%), followed by 131 with sclerotic chronic GVHD (30.0%), and 76 with combination disease (17.4%). After adjusting for confounders, patients with sclerotic chronic GVHD had mean FACT-BMT scores 6.1 points worse than those with epidermal disease (95% CI, 11.7-0.4; P = .04). Patients with combination disease had mean LSS skin subscale scores 9.0 points worse than those with epidermal disease (95% CI, 4.2-13.8; P < .001). Clinically meaningful differences were defined as at least 7 points lower for FACT-BMT and 11 points higher for LSS skin subscale. At diagnosis, clinically meaningful worsening in FACT-BMT score was associated with an adjusted odds of nonrelapse mortality increased by 9.1% (95% CI, 2.0%-16.7%; P = .01). Similarly, for clinically meaningful worsening in LSS skin subscale score, adjusted odds of nonrelapse mortality increased by 16.4% (95% CI, 5.4%-28.5%; P = .003). These associations held true after adjusting for clinical severity by the National Institutes of Health Skin Score., Conclusions and Relevance: The results of this cohort study demonstrated that skin chronic GVHD was independently associated with long-term PRO impairment, with sclerotic and combination disease carrying the highest morbidity. The degree of impairment at skin chronic GVHD diagnosis was a prognostic marker for mortality. Therefore, PROs could be useful for risk stratification and treatment selection in clinical practice and clinical trials.

The population of cancer survivors has markedly increased due to the rapid improvements in cancer treatment. However, cancer survivors experience accelerated aging, which leads to chronic diseases and other age-related conditions, such as frailty. Those conditions may persist years after cancer diagnosis and treatment. Cellular senescence, a hallmark of aging, is one of the mechanisms that contribute to accelerated aging in cancer survivors. Several aging measures, including measures based on clinical markers and biomarkers, have been proposed to estimate the aging process, and some of them have shown associations with mortality and frailty in cancer survivors. Several anti-aging interventions, including lifestyle changes and anti-aging drugs, have been proposed. Future research, particularly in large-scale studies, is needed to determine the efficiency of these aging measures and anti-aging interventions before considering their application in clinics. This review focuses on the mechanisms of cellular senescence and accelerated aging in cancer survivors, assessment of the aging process using clinical markers and biomarkers, and the high prevalence of frailty in that population, as well as possible opportunities for anti-aging interventions. A deeper understanding of aging measures and anti-aging interventions in cancer survivors will contribute to the development of effective strategies to mitigate accelerated aging in cancer survivors and improve their quality of life.

Chronic graft-versus-host disease (GvHD) treatment response is assessed using National Institutes of Health (NIH) Consensus Criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GvHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well-studied. We aimed to characterize 6-month patientreported response, determine associated chronic GvHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GvHD symptom burden measures correlated with patient-reported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) versus not improved (about the same, a little worse, moderately worse, very much worse). At six months, 270 (71%) patients perceived chronic GvHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GvHD response criteria (kappa 0.18). Notably, patient-reported response at six months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GvHD clinical trials and drug development.

Options for GVHD prophylaxis after allogeneic hematopoietic cell transplantation can best be chosen by understanding the pathophysiology of GVHD. Interventions to limit T cell activation, expansion and subsequent tissue injury can each be utilized in designing successful GVHD prevention strategies Depleting, tolerizing or blunting T cells or host antigen presenting cells (APCs), blocking co-stimulation or more broadly suppressing inflammation have all been used. Interventions which spare regulatory T cells (Tregs) may prevent GVHD and facilitate controlled allo-responses and not compromise subsequent relapse risks. Graft manipulations and pharmacologic interventions each have potential to limit the morbidity of GVHD while permitting the immunocompetence to prevent infection or relapse., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The role of the gastrointestinal microbiome in predisposing to chronic graft-versus-host disease (cGVHD), an immune-mediated