Non-relapse Mortality In Patients Research Articles

Surrogates of Endothelial Injury Predict Survival After Post-transplant Cyclophosphamide

Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. We evaluate the prognostic ability of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy-based GVHD prophylaxis. Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease, and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 year after alloHCT (34.5% versus 12.3%, P = .003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 to 6.17, P = .005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 to 4.36, P = .034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 to 4.33, P = .005) and high-risk (HR 5.77, 95% CI 2.31 to 14.39, P < .001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

Real-World Outcomes of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation in Japan: Retrospective Analysis of the Transplant Registry Unified Management Program Registry

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option for patients with hematologic malignancies. However, the development of graft-versus-host disease (GVHD) after allo-HSCT remains a challenge. Although systemic steroid therapy is the established first-line therapy for acute GVHD (aGVHD) and chronic GVHD (cGVHD), many patients are unresponsive or resistant to corticosteroid therapy, and the response is insufficient. This study aimed to evaluate the clinical characteristics of patients who developed aGVHD and cGVHD after allo-HSCT. This noninterventional, retrospective study used large national registry data from the Transplant Registry Unified Management Program. The study included 29,690 patients with a hematologic disease who underwent their first allo-HSCT between January 2010 and December 2019. The primary study endpoints were the cumulative incidence of aGVHD and cGVHD. The secondary endpoints were overall survival (OS) and nonrelapse mortality (NRM) of patients with aGVHD and cGVHD and OS and NRM of patients who received second-line therapy for aGVHD. Of 29,690 patients who underwent allo-HSCT, the graft source was related bone marrow (RBM) in 2807, related peripheral blood (RPB) in 6167, unrelated bone marrow in 10,556, unrelated peripheral blood (UPB) in 774, and unrelated cord blood in 9339. The cumulative incidence of grade II-IV aGVHD at 100 days was high after the related and unrelated mismatched transplantation. The response rates for first- and second-line therapy for aGVHD were low in the RBM/RPB-mismatched (59.6%/61.6%) and UPB-mismatched subgroups (45.5%), respectively. The 3-year NRM in patients with aGVHD was high in the RPB and UPB mismatched subgroups (37.9% and 31.2%, respectively). Developing a novel treatment for steroid-refractory aGVHD is necessary to improve transplantation outcomes, particularly for patients undergoing HLA-mismatched allo-HSCT.

Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD

AbstractGraft-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.

Geriatric Nutritional Risk Index Is an Important Predictor of Survival in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Introduction:The body mass index (BMI) and geriatric nutritional risk index (GNRI) are nutrition-related risk assessment tool and has been used in various clinical settings. The relationship between BMI and the associated risk of hematopoietic stem cell transplantation (HSCT), such as relapse and non-relapse mortality (NRM), have been reported (Fuji S et al. BMT. 2014;49:1505). However, the relationship between GNRI and HSCT outcome remains inconclusive. We aimed to evaluate the association between GNRI and overall survival (OS), relapse, and NRM of patients who received allogenic HSCT for hematological malignancies. Methods:We retrospectively analyzed aged 16 years or older patients who underwent first allogeneic HSCT from January 2010 to December 2022 at the Jikei university hospital. The primary endpoints of this study was OS at 5 years. Secondary endpoints were NRM, the incidences of relapse, all-grade acute GVHD and chronic GVHD. Nutritional risk was evaluated both BMI and GNRI. Patients were classified into three groups based on pre-transplant BMI (underweight; BMI &amp;lt;18.5, overweight; BMI ≥25, and others as standard), and also classified into three groups based on pre-transplant GNRI (low-risk; GNRI&amp;gt;98, intermediate-risk; 92≤GNR≤98, and high-risk; GNR&amp;lt;92). GNRI was calculated as follows: (1.519 x serum albumin) + (41.7 x current body weight/ ideal body weight). Data on serum albumin level and body weight were collected at the beginning of conditioning regimen. Results:Two hundred and three patients who received allogeneic HSCT for hematological malignancies (acute myeloid leukemia; n=98, acute lymphoblastic leukemia; n=51, myelodysplastic syndrome; n=27, myeloproliferative neoplasms; n=8, chronic myeloid leukemia; n=18, and other leukemias; n=2) were evaluated. The median age was 52 years old (range 16-69). The median follow-up period of survivors was 1394 days (range 51-4420) after allogeneic HSCT. The donor sources consisted of 39 (19.2%) HLA-matched related donor, 50(24.6%) HLA-mismatched related donor, 26(12.8%) HLA-matched unrelated donor and 88(43.4%) HLA-mismatched unrelated donor. One hundred and nine patients (53.7%) received myeloablative conditioning regimens. Based on the BMI, underweight, standard, overweight were included 33 (16.3%), 139 (68.4%), and 31 (15.3%) patients, respectively. While, based on the GNRI, the low-risk, intermediate-risk and high-risk were divided into 105 (51.7%), 46 (22.8%), and 51 (25.2%) patients, respectively . The 5-year OS rates of standard, underweight, and overweight were 52.6%, 39.5%, and 62.1%, respectively (p=0.07). On the other hand, the 5-year OS of low-risk, intermediate-risk, and high-risk were 62.6%, 50.4%, and 33.2%, respectively (p=0.01). In addition, multivariate analysis showed high-risk group showed significantly lower OS (p=0.03). Five-year cumulative incidences (CI) of relapse in the standard, underweight, and overweight, were 46.4%, 45.4%, and 25.0%, respectively (p=0.11). However, multivariate analysis showed that CI of relapse ratio was significantly lower in overweight group (p=0.02). While, 5-year CI of relapse rates in the low-risk, intermediate-risk, and high-risk were 36.5%, 47.2%, and 52.5%, respectively (p=0.03). However, multivariate analysis showed that there were no significant differences in relapse among three risk groups (p=0.06). There were no significant differences in CI of NRM, acute GVHD and chronic GVHD either BMI or GNRI. Subgroup analysis in the patients who underwent HSCT in complete remission revealed that there was no significant difference in OS among the three BMI groups (p=0.11), as well as the three GNRI groups (p=0.06). For the patients in non-remission at the time of allogeneic HSCT, there was no significant difference in OS between the three groups in BMI; however, OS was shorter in the high-risk group in GNRI (p=0.01). Conclusions:In our study, OS of high-risk group defined by GNRI showed significantly poor , especially in non-remission patients. Although overweight defined by BMI did predict low CI of relapse, overweight did not predict OS. These results suggest that nutrition-related risk assessed by GNRI could be prognostic marker for survival in patients who received allogeneic HSCT.