haematopoietic cell transplant (HCT) complication, is not well defined. We examined the relationship of the host faecal microbiome with subsequent cGVHD development by analysing baseline stool samples as well as post-HCT changes in microbiome composition and metabolite pathway analyses. We analysed pre-transplant baseline samples from 11 patients who subsequently developed cGVHD compared to 13 controls who did not develop acute GVHD or cGVHD at any time. We found a significant differential abundance of multiple taxa at baseline between cGVHD versus controls, including the Actinobacteria phylum and Clostridium genus. A subgroup analysis of longitudinal samples within each patient revealed a greater loss of alpha diversity from baseline to post-engraftment in patients who subsequently developed cGVHD. Metabolic pathways analysis revealed that two pathways associated with short-chain fatty acid metabolism were enriched in cGVHD patient microbiomes: β-oxidation and acyl-CoA synthesis, and γ-aminobutyrate shunt. In contrast, a tryptophan catabolism pathway was enriched in controls. Our findings show a distinct pattern of baseline microbiome and metabolic capacity that may play a role in modulating alloreactivity in patients developing cGVHD. These findings support the therapeutic potential of microbiome manipulation for cGVHD prevention., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Autologous hematopoietic cell transplantation (AHCT) is a well-established treatment for lymphoma. Unintended effects of this therapy include oral mucositis (OM) and gastrointestinal toxicities, resulting in poor clinical outcomes. The gut microbiome has been previously linked to transplant toxicities among allogeneic recipients, but little is known about the effects of AHCT on the oral microbiome., Methods: Seven patients with non-Hodgkin or Hodgkin lymphoma undergoing AHCT with palifermin (keratinocyte growth factor) were included. Buccal swab samples were collected at baseline and 14- and 28-days post-treatment. Oral microbial communities were characterized with 16 S rRNA amplicon sequencing. Temporal trends in community composition, alpha diversity, and beta diversity were investigated., Results: A significant reduction in the relative abundance of the genera Gemella and Actinomyces were observed from baseline. No significant temporal differences in alpha diversity were observed. Significant changes in beta diversity were recorded., Conclusion: Results of this pilot study suggest treatment with AHCT and palifermin affects the oral microbiome, resulting in temporal shifts in oral microbial community composition. Future studies are warranted to confirm these trends and further investigate the effects of AHCT on the oral microbiome and how these shifts may affect health outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Chronic graft-versus-host disease (cGVHD) is a major limitation to the long-term success of allogeneic hematopoietic cell transplantation (HCT). Our prior study of acute GVHD (aGVHD) defined distinct treatment-response groups based on the response to first-line corticosteroids: steroid-sensitive (SS), steroid-resistant (SR), and steroid-dependent (SD) aGVHDs. We conducted a retrospective, single-institution, cohort study to assess the incidence, risk factors, and clinical outcomes of patients with cGVHD after a previous diagnosis of SS, SD, or SR aGVHD, compared with those with no history of aGVHD. Among 784 consecutive adult and pediatric recipients of HCT for hematologic malignancies between 2008 and 2016, 347 (44%) developed aGVHD, with 13% SS, 12% SD, and 19% SR aGVHD. The 3-year cumulative incidence of cGVHD was 25%. Among those with cGVHD, 39% had no prior aGVHD diagnosis, whereas among those with a prior aGVHD diagnosis, 16% had SS, 24% had SD, and 21% had SR aGVHD. Mild or moderate cGVHD was highest among those with preceding SD aGVHD, whereas severe cGVHD was most frequent among those with previous SR aGVHD. We identified SD and SR aGVHDs as significant independent risk factors for the development of cGVHD after allogeneic HCT, whereas SS aGVHD was not a risk factor. Our study demonstrates that cGVHD after SD aGVHD did not have an intermediate prognosis between SR and SS groups as hypothesized; rather, cGVHD after both SD and SR aGVHD have similar prognoses. Our findings suggest that previous aGVHD response states are important predictors of cGVHD severity and outcomes., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The Blood and Marrow Transplant Clinical Trials Network study 1101 (BMT CTN 1101; ClinicaTrials.gov identifier NCT01597778) was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QoL) of patients with hematologic malignancies undergoing double umbilical cord blood transplantation (dUCBT) or HLA-haploidentical bone marrow transplantation (haplo-BMT) after reduced-intensity conditioning. At a 5-year follow-up, there were no significant differences in progression- free survival (PFS) or overall survival (OS) between the 2 cohorts. The impact of alternative donor source on QoL is unknown, however. English- and Spanish-speaking patients completed the Functional Assessment of Cancer Therapy-General (FACT-G), Short Form 36 (SF-36), EuroQoL-5 Dimensions EQ-5D, and Global QoL patient-reported outcome (PRO) assessments pretransplantation and at 12 and 24 months post-transplantation. We compared longitudinal QoL measures between the dUCBT and haplo-BMT cohorts and investigated the association of QoL and clinical outcomes using an inverse probability weighted-independent estimating equations method, accounting for missingness and baseline variables. We found no significant differences between the 2 cohorts in any of the QoL scores pretransplantation and at 12 and 24 months post-transplantation. Pretransplantation scores were the only significant predictors of post-transplantation QoL scores. Relapse and grade III-IV acute graft-versus-host disease (GVHD) were associated with significant declines in mean FACT-BMT and SF-36 Physical Component scores, and chronic GVHD was associated with a decline in mean EQ-5D utility scores. There were no significant associations between pretransplantation QoL scores and OS or PFS. Donor type did not impact post-transplantation QoL. Pretransplantation QoL scores and clinical events of GVHD and relapse were the only predictors of post-transplantation QoL. QoL was not associated with survival in either treatment arm. PROs may be valuable tools in pretransplantation risk assessment strategies to improve QoL outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Importance: Prior studies have demonstrated an association between cutaneous chronic graft-vs-host disease (cGVHD) and mortality. Assessment of the prognostic value of different measures of disease severity would assist in risk stratification., Objective: To compare the prognostic value of body surface area (BSA) and National Institutes of Health (NIH) Skin Score on survival outcomes stratified by erythema and sclerosis subtypes of cGVHD., Design, Setting, and Participants: Multicenter prospective cohort study from the Chronic Graft-vs-Host Disease Consortium including 9 medical centers in the US, enrolled from 2007 through 2012 and followed until 2018. Participants were adults and children with a diagnosis of cGVHD requiring systemic immunosuppression and with skin involvement during the study period, who had longitudinal follow-up. Data analysis was performed from April 2019 to April 2022., Exposures: Patients underwent continuous BSA estimation and categorical NIH Skin Score grading of cutaneous cGVHD at enrollment and every 3 to 6 months thereafter., Main Outcomes and Measures: Nonrelapse mortality (NRM) and overall survival (OS), compared between BSA and NIH Skin Score longitudinal prognostic models, adjusted for age, race, conditioning intensity, patient sex, and donor sex., Results: Of 469 patients with cGVHD, 267 (57%) (105 female [39%]; mean [SD] age, 51 [12] years) had cutaneous cGVHD at enrollment, and 89 (19%) developed skin involvement subsequently. Erythema-type disease had earlier onset and was more responsive to treatment compared with sclerosis-type disease. Most cases (77 of 112 [69%]) of sclerotic disease occurred without prior erythema. Erythema-type cGVHD at first follow-up visit was associated with NRM (hazard ratio, 1.33 per 10% BSA increase; 95% CI, 1.19-1.48; P < .001) and OS (hazard ratio, 1.28 per 10% BSA increase; 95% CI, 1.14-1.44; P < .001), while sclerosis-type cGVHD had no significant association with mortality. The model with erythema BSA collected at baseline and first follow-up visits retained 75% of the total prognostic information (from all covariates including BSA and NIH Skin Score) for NRM and 73% for OS, with no statistical difference between prognostic models (likelihood ratio test χ2, 5.9; P = .05). Conversely, NIH Skin Score collected at the same intervals lost significant prognostic information (likelihood ratio test χ2, 14.7; P < .001). The model incorporating NIH Skin Score instead of erythema BSA accounted for only 38% of the total information for NRM and 58% for OS., Conclusions and Relevance: In this prospective cohort study, erythema-type cutaneous cGVHD was associated with increased risk of mortality. Erythema BSA collected at baseline and follow-up predicted survival more accurately than the NIH Skin Score in patients requiring immunosuppression. Accurate assessment of erythema BSA may assist in identifying patients with cutaneous cGVHD at high risk for mortality.