Pre-Transplant Levels of Multiparametric Flow-Cytometry Measurable Residual Disease (MFC-MRD) Predict Outcomes in Children with Acute Myeloid Leukemia Given Allogeneic Hematopoietic Stem Cell Transplantation

Background: Measurable residual disease assessed by multiparametric flow-cytometry (MFC-MRD) is largely used in trials for childhood de novo acute myeloid leukemia (AML) in the early phase of treatment, to stratify patients into different risk groups and to tailor treatment. Despite this, unlike acute lymphoblastic leukemia, the impact of MFC-MRD before allogeneic hematopoietic stem cell transplantation (HSCT) on patients' outcomes has yet to be established. The aim of this study was to evaluate the prognostic role of MFC-MRD before HSCT in a cohort of children with AML treated in centers belonging to Associazione Italiana Ematologia/Oncologia Pediatrica (AIEOP) cooperative group. Patients and Methods: We analyzed MFC-MRD in 208 pediatric patients affected by de novo AML who underwent a first allo-HSCT after a myeloablative conditioning regimen in an AIEOP Centre between 12/2011 and 12/2021. Assessment of MFC-MRD was performed on BM sample within 60 days from the transplantation date. Analysis of 5-10 color-panel MFC-MRD was centrally performed at the Laboratory of Diagnosis and Research, University of Padova, according to standardized operating procedures previously described (Buldini et al., BJH 2017). We defined MFC-MRD positivity as the presence of at least 50 leukemic events of 500,000 acquired nucleated cells. Five-year overall (OS) and event-free survival (EFS) were estimated using Kaplan and Meier method and differences between groups were tested using the log-tank test; the cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated using the Fine&amp;Gray method to take into account the respective competitive risks. Results: Median age at HSCT of these 208 patients was 7.8 years (range 0.4-23.3); 168 patients (80.8%) were transplanted in CR1, 30 (14.4%) in CR2 and 10 (4.8%) in CR3 or more advanced disease. Forty-eight patients (23.1%) were transplanted from a matched family donor, 85 (40.9%) from an unrelated donor (59 fully-matched and 26 mismatched), while 75 (36%) from a partially matched family donor. The source of stem cells was bone marrow in 117 patients (56.2%), peripheral blood in 81 (39%) and cord blood in 10 (4.8%). Median time from MRD evaluation and HSCT was 22 days (range, 6-57). Overall,168 out of 208 (78.9%) patients were MFC-MRD negative in the pre-HSCT BM, while 44/208 (21.1%) showed a positive MFC-MRD. Among those, MFC-MRD was &amp;lt; 0.1% in 12/44 (27%) patients, 0.1-&amp;lt;1% in 16 patients (36.5%) and ≥ 1% in 16 patients (36.5%). The 5-year OS and EFS of the whole cohort were 79.2% and 65.7%, respectively, while CIR and NRM were 24.7% and 8.6%. Notably, patients with negative MFC-MRD had a significantly better 5-yr OS and EFS (Fig.A) as compared to those with any MFC-MRD positivity (OS 86.3% vs 50.2%; EFS 71.6% vs 42.4%, p &amp;lt;0.0001 in both analysis). CIR significantly differed between patients with MFC-MRD negative and positive (21.1% vs 43.9%, p=0.001) (Fig.B). We also observed a higher NRM in patients with MFC-MRD positivity (13.6%) as compared to those with negative MFC-MRD (7.2%), although this was not statistically significant (p=0.1). Disease status (CR1 vs CR2 vs other CR) did also influence EFS (69.9% vs 55.6% vs 23.3%, p&amp;lt;0.001), OS (83.2% vs 66.6% vs 40.6%, p=0.02) and CIR (21.1% vs 37.7% vs 66.6%, p&amp;lt;0.001), while other variables (including year of HSCT, type of donor and stem cell source employed) did not. In a multivariable model for OS, EFS and CIR, including MFC-MRD, disease status and year of HSCT, MFC-MRD (pos vs neg) remained statistically significant (HR for OS 3.5, p=0.0004; HR for EFS 2.38, p=0.003; HR for CIR 2.14, p=0.02). In addition, advanced disease phase was an independent risk factor for CIR (HR 1.81, p=0.008). Conclusion: These data document the independent prognostic value of MFC-MRD before HSCT in a large cohort of pediatric AML patients, using a centralized evaluation by 5-10 color MFC. Patients with negative MFC-MRD before HSCT have a significantly lower risk of treatment failure. In light of these results, we recommend monitoring MFC-MRD before HSCT in pediatric AML patients as a critical tool for therapy-intervention decision before or after HSCT (e.g., additional treatment for improving leukemia control or less intensive/shorter GvHD prophylaxis) with the aim to improve patients' outcomes.