Patients with acute graft-versus-host disease (GVHD) have an increased risk for infectious complications after allogeneic hematopoietic cell transplantation (HCT), but the risk according to response to therapy has not been well studied. We performed a retrospective analysis of the infectious complications for 1 year following allogeneic HCT at the University of Minnesota including 1143 pediatric and adult patients with and without aGVHD. The patients with aGVHD were classified into treatment response groups based on response to corticosteroids as first-line therapy: steroid-sensitive (SS; n = 114), steroid-resistant (SR; n = 103), and steroid-dependent (SD; n = 168) aGVHD. We observed that the cumulative incidence and density of infections in patients with SS aGVHD parallel the values in patients without GVHD. Infection density (ie, number of infections occurring per 100 days at risk) was greater in the patients with aGVHD compared with patients in both early and later post-transplantation periods. In GVHD patients, among the infections developed from the onset of aGVHD through 80 days of treatment, and until 1 year following transplantation, SS and SD patients had fewer bacterial and viral infections than SR patients. The overlap of nonrelapse mortality between SS and SD GVHD patients is a function of SD GVHD being responsive to steroid therapy, even if continued therapy is required. In summary, although valid goals may include reducing unneeded antibacterial antibiotic therapy and preserving microbiome diversity, these data suggest that anti-infective therapy is justified by the density of infections observed during active GVHD treatment., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The use of opioids and/or benzodiazepines in older adults (65 y+) who received an allogeneic hematopoietic cell transplant (HCT) is not known. In March 2016, the CDC released its strongest guidelines against prescription of opioids and co-prescription of opioids + benzodiazepines. We evaluated the use of opioids and/or benzodiazepines in older (65 y + , n = 114) vs. younger (40-64 y, n = 240) allogeneic-HCT recipients before and after the CDC guidelines. The proportion of patients with >10-days of use of opioids and/or benzodiazepines peri-HCT (day-14 to +28) was compared. Opioids: the older (65 + y) group had similar odds of receiving opioids as the younger group (40-64 y) [O.R. 0.7 (95%CI:0.4-1.2)]. Those transplanted after the CDC guideline had 0.4 (95%CI:0.2-0.7) times the odds of receiving opioids. Benzodiazepines: The older (65 + y) group was 0.6 times (95%CI:0.3-0.9) as likely to receive benzodiazepines. There was no significant change in benzodiazepines use after the CDC guideline. Opioids + Benzodiazepines: The older group (65 + y) was 0.5 (95%CI:0.3-0.9) times as likely to receive both opioids+benzodiazepines. There was no significant change in opioids+benzodiazepines use after the CDC guideline. Though we observed a significant decrease in use of opioids after the CDC guideline, the use of benzodiazepines and combined opioids+benzodiazepines remained constant. Older recipients (65 + y) received less opioids, benzodiazepines, and combined opioids+benzodiazepines., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007-2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60-64; 65-69; 70+). With median follow-up of nearly 3 years, patients aged 60-64 had modestly, though significantly better OS, DFS and lower TRM than those either 65-69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p = 0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥3. Conditioning intensity was not a significant predictor of OS in the 60-69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p = 0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) requires prolonged immunosuppressive therapy (IST), often requiring slow tapering with patients experiencing cGVHD flares and treatment failure. In 145 adult recipients developing cGVHD after matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 2-year cumulative incidence of flares after cGVHD diagnosis was estimated at 60% (95% CI, 51-70%), with median time-to-first flare of 188 days (range, 16-751). Of 88 patients experiencing a flare, 32 (36%) had multiple flares (range, 2-4). First flare treatment consisted of an increase in prednisone dose in 77 patients (88%), plus topical therapy in 8 (9%) or another systemic IST in 43 patients (49%). Higher flare risk was associated with quiescent type of cGVHD at onset (HR 1.8; 95% CI: 1.1-2.7; p = 0.04). Patients without a flare required a shorter duration of IST and were more likely to achieve a durable discontinuation of systemic IST (86% vs. 31% for ≥6 consecutive months). Flares were associated with protective effect on relapse (HR 0.2, 95% CI: 0.1-0.3), however not with worsened 2-year NRM or OS. Flares of cGVHD identify a group needing better approaches to limit the duration of IST and thus the morbidity of cGVHD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Endothelial dysfunction is characterized by altered vascular permeability and prothrombotic, pro-inflammatory phenotypes. Endothelial dysfunction results in end-organ damage and has been associated with diverse disease pathologies. Complications observed after hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor-T cell (CAR-T) therapy for hematologic and neoplastic disorders share overlapping clinical manifestations and there is increasing evidence linking these complications to endothelial dysfunction. Despite advances in supportive care and treatments, end-organ toxicity remains the leading cause of mortality. A new strategy to mitigate endothelial dysfunction could lead to improvement of clinical outcomes for patients. Statins have demonstrated pleiotropic effects of immunomodulatory and endothelial protection by various molecular mechanisms. Recent applications in immune-mediated diseases such as autoimmune disorders, chronic inflammatory conditions, and graft-versus-host disease (GVHD) have shown promising results. In this review, we cover the mechanisms underlying endothelial dysfunction in GVHD and CAR-T cell-related toxicities. We summarize the current knowledge about statins and other agents used as endothelial protectants. We propose further studies using statins for prophylaxis and prevention of end-organ damage related to extensive endothelial dysfunction in HCT and CAR-T., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Lenalidomide (LEN) is increasingly being used for the treatment of multiple myeloma (MM). Adverse cutaneous reactions to LEN are common and present almost exclusively within one month of initiating therapy. We report a case of delayed-onset LEN-associated eruption presenting over three years after starting treatment. Histopathologic findings are also described, which are infrequently reported for LEN-associated eruptions. Our case serves as a reminder that proper recognition and management of LEN-associated eruption is important in the treatment of MM. Dermatologists should be aware of the potential for delayed presentations of adverse cutaneous reactions to LEN, even years after initiation.