Role of Measurable Residual Disease (MRD) Testing for the Prediction of Late Relapses Following Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia

BACKGROUND: Measurable residual disease (MRD) before and/or shortly after allogeneic hematopoietic cell transplantation (HCT) is an independent indicator of high post-HCT relapse risk in acute myeloid leukemia (AML). However, many relapses, particularly among patients with MRD, occur within the first 3 months after allografting, and the role of MRD testing in the identification of patients at risk of relapses occurring at later times is unknown. METHODS: To address this uncertainty, we studied all adults ≥18 years with AML or MDS/AML based on 2022 International Consensus Classification criteria who received a first allograft while in first or second morphologic remission at a single institution between 4/2006 and 3/2023 and underwent MRD testing via multiparameter flow cytometry during the pre-HCT evaluation. In line with the performance characteristics of the assay, any detectable MRD was considered positive. RESULTS: One thousand two hundred and sixty-two patients with AML (n=1,112 [88%]) or MDS/AML (n=150 [12%])underwent allograft following myeloablative (n=732 [58%]) or non-myeloablative (n=530 [42%]) conditioning regimens. Of these, 260 (21%) tested positive for MRD during the pre-HCT evaluation. With a median follow-up of 60.6 (range: 1.9-196.3) months after HCT among survivors, there were 589 deaths, 381 relapses, and 259 NRM events contributing to the probability estimates for relapse, overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM) in this cohort. 239/1,262 patients (19%) experienced disease recurrence (n=181 [14%]) and/or death (n=89 [7%]) within the first 100 days after allografting. Relapse ( P&amp;lt;0.001) and death ( P=0.002) but not NRM ( P=0.29) before day +100 were more common among patients with pre-HCT MRD. Of patients alive without relapse at day +100, 93% (954 of 1,023) underwent bone marrow restaging studies between day 70 and 100 post-HCT. Among these 954 patients, 146 (15%) had MRD before HCT, whereas only 25 (3%) had MRD at day +70-100 testing. The latter had a significantly higher 3-year relapse risk (37% vs. 18%; P=0.002), and worse RFS (17% vs. 68%; P&amp;lt;0.001) OS (16% vs. 72%; P&amp;lt;0.001) and NRM (46% vs. 14%; P&amp;lt;0.001) relative to the 929 patients without MRD; for results of univariate regression models, see Table 1. Importantly, however, while 130 of the 146 patients (89%) with MRD before HCT tested negative for MRD at day +70-100, their outcomes were substantially worse compared to patients who tested negative for MRD before HCT and at day +70-100, with 3-year relapse risk of 38% vs. 15% ( P&amp;lt;0.001), 3-year RFS of 47% vs. 71% ( P&amp;lt;0.001), and 3-year OS of 53% vs. 75% ( P&amp;lt;0.001), whereas 3-year NRM estimates were similar (14% vs. 14% ( P=0.21). Qualitatively similar results were obtained when the cohort was restricted to patients with AML, and also when comparing patients undergoing myeloablative conditioning with those undergoing non-myeloablative conditioning, with a statistically significantly higher relapse risk and lower RFS and OS but not NRM for patients with MRD before HCT but no MRD at day +70-100 compared to those who tested negative for MRD before HCT and at day +70-100 (Table 1). CONCLUSION: For AML and MDS/AML patients alive without relapse at day +100 after allografting, MRD testing at day +70-100 post-HCT identifies patients at increased risk of relapse and worse survival, but only a small number of patients will test positive at this post-HCT timepoint. While a high proportion of patients with MRD before HCT will test negative for MRD at day +70-100, their outcomes are substantially inferior to patients without MRD both before and at day +70-100 after HCT. These data suggest that all patients with pre-HCT MRD should be considered for pre-emptive therapeutic strategies, ideally in the setting of well-controlled clinical trials, given their high risk of disease recurrence regardless of the post-HCT MRD information.

Lower Cumulative Incidence of Relapse but Higher Incidence of NRM in Patients with Poor Graft Function Following Allogeneic Stem Cell Transplantation