Background: Transfusions are essential for allogeneic hematopoietic cell transplant (HCT), yet they are influenced by graft, donor, and other factors., Study Design: We analyzed transfusions in 165 adult reduced intensity HCTs (2016-2019): HLA matched sibling donor (MSD) (n = 59), matched URD (n = 25), UCB (n = 33), and haploidentical (haplo, n = 48) detailing the cumulative incidence of platelet and RBC transfusion independence, total transfusions (day-10 to day+100) plus transfusion densities (per week) over 110 days., Results: Platelet recovery to 20 × 10 9 /L by 6 months occurred in 39/48 (81.25%) haplo recipients (median 33 [range, 0-139]) days vs. 58/59 (98.3%) MSD (median 10 [0-37]), 21/25 (84%) matched URD (median 20 [0-153]), and 29/33 (87.87%) UCB (median 48 [29-166]) days, p < .01. Regression analysis demonstrated a lower likelihood of prompt platelet recovery in matched URD, UCB, or haplo HCTs vs. MSD. Recovery to platelet independence was quickest in MSD (median 8 days [range 0-94]), vs. URD (median 16 days [0-99]), UCB (median 57 [0-94]), or haplo (median 45 [12-97]) days, p < .01. Platelet needs were unaffected by age, conditioning, or acute GVHD. RBC transfusion independence was achieved in 78% of MSD, 64% URD, and 82% UCB, though less frequent (58%) and slowest in haplo recipients, p < .01. All haplo and UCB recipients required platelet transfusions vs. only 51% of MSD and 76% of URD. RBC needs were highest in UCB and haplo HCTs., Discussion: The transplant donor influences the transfusion burden with greater platelet and RBC needs in haplo and UCB HCT which directly contributes to increased cost of care., (© 2021 AABB.)

We compared chronic graft-versus-host disease (cGvHD) following umbilical cord blood (UCBT) and matched sibling donor peripheral blood transplant (MSD). 145 patients (2010-2017) with cGvHD after MSD (n = 104) and UCBT (n = 41) were included. Prior acute GvHD was less frequent in MSD (55% vs. 85%; p = 0.01). Severe cGvHD (32% vs. 15%, p = 0.01) and de-novo onset (45% vs. 15%, p < 0.01) were more frequent following MSD. Liver was more frequently involved in MSD recipients (38% vs. 6%); and GI in UCBT (33% vs. 63%), both p < 0.01. Overall response (CR + PR) was similar between both cohorts. 2-year CR was higher in UCBT (14% vs 33%, p = 0.02). Karnofsky score (KPS) ≥ 90 at cGvHD diagnosis was associated with higher odds of response (95%CI: 1.42-10, p < 0.01). The cumulative incidence of durable discontinuation of immune-suppressive therapy, failure-free survival (FFS) and NRM at 2-years were similar between cohorts. KPS < 90 (95%CI: 3.1-24.9, p < 0.01) and platelets <100 × 10e9/L (95%CI: 1.25-10, p = 0.01) were associated with higher risk of NRM. UCBT patients were more likely to have a prior acute GvHD, less severe cGvHD and more likely to attain CR. Despite differences, both cohorts had similar NRM and FFS. High-risk groups, including those with platelets <100 × 10e9/L and KPS < 90, need careful monitoring and intensified therapy.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15-29%) with a median time from cGVHD to TEE of 234 days (range, 12-2050). Median time to the development of LE DVT or PE was 107 (range, 12-1925) compared to 450 days (range, 158-1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0-20%), 17% (95% CI, 9-25%), and 38% (95% CI, 22-55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1-22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0-7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1-5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival.

Acute graft-versus-host disease (aGVHD) has various risk factors and outcomes. We defined distinct aGVHD treatment response groups based on response to first-line corticosteroids: steroid sensitive (SS), steroid resistant (SR), and the rarely studied steroid dependent (SD) aGVHD. In 1143 consecutive adult and pediatric allogeneic hematopoietic cell transplant recipients, 385 (34%) developed aGVHD, with 10% having SS aGVHD, 9% SD aGVHD, and 14% SR aGVHD. The only factor significantly associated with SD in comparison with SS was older age (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.4-11.3, when comparing 18- to 60-year-olds with <18-year-olds). Factors significantly associated with SR in comparison with SS were unrelated donor (OR, 3.0; 95% CI, 1.2-7.4) and Minnesota high-risk aGVHD (OR, 2.4; 95% CI, 1.3-4.6). SR aGVHD was independently associated with higher risk for 2-year overall mortality (hazards ratio [HR], 1.8; 95% CI, 1.2-2.8) and nonrelapse mortality (NRM; HR, 2.1; 95% CI, 1.2-3.9). SS and SD GVHD groups had similar overall survival and NRM. The cumulative incidence of chronic GVHD was highest in the SD group, followed by the SR and SS groups (46%, 41%, and 29%, respectively). SD and SS GVHD had similar prognoses, both markedly better than those of the SR groups., (© 2021 by The American Society of Hematology.)

Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates. Palifermin is a recombinant keratinocyte growth factor that is Food and Drug Administration-approved to decrease severe oral mucositis (OM) associated with autologous hematopoietic cell transplantation (ASCT) for hematologic malignancies. We added palifermin as a supportive care measure for patients with lymphoma undergoing ASCT with BEAM conditioning. We compared patients receiving palifermin (n = 35) with historical controls (n = 38) for toxicity and readmission outcomes. The cumulative incidence of OM of any grade was 23% in the palifermin-treated patients and 42% in the control group. Patients receiving palifermin were less likely to be readmitted (57% versus 82%; P = .04), had fewer hospital readmission days (median, 4 days versus 7 days; P < .01), and had fewer total days in the hospital through day +30 after ASCT (median, 12 days versus 15 days; P = .05). Fewer patients in the palifermin group had >20 days in the hospital through day +30 (9% in the palifermin group versus 23% of controls). Adverse events associated with palifermin were mild and transient. The addition of palifermin limits severe regimen-related toxicities and decreases readmissions and duration of hospital stay. This and other measures are needed to identify comprehensive and cost-effective approaches, possibly including palifermin, to prevent severe regimen-related toxicities and decrease health care resource utilization., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Rapid quantitative recovery of NK cells but slower recovery of T-cell subsets along with frequent viral infections are reported after umbilical cord blood (UCB) compared with matched sibling donor (MSD) hematopoietic cell transplantation (HCT). However, it remains unclear whether increased propensity for viral infections is also a result of slower recovery of virus-specific immunity after UCB as compared to MSD HCT., Objectives: We examined the differences in the function of virus-specific peripheral blood mononuclear cells (PBMC) after UCB (N=17) vs. MSD (N=9) using previously collected patient blood samples at various time points after HCT., Methods: Interferon-gamma (IFN-γ) enzyme-linked immune absorbent spot (ELISpot) assay was used to quantify the PBMC frequencies that secrete IFN-γ in response to 11 immunopeptides from 5 common viruses. We included the patients who received the same reduced intensity conditioning regimen without ATG, no systemic glucocorticoids and had no relapse or acute/chronic graft-versus-host disease within 1 year after HCT., Results: The CMV-reactive PBMC frequencies were higher in CMV seropositive vs. seronegative patients after HCT. Among CMV seropositive patients, the frequency of CMV-reactive PBMC was lower after UCB compared to MSD throughout one year of HCT. We observed no differences in virus-specific PBMC responses towards HHV6, EBV, BK, and adenovirus antigens between UCB and MSD., Conclusion: Our data demonstrate that the reconstitution of CMV-specific immunity is slower in CMV seropositive recipients of UCB vs. MSD HCT in contrast to other viruses which had similar recoveries. These study findings support implementation of more potent prophylactic strategies for preventing CMV reactivation in CMV seropositive patients receiving UCB HCT., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

There is a growing population of transplant survivors receiving both a solid organ transplantation (SOT) and a hematopoietic cell transplantation (HCT). This group remains underreported and not well described. We conducted a single-center retrospective study aimed at assessing safety and long-term survival outcomes of 40 patients receiving both HCT and SOT at the University of Minnesota. Twenty-seven patients underwent HCT followed by SOT (13 kidney, 10 lung, 2 liver, 1 heart, 1 heart/kidney) with a median age of 40 years (range, 5 to 72) at the time of SOT at a median of 88 months (range, 24 to 302) following the HCT. The 1-, 5-, and 10-year overall survival (OS) from the SOT was 93%, 76%, and 49%, respectively, with only 4 organ failures reported. Thirteen other patients received a HCT following a prior kidney (n = 8), liver (n = 4), or pancreas/kidney (n = 1) SOT with a median age of 42 years (range, 3 to 66) at the time of the HCT and a median 154 months (range, 1 to 304) from the SOT. The 1-, 5-, and 10-year OS from HCT were 46%, 46%, and 17% respectively. In patients receiving SOT followed by HCT, survival outcomes were better in kidney transplant recipients and patients subsequently requiring an autologous rather than an allogeneic HCT. There were no HCT engraftment failures. Our findings show that in a select patient population, undergoing a second transplant at a specialized center can lead to favorable outcomes with long-term survival and low incidence of graft rejection, organ failure, and malignant disease relapse. A large-scale study is needed to determine the incidence and risk factors preferred for a successful subsequent SOT or HCT. Those studies are crucial to further guide selection and management of patients who would benefit most from a second transplant., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P = .65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P = .03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P = .02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P = .02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P = .02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P = .01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P = .01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P = .05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P = .04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P = .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported significantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029., (© 2020 by The American Society of Hematology.)

Microbiome dysbiosis has been associated with adverse outcomes of hematopoietic cell transplantation (HCT). We hypothesized that exposure to high-dose melphalan and antimicrobials in patients undergoing autologous HCT for plasma cell disorders results in oral and gastrointestinal microbial dysbiosis, which in turn is associated with regimen-related toxicities. We conducted a prospective study describing the longitudinal changes in oral and gastrointestinal bacteriome and mycobiome in this patient population. Our findings show that microbiome composition present at baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and culture-negative neutropenic fever, as well as with the rate of neutrophil engraftment. We also have evidence of an association between the microbial communities at count nadir and the development of regimen-related gastrointestinal toxicities commonly observed after exposure to high-dose melphalan. Although bacteriome diversity largely recovers within 1 month after transplantation, we observed a continuous decrease in oral and gastrointestinal mycobiome diversity, suggesting that the mycobiome requires a longer time to recover compared with the bacteriome., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Patients with early relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) have a poor prognosis, and no standard treatment. Twenty-nine patients with early disease recurrence post-transplantation were treated with azacitidine (AZA; median dose, 40 mg/m 2 /day for 5 to 7 days). At a median follow-up of 6.3 months (range, 1.3 to 41.1 months), 7 patients (27%) had a response to AZA, defined as complete remission, hematologic improvement, or improved donor chimerism. Response occurred after a median of 3 cycles, and the median duration of response was 70 days (range, 26 to 464 days). Median survival was 6.8 months (95% confidence interval, 3.8 to 11.1 months). Survival was similar in the patients receiving an AZA dose ≤40 mg/m 2 and those receiving an AZA dose >40 mg/m 2 . Six patients receiving donor lymphocyte infusion with AZA had a response or stable disease without worsening graft-versus-host-disease. We retrospectively used a flow cytometry assay to explore DNA-methyltransferase-1 in blood mononuclear cells as a potential pharmacodynamic marker to assess intracellular drug targeting in 8 patients. No correlation with AZA dose or response was observed. Low-dose AZA appears to have comparable efficacy to higher-dose AZA post-HCT. A significant proportion of this poor-risk population responded to low-dose AZA, suggesting a dose-independent, noncytotoxic mechanism for antileukemic activity., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: Induction chemotherapy with cytarabine and an anthracycline (7+3) remains the standard of care for acute myeloid leukemia (AML)., Patients and Methods: We retrospectively analyzed 183 newly diagnosed AML patients to compare the utility of rapid peripheral blast clearance (PBC), day of peripheral blast disappearance, residual blasts, and cellularity at day 14 bone marrow biopsy (D14BM) in predicting clinical response to 7+3 induction, overall survival (OS), and relapse-free survival (RFS)., Results: In multivariable logistic regression analysis, day 2 PBC > 85% [P = .0016] was the only predictor of remission status, with sensitivity and specificity of 75%. Peripheral blast disappearance within 5 days after induction and < 10% cellularity in D14BM predicted superior OS and RFS in multivariate analysis. Median follow-up of patients was 28 months since diagnosis. Two-year OS and RFS for patients with ≤ 10% versus > 10% cellularity at D14BM was 60.6% [95% confidence interval (CI), 50.8%-72.2%] versus 32.5% [95% CI, 23.0%-45.8%], and 51.9% [95% CI, 41.9%-64.3%] versus 28.8% [95% CI, 19.1%-43.4%], respectively [P = .0003 for OS and .002 for RFS]., Conclusion: Rapid PBC after 7+3 induction showed a significant improvement in specificity compared with D14BM, with similar sensitivity. Neither of these methods were reliably specific tools for the decision of early reinduction, despite their prognostic value. Our findings indicate that morphological cellularity in D14BM is an independent prognostic factor for OS and RFS, regardless of blast percentage, and that ≤ 10% cellularity defines D14BM hypoplasia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