Introduction Poor Graft Function(PGF), defined as multilineage cytopenias in the setting of complete donor chimerism is a significant complication of allogeneic stem cell transplantation (alloSCT). Recently our group, in a published retrospective analysis of 929 patients, demonstrated that the following factors were associated with the development of PGF: Non matched sibling donor, ICU admission/ positive blood cultures within 1 st 30 days of alloSCT, severe graft versus host disease (GVHD), CMV viremia (Prabahran et al 2021). We extended our prior cohort study to validate risk factors previously associated with PGF and describe outcomes such as recovery from PGF, relapse and non-relapse mortality following a diagnosis of PGF. Methods This was a retrospective analysis of alloSCT recipients at our institution from 2017-2020. Patients 17 years and older were included. Patients who died prior to D60 of alloSCT were excluded as chimerism data was often not available prior to this timepoint. PGF was defined as follows: 1) ≥95% donor chimerism at last reading OR ≥95% CD3 negative chimerism; 2) ≥2 Lineage cytopenias defined as: Thrombocytopenia :≤30x10 9 /L from D40-D60 OR ≤50 x10 9/L from D60 onwards; neutropenia requiring filgrastim support at any time post D40; Hb &amp;lt;80g/L. Factors associated with PGF were evaluated using a logistic regression, with development of PGF being the dependent variable. The predictive power of the subsequent logistic regression model was validated utilizing bootstrapping re-sampling procedure and testing of the concordance index (C-index). Variables associated with PGF were also evaluated in a cox-proportional model and coded as time-dependent covariates. Relapse and non-relapse mortality (NRM) were evaluated in a competing risk model from a landmark of 200 days post alloSCT, performed as per the method of Fine and Gray. Results 308 patients were included in the analysis of which 259 patients did not have PGF (nPGF) and 49 had PGF. Baseline variables of nPGF and PGF patients were matched for median age (53 versus 56 p=0.28), recipient sex (68% versus 65% male, p=0.74)), median CD34 dose (5.00 versus 5.2 x10 9/L p=0.49), donor source (p=0.12) and CMV serostatus (p=0.23). In multivariate analysis, ICU admission within 30 days (p=0.002), non-CMV viral infections (p=0.032) and GVHD (p&amp;lt;0.001) were associated with the development of PGF. The c-index of the model at baseline was 0.77 and 0.75 after bootstrapping validation indicating reasonable predictive performance of this model. ICU admission, non-CMV viral infections and GVHD were still significantly associated with the development of PGF when utilised as time dependent variables in a cox-regression model. Patients with PGF had worse 2-year survival compared to nPGF (60 versus 75% p=0.02). PGF patients without marrow recovery at last follow up had a 6-month OS of 20%. Twenty three out of 49 patients recovered marrow function at last follow up with a median duration of cytopenias of 142 days (51-789). The cumulative incidence (CI) of recovery was 44% and 53% at 1- and 2-years following onset of cytopenias respectively. From a landmark of 200 days (33 patients excluded due to death prior to this timepoint) PGF patients had a higher CI of NRM (Figure 1A =0.001) but lower CI of relapse (Figure 1B p=0.027) compared to nPGF patients. Conclusions PGF is strongly associated with early ICU admission, severe GVHD and non-CMV viral infections. Survival is inferior in patients with PGF particularly those with poor marrow recovery and this is mainly driven by non-relapse mortality. The lower CI of relapse in PGF is a novel finding of this study and may suggest a protective effect of PGF against the development of relapse but this finding requires further validation in external cohorts.

Blinatumomab Therapy Is Associated with Favorable Outcomes after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with B Cell Acute Lymphoblastic Leukemia

Blinatumomab, a bispecific T cell engager that binds CD19 in leukemic cells and CD3 in cytotoxic T cells and leads to leukemic blast lysis, is often used in pediatric patients with relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) prior to allogeneic hematopoietic cell transplantation (allo-HCT). Concerns about the potential risk of blinatumomab-related immune-mediated toxicities after allo-HCT have not been adequately addressed. These include graft-versus-host disease (GVHD), delayed engraftment, and graft failure or rejection. Pediatric-specific data reporting post-HCT outcomes of patients treated with blinatumomab are scarce and limited to small cohorts. We sought to investigate the clinical outcomes of pediatric patients with R/R B-ALL who received blinatumomab therapy pre-HCT, focusing on overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM), as well as the incidence of immune-mediated post-HCT complications including GVHD, delayed neutrophil or platelet engraftment, graft failure, and graft rejection. We also investigated blinatumomab's effects on B cell reconstitution based on achievement of i.v. immunoglobulin (IVIG) independence post-HCT. This single-center, retrospective study included patients with B-ALL receiving blinatumomab therapy before undergoing allo-HCT, with transplantation performed between 2016 and 2021 at our institution. Patients receiving blinatumomab for relapse after allo-HCT were excluded. Patients receiving chemotherapy alone before allo-HCT during the same period composed the control group. Seventy-two patients were included, 31 of whom received blinatumomab before allo-HCT. Survival estimates were obtained using the Kaplan-Meier method, and the log-rank test was used to analyze differences between groups. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and continuous variables were compared using the Wilcoxon rank-sum test. Cumulative incidences were estimated using the competing risks method, and Gray's test was used to analyze differences between groups. A Cox proportional hazards regression model was used for univariate and multivariable analyses for OS. Landmark analysis was performed at the set time points of 30 days and 100 days post-allo-HCT. Most patients in the study cohort had high-risk relapsed B-ALL. Blinatumomab therapy induced minimal residual disease (MRD)-negative remissions in all patients, whereas 5 patients (12.2%) receiving chemotherapy alone had persistent MRD pre-allo-HCT. Time from the start of therapy to the date of allo-HCT was shorter for patients who received blinatumomab compared with those who received chemotherapy (P < .0001). Blinatumomab therapy was associated with greater LFS compared to chemotherapy alone (P = .049), but when limited to 1 year, LFS was not significantly different from control (P = .066). There appeared to be higher OS, lower CIR, and lower NRM in patients receiving blinatumomab compared to the control group; however, the differences were not significant. None of the variables assessed in multivariable analysis was associated with differences in OS. When compared to the controls, blinatumomab therapy did not result in a higher incidence of acute or chronic GVHD, delayed neutrophil or platelet engraftment, or graft failure or rejection. The time to IVIG infusion independence post-allo-HCT was similar in the 2 groups. This study supports the use of blinatumomab salvage therapy for R/R B-ALL before allo-HCT given its efficacy in inducing MRD-negative remissions and optimizing LFS, as well as its lack of association with an increased incidence of post-allo-HCT adverse immune-mediated toxicities. Larger, prospective studies are needed to confirm these findings and to investigate blinatumomab's effects in long-term post-allo-HCT events.