High-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) has been anecdotally prescribed in gray zone lymphoma (GZL), showing encouraging efficacy. We conducted a multicenter retrospective study aimed at assessing outcomes after auto-HCT in 32 patients with GZL treated at 9 transplantation centers in the United States. The median age of patients at transplantation was 38 years (range, 18 to 70 years), and the majority were male (n = 21; 66%). The median number of lines of therapy before transplantation was 2 (range, 1 to 4). BEAM was the most commonly prescribed regimen (n = 23; 72%). The median duration of follow-up for surviving patients was 34 months (range, 1 to 106 months). Median overall survival (OS) was not reached. The 3-year progression-free survival (PFS) and OS for all patients were 69% and 78%, respectively. Three-year PFS and OS were 100% for patients who received only 1 line of therapy before auto-HCT versus 65% (PFS, P = .25) and 75% (OS, P = .39) for those receiving >1 line. The cumulative incidence of relapse/progression was 4% at 1 year post-transplantation and 31% at 3 years post-transplantation. The 3-year nonrelapse mortality was 0%. These findings suggest that HDT and auto-HCT is an effective treatment in patients with GZL. Our findings ideally require confirmation in a larger cohort of patients, preferably in the setting of large prospective multicenter randomized controlled trials. However, we acknowledge that such studies could be difficult to conduct in patients with GZL owing to the disease's rarity. Alternatively, a multicenter prospective study that includes tissue banking and a data registry is warranted to help better understand the biology and natural history of the disease., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) cure remains elusive despite the availability of newer anti-myeloma agents. Patients with high-risk disease often suffer from early relapse and short survival. Allogeneic hematopoietic cell transplantation (allo-HCT) is an "immune-based" therapy that has the potential to offer long-term remission in a subgroup of patients, at the expense of high rates of transplant-related morbidity and mortality. Donor lymphocyte infusion (DLI) upon disease relapse after allo-HCT is able to generate an anti-myeloma response suggestive of a graft-versus-myeloma effect. Allo-HCT provides a robust platform for additional immune-based therapy upon relapse including DLI and, maintenance with immunomodulatory drugs and immunosuppressive therapy. There have been conflicting findings from randomized prospective trials questioning the role of allo-HCT. However, to this date, allo-HCT remains the only potential curable treatment for MM and its therapeutic role needs to be better defined especially for patients with high-risk disease. This review examines different aspects of this treatment and summarizes ongoing attempts at improving its therapeutic index.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo-HCT and auto-HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo-HCT (n = 37) or an auto-HCT (n = 8) regardless of age, pre-transplant therapies, or remission status at transplantation. Allo-HCT recipients were younger (50 (14-74) vs. 67 (45-72) years, P = 0·01) and had 1-year and 3-year OS of 68% [95% confidence interval (CI) = 49-81%] and 58% (95% CI = 38-75%), respectively. Allo-HCT in first complete remission (CR1) yielded superior 3-year OS (versus not in CR1) [74% (95% CI = 48-89%) vs. 0, P < 0·0001]. Allo-HCT outcomes were not impacted by regimen intensity [3-year OS for myeloablative conditioning = 61% (95% CI = 28-83%) vs. reduced-intensity conditioning = 55% (95% CI = 28-76%)]. One-year OS for auto-HCT recipients was 11% (95% CI = 8-50%). These results demonstrate efficacy of allo-HCT in BPDCN, especially in patients in CR1. Pertaining to auto-HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN., (© 2017 John Wiley & Sons Ltd.)

Improving long-term outcomes of adult acute myeloid leukemia (AML) patients remains a challenge. Major scientific and clinical advances have led to a better understanding of the disease biology, and the majority of patients achieve a complete remission (CR) after induction therapy. Relapse risk, however, remains considerable and is the leading cause of death in this patient population. Significant efforts to improve outcomes emphasize use of post-remission therapies such as hematopoietic cell transplantation (HCT), an increasingly utilized modality. Improvement in transplantation techniques, understanding of donor:recipient histocompatibility, and increased availability of alternative donors have resulted in greater use of allogeneic HCT. Despite a graft-versus-leukemia effect and lower post-HCT relapse rates, allogeneic HCT continues to be plagued by treatment-related mortality (TRM) and chronic graft-versus-host disease. Better understanding of AML risk stratification and issues relating to minimal residual disease (MRD) as well as extremely low TRM rates with autografts have prompted clinicians to re-explore use of autologous HCT in subsets of favorable and intermediate-risk CR1 AML patients. Herein, we highlight the evolving literature and treatment outcomes for autologous HCT in AML. We provide recommendations for considering this therapeutic modality for treatment intensification in AML., (Copyright © 2017 Elsevier Ltd. All rights reserved.)