Clonal Hematopoiesis Is Associated with Cardiovascular Disease Risk and Worse Survival after Autologous Hematopoietic Cell Transplantation for Lymphoma

Introduction: Autologous hematopoietic cell transplantation (HCT) is an effective treatment for patients with relapsed or refractory lymphoma, and use of HCT has contributed to a growing number of survivors. Despite these improvements in outcomes, long-term survivors of lymphoma are at high risk of developing clinically significant cardiovascular disease (CVD) which, to date, has largely been attributed to pre-HCT cardiotoxic therapeutic exposures (e.g. anthracyclines, radiation) and modifiable risk factors (e.g. hypertension, diabetes, dyslipidemia) after HCT. In the general population, clonal hematopoiesis of indeterminate potential (CHIP), which refers to clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with aging-related health conditions including CVD. Accumulating data suggests CHIP is more prevalent in cancer patients compared to age-matched controls, due in part to clonal selection after genotoxic stressors. There is a paucity of information about the association between CHIP and CVD after HCT, including its interaction with modifiable risk factors and subsequent impact on survival after HCT. Methods: This was a retrospective cohort study of 861 consecutive patients who underwent autologous HCT for lymphoma between 2010 and 2016, with available pre-HCT DNA obtained from peripheral blood stem cells. We performed targeted exome sequencing of DNA (92 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CHIP (variant allele frequency ≥2%). CVD outcomes of interest included de novo heart failure, coronary artery disease and stroke after HCT. Five-year cumulative incidence of CVD was calculated taking into consideration competing risk of death. Fine-Gray multivariable regression was used to evaluate the association between CHIP and CVD, adjusting for demographic, clinical and therapeutic factors. The Kaplan-Meier method was used to examine the effect of CHIP on overall survival after HCT. Results: Median age at HCT was 55.7 years (range 18.4-78.1 years); 63.3% were male; race/ethnicity: non-Hispanic White (56.9%), Hispanic (26.1%), Asian (10.8%), Black (5.1%); 78.0% had non-Hodgkin lymphoma; comorbidities at HCT: hypertension (32.1%), dyslipidemia (16.4%), diabetes (10.1%), high (≥3) HCT-comorbidity index (CI) score (46.1%). Nearly all patients (94.3%) had received anthracycline-based chemotherapy prior to HCT, and 63.3% were treated with cumulative dose ≥300mg/m 2; 6% had chest radiotherapy. Overall, 186 patients (21.7% of the cohort) had at least one CHIP variant and 57 (6.6%) had ≥2 variants. DNMT3A, PPM1D, TET2 and TP53 were the most frequently mutated genes. In total, 74 patients developed CVD within five years from HCT. The 5-year cumulative incidence of CVD was significantly higher in patients with CHIP (20.9% vs 9.1%, p&amp;lt;0.001), compared to those without CHIP, and there was a graded relationship between number of CHIP variants and incidence of CVD. In the adjusted (age, cancer diagnosis, HCT-CI, modifiable cardiovascular risk factors) multivariable model, CHIP was significantly and independently associated with a nearly two-fold (HR: 1.8, 95% CI=1.1-3.1; P=0.020) risk of CVD, as well as the individual outcome of heart failure (HR: 2.3, 95%CI=1.3-4.3; P=0.008). Patients who had both CHIP and hypertension had a 3-fold (HR: 3.0, 95%CI=1.4-6.5, p=0.006) risk of CVD (reference: no CHIP, no hypertension). Overall 5-year survival after HCT was significantly worse in patients with CHIP, compared to those without CHIP (47.2% vs 68.2%, p&amp;lt;0.001; adjusted HR: 1.9, 95%CI=1.4-2.6), attributed to the higher burden of non-relapse mortality in patients with CHIP. Conclusions: In this well-characterized and demographically diverse cohort of lymphoma patients undergoing HCT, CHIP was highly prevalent and associated with a significantly higher risk of CVD after HCT, with the highest risk among those with CHIP and hypertension. We confirmed the poor overall survival rate in patients with CHIP, independent of patient and disease-related risk factors. These findings highlight the potential role of CHIP as a novel biomarker to better define CVD risk in patients with lymphoma prior to HCT, setting the stage for better screening and implementation of interventions (e.g., aggressive management of modifiable risk factors) to reduce the risk of CVD and to ultimately improve long-term health outcomes after HCT.

Effect of graft-versus-host disease on outcomes of HLA-haploidentical peripheral blood transplantation using post-transplant cyclophophamide.

There is limited evidence regarding the association between graft-versus-host disease (GVHD) and reduced relapse in patients who undergo allogeneic hematopoietic stem cell transplantation from haploidentical donors (haplo-HSCT) using post-transplant cyclophosphamide (PTCY). We investigated the association between GVHD and transplant outcomes in 938 patients who received haplo-HSCT using PTCY. Overall survival (OS), relapse rate, and non-relapse mortality (NRM) were evaluated using landmark analysis at the landmark points at 100 and 360 days after HSCT for acute and chronic GVHD, respectively. Grade I-II acute GVHD was not associated with OS (adjusted hazard ratio: 1.15, 95% confidence interval: 0.85-1.57), relapse (1.03, 0.74-1.45) and NRM (1.15, 0.74-1.77). Conversely, grade III-IV acute GVHD was associated with higher NRM (3.16, 1.61-6.19), but no other outcomes. Limited chronic GVHD was not associated with OS (1.11, 0.48-1.95), relapse (1.05, 0.30-3.75) and NRM (1.30, 0.45-3.79). Extensive chronic GVHD was associated with higher NRM (2.40, 1.03-5.57), but no other outcome. In conclusion, any GVHD was not associated with a reduced relapse rate and improved OS, and Grade III-IV acute GVHD and extensive chronic GVHD were associated with higher NRM in patients who received haplo-HSCT using PTCY.

The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation.

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.

Novel risk assessment for the intensity of conditioning regimen inolder patients.

Reduced-intensity conditioning (RIC) regimens have long-term outcomes that are generally comparable with those of myeloablative conditioning (MAC) because of a lower risk of nonrelapse mortality (NRM) but a higher risk of relapse. However, it is unclear how we should select the conditioning intensity in individual cases. We propose the risk assessment for the intensity of conditioning regimen in elderly patients (RICE) score. We retrospectively analyzed 6147 recipients aged 50 to 69 years using a Japanese registry database. Based on the interaction analyses, advanced age (≥60 years), hematopoietic cell transplantation-specific comorbidity index (≥2), and umbilical cord blood were used to design a scoring system to predict the difference in an individual patient's risk of NRM between MAC and RIC: the RICE score, which is the sum of the 3 factors. Zero or 1 implies low RICE score and 2or 3, high RICE score. In multivariate analyses, RIC was significantly associated with a decreased risk of NRM in patients with a high RICE score (training cohort: hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.60-0.90; P= .003; validation cohort: HR, 0.57; 95% CI, 0.43-0.77; P< .001). In contrast, we found no significant differences in NRM between MAC and RIC in patients with a low RICE score (training cohort: HR, 0.99; 95% CI, 0.85-1.15; P=.860; validation cohort: HR, 0.81; 95% CI, 0.66-1.01; P= .061). In summary, a new and simple scoring system, the RICE score, appears to be useful for personalizing the conditioning intensity and could improve transplant outcomes in older patients.

Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis.

Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.

Comparison of Pretransplantation Prediction Models for Nonrelapse Mortality in Patients with Myelofibrosis Undergoing Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation (alloSCT) is the only known curative treatment for myelofibrosis (MF). Risk assessment remains important for patient counseling and predicting survival outcomes for relapse and non-relapse mortality (NRM). Outcome-prediction tools can guide decision-making. Their use in MF has relied on their extrapolation from other malignancies. The primary objective of this study was to assess the performance of the HCT-CI, the augmented HCT-CI (aHCT-CI), and the Endothelial Activation and Stress Index (EASIX) in predicting non-relapse mortality (NRM) in patients with MF undergoing alloSCT. We retrospectively reviewed patients with MF undergoing alloSCT from 2012 to 2020 at the Mayo Clinic. Data were abstracted from electronic medical records. EASIX score was calculated, prior to starting conditioning therapy, and analyzed based on log2 transformed values. We evaluated the log2-EASIX scores by quartiles to assess the effect of increasing values on NRM. NRM was evaluated using competing risk analyses. We used Kaplan-Meier and log-rank method to evaluate OS. Fine-Gray model was used to determine risk factors for NRM. Comparison of performance of HCT-CI and aHCT-CI was performed by evaluation of model concordance given the high correlation between HCT-CI and aHCT-CI (r = 0.75). A total of 87 patients were evaluated. The median follow-up after alloSCT was 5 years (95% CI: 4.4 - 6.31). Patients with a high HCT-CI score had significantly increased cumulative incidence of NRM at 3-years (35.5% vs. 11.6%, P = 0.011) after alloSCT. A progressively increasing 3-year NRM was observed with an increasing aHCT-CI risk category, and patients with a high- or very-high aHCT-CI score had significantly higher 3-year NRM compared to those with intermediate or low-risk aHCT-CI scores at 3-years after alloSCT (31.9% vs. 6.52%, P = 0.004). An increasing log2-EASIX score quartile was not associated with 3-year NRM (19.0% vs. 10.1% vs. 25% vs. 14.3%, P = 0.59) and the EASIX score was not found to be a predictor of post-transplant NRM. A high HCT-CI was associated with a significantly worse 3-year OS (HR 4.41, 95%CI 1.97 - 9.87 P < 0.001). A high- or very-high aHCT-CI was significantly associated with poor 3-year OS (HR 3.99, 95% CI 1.56 - 10.22, P = 0.004). An increasing log2-EASIX score quartile group was not associated with 3-year OS (3-year OS rate: 66.7% vs. 80.4% vs. 64.6% vs. 76.2%, P = 0.57). The EASIX score should not be routinely used in patients with MF. Both the HCT-CI and the aHCT-CI are accurate in predicting long term survival outcomes in this patient population. Further studies are important to validate our findings of the role of EASIX in predicting NRM in patients with MF or other myeloproliferative neoplasms undergoing alloSCT.

21 - The Simplified Comorbidity Index Predicts Non-Relapse Mortality in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplant after Reduced-Intensity Conditioning

21 - The Simplified Comorbidity Index Predicts Non-Relapse Mortality in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplant after Reduced-Intensity Conditioning

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%–60.8%) and 32.2% (95% CI, 22.4–42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30–3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Impact of total marrow/lymphoid irradiation dose to the intestine on graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for hematologic malignancies.

Graft-versus-host disease (GvHD) is a leading cause of non-relapse mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The Perugia Bone Marrow Transplantation Unit designed a new conditioning regimen with total marrow/lymphoid irradiation (TMLI) and adaptive immunotherapy. The present study investigated the impact of radiotherapy (RT) doses on the intestine on the incidence of acute GvHD (aGvHD) in transplant recipients, analyzing the main dosimetric parameters. Between August 2015 and April 2021, 50 patients with hematologic malignancies were enrolled. All patients underwent conditioning with TMLI. Dosimetric parameters (for the whole intestine and its segments) were assessed as risk factors for aGvHD. The RT dose that was received by each intestinal area with aGvHD was extrapolated from the treatment plan for each patient. Doses were compared with those of the whole intestine minus the affected area. Eighteen patients (36%) developed grade ≥2 aGvHD (G2 in 5, G3 in 11, and G4 in 2). Median time to onset was 41 days (range 23-69 days). The skin was involved in 11 patients, the intestine in 16, and the liver in 5. In all 50 TMLI patients, the mean dose to the whole intestine was 7.1 Gy (range 5.07-10.92 Gy). No patient developed chronic GvHD (cGvHD). No dosimetric variable emerged as a significant risk factor for aGvHD. No dosimetric parameter of the intestinal areas with aGvHD was associated with the disease. In our clinical setting and data sample, we have found no clear evidence that current TMLI dosages to the intestine were linked to the development of aGvHD. However, due to some study limitations, this investigation should be considered as a preliminary assessment. Findings need to be confirmed in a larger cohort and in preclinical models.

Gvhd Prophylaxis Incorporating Methotrexate in Allo-HCT for Chronic Myeloid Malignancies and sAML: A Retrospective Analysis from the Cmwp of the EBMT

Introduction: Methotrexate (MTX) given on days 1, 3, 6 (and 11) after allogeneic haematopoietic cell transplantation (allo-HCT) along with calcineurin inhibitors (CNI) was established as effective GVHD prophylaxis decades ago when myeloablative conditioning was standard. Mycophenolate mofetil (MMF) replaced MTX initially in minimal intensity conditioning protocols and then became increasingly popular due to its favorable toxicity profile. Although MMF was associated with more severe GVHD in some reports, similar survival outcomes were reported for both regimens in most randomized trials. However, two large retrospective studies from the CIBMTR reported inferior outcomes of MMF-based regimens in allo-HCT standard indications. Taking advantage of a very large sample size within the EBMT registry, the aim of this retrospective study was to determine outcome differences after allo-HCT between MTX- and MMF-based GVHD prophylaxis regimens considering subgroup heterogeneity. Patients and Methods: Eligible were patients from the EBMT registry with select chronic myeloid malignancies (CML, CMML, MDS, myelofibrosis, secondary AML) who were transplanted from matched related, matched unrelated and mismatched unrelated donors between 2007 and 2017 and received either MTX or MMF prophylaxis in combination with a CNI. Endpoints were overall (OS) and relapse-free survival (RFS), relapse incidence, non-relapse mortality (NRM), and cumulative incidence of grade 2-4 acute GVHD. Multivariable Cox regression analyses included age, conditioning intensity, TBI, diagnosis, disease stage, ATG, graft source, donor type, gender match, CMV (recipient), year of transplantation, and Karnofsky index. We tested whether the association between the type of prophylaxis and the outcome was different in patient subgroups by including interaction terms in multivariable analyses between prophylaxis type (MTX/MMF) and ATG, age, Tacrolimus, conditioning intensity, use of TBI, diagnosis, disease stage and recipient CMV status. Finally, we studied the association between the same set of variables and OS, relapse and NRM in patients after aGvHD and separately in a landmark analysis at 3 months in patients without aGvHD. Results: Overall, 13699 patients from 321 centers were included. Diagnoses were MDS (44%), Myelofibrosis (18%), CML (11%), CMML (6%), atypical CML (1%) and secondary AML (21%). The conditioning / prophylaxis combination was RIC/MMF in 34%, RIC/MTX in 22%, MAC/MMF in 12% and MAC/MTX in 32%. CNI prophylaxis was Tacrolimus (n=1248), ciclosporin (n=12286), both (n=165). Median follow up was 42.8 months (IQR 19.8-74.5 months). Unadjusted analyses demonstrated significantly better outcomes with MTX in all subgroups of patients (TBI/no TBI, RIC/MAC, diagnoses except myelofibrosis, ATG/no ATG, age at allo-HCT < or ≥60 years). Figure 1a shows OS curves for conditioning/prophylaxis combinations. The cumulative incidence of acute GVHD grade 2-4 was lower in in particular RIC patients (Figure 1b). MTX was associated with significantly reduced overall mortality (HR 0.88, 95%CI 0.81-0.95, p<0.001) and NRM (HR 0.87, 95% CI 0.78-0.96, p=0.008) in multivariable analyses in the whole cohort. In contrast, MTX prophylaxis was not significantly associated with relapse (HR 1.02, 95% CI 0.92-1.12, p=0.72) and relapse-free survival (RFS) (HR 0.94, 95% CI 0.88-1.01, p=0.11). Notably, there was no significant interaction effect between prophylaxis type and any of the eight variables (ATG, age, tacrolimus, conditioning intensity, use of TBI, diagnosis, disease stage and CMV status in recipients) tested for OS and NRM, except that the beneficial association of MTX on OS was weaker for patients with Myelofibrosis. OS after acute GVHD was significantly lower with MTX prophylaxis and this was similar in RIC and MAC. MTX did not significantly associate with improved outcome in a landmark analysis in patients without aGvHD at 3 months after allo-HCT. Conclusion: Compared to MMF, MTX-complemented calcineurin inhibitor prophylaxis was associated with favorable early OS and NRM, and in particular with favorable OS after aGVHD, in this large cohort of patients with chronic myeloid malignancies or sAML transplanted in a recent time period. This effect was observed across various subgroups. These results may have future impact on clinical practice and trial design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Novel Prediction Models of Nonrelapse Mortality in Patients Specific to Each Reduced-Intensity Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter Analysis from the Kanto Study Group for Cell Therapy (KSGCT)

Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning (RIC). Conversely, for those who has a low HCT-CI score but prefer allo-SCT with RIC, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each RIC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with fludarabine/ busulfan (Flu/Bu) or fludarabine/melphalan (Flu/Mel). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy. The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin value (Alb), liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein, stem cell source, donor type, usage of antithymocyte globulin, performance status (PS), recipient/donor sexes, time interval from diagnosis to transplant, usage of total body irradiation (TBI), and HCT-CI score. To identify a set of variables for Fine-Gray competing risk regression model, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Fine-Gray models. The identified model's discriminative ability was assessed by Harrell's C-statistic. Results Among the 430 patients analyzed, 202 received Flu/Bu, and 228 received Flu/Mel. In Flu/Bu and Flu/Mel, the mean age was 60.6±6.2 and 57.8±8.5 years, the HCT-CI score ≤ 2 was observed in 77.2% and 78.1%, and 2-year NRM was found in 19.7% and 17.9% of the patients, respectively. Before transplantation, the most dominant parameters in Flu/Bu were Alb < 4.0 g/dL and EF < 55 %, whereas those in Flu/Mel were PS > 0, Alb < 4.0 g/dL, stem cell source, recipient/donor sexes and usage of TBI. Each of the abovementioned parameters, including PS > 0, was scored based on regression coefficients. To evaluate the 2-year NRM, we divided the total scores into several risk groups. In the Flu/Bu group, the NRM was 10.3 % in low (score 0, n = 69), 19.2 % in intermediate-1 (score 1, n =46), 25.4 % in intermediate-2 (score 2-3, n = 81) and 50.0 % in high (score 4-5, n = 6) scores. In the Flu/Mel group, the NRM was 8.6 % in low (score 0-2, n = 48), 15.2 % in intermediate (score 3-4, n = 139), and 37.4 % in high (score 5-8, n = 41) scores (Figure). Higher scores were strongly associated with worse NRM and survival. These models showed good discrimination, with C-statistic values of 0.64 in Flu/Bu and 0.67 in Flu/Mel. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each RIC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Prevalence and Effects of Frailty in Chronic Graft-Versus-Host Disease

Background: Frailty has been associated with increased rates of mortality in patients with malignancies. Studies have evaluated the role of frailty after hematopoietic cell transplantation (HCT) and found it to be associated with increased non-relapse mortality (NRM) and decreased overall survival (OS). Frailty has not been extensively studied among patients who develop chronic graft-versus-host disease (cGVHD). Objectives: The objectives of this study were to assess the prevalence and predictors of frailty and the effects of frailty on transplant outcomes such as OS and NRM in patients enrolled in the Chronic GVHD Consortium. Patients were characterized as frail if they met Fried's definition: ≥3 of the following criteria at enrollment based on the 2 minute walk test and patient-reported outcomes: unintentional weight loss, exhaustion, slow walking speed, low physical activity, and weakness. Patients meeting <3 criteria were considered not frail. Chronic GVHD variables were measured at the time of enrollment. Because cGVHD severity is calculated from organ scores, models included cGVHD severity or organ manifestations, but not both. OS and NRM were calculated from the time of enrollment. Patients with newly diagnosed and established cGVHD were included; this was not associated with frailty or other outcomes, thus the two groups were combined for analysis. Results: This study included 399 patients from 9 centers in the United States with 32.3% characterized as frail and 67.7% as not frail. At enrollment, cGVHD was severe in 29%, moderate in 54%, and mild/less than mild in 17%. The median follow-up time was 9.3 years. Frailty was associated with higher severity of cGVHD (p<.001). In a multivariable analysis that excluded cGVHD severity, thrombocytopenia (OR 1.6, 95% CI 0.9-2.9, p=0.08), lung cGVHD (OR 2.4, 95% CI 1.5-4.0, p<0.001), liver cGVHD (OR 1.9, 95% CI 1.1-3.3, p=0.01), and older age (p=0.003) were associated with frailty. Frail patients had a significantly lower 10-year OS (Figure 1, p<0.001), 43% (95% CI 34-52%) vs 63% (95% CI 57-69%) and higher 10-year NRM (p<0.001), 41% (95% CI 32-49%) vs 22% (95% CI 17-28%) than not frail patients. In multivariable analysis, cGVHD severity was associated with NRM (p=.006) but not OS (p>.10) while frailty remained strongly associated with both endpoints (p<.001). There was no significant interaction between cGVHD severity and frailty in the NRM (p=0.44) or OS model (p=0.99). In a multivariable analysis (Table 1) excluding cGVHD severity and adjusting for older age (p=0.004) and transplant center (p=0.02), shorter OS was associated with being frail, having progressive-type onset of cGVHD, and having skin, lung or liver involvement. Results were similar for NRM (data not shown). Conclusions: Among patients who have cGVHD, frailty remains strongly associated with worse OS and higher NRM after adjusting for cGVHD severity or organ manifestations. Patients older than 55 years and with lung or liver cGVHD are at higher risk of both being frail and for having worse transplant outcomes. Patients who develop cGVHD, especially in higher risk groups, may benefit from clinical and rehabilitation interventions to alleviate frailty. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal