The Composite Health Risk Assessment Model (CHARM) Predicts Overall Mortality and Relapse, But Not Non-Relapse Mortality, in Adults Following Unrelated Single-Unit Cord Blood Transplantation

Introduction

Allogeneic hematopoietic cell transplantation (HCT) is a possibly curative intervention for refractory hematopoietic disorders. Nonetheless, apprehensions persist regarding elevated non-relapse mortality (NRM) as a substantial problem in allogeneic HCT. Several prognostic models, such as the HCT-Specific Comorbidity Index (HCT-CI) [ 1 ], the Pretransplantation Assessment of Mortality (PAM) score [ 2 , 3 ], the European Society for Blood and Marrow Transplantation risk score [ 4 ], the NRM-J index [ 5 ], and the Treatment-Related Mortality (TRM) score [ 6 ], have been developed to predict NRM following allogeneic HCT. Among these, the HCT-CI has set a global standard for estimating NRM risk and guiding treatment decisions before HCT [ 7 , 8 ]. Recently, the Composite Health Risk Assessment Model (CHARM) was developed to improve the risk stratification of 1-year NRM and overall mortality following allogeneic HCT in older patients, as demonstrated in the prospective BMT CTN 1704 study [ 9 ]. The CHARM score was found to be more effective than the HCT-CI alone in this context [ 9 ].

Cord blood transplantation (CBT) serves as a recognized alternative to allogeneic HCT [ 10 , 11 , 12 , 13 ]. Delayed hematological recovery and an elevated risk of infectious complications are recognized disadvantages of CBT, resulting in an increased risk of NRM [ 14 ]. Despite this, several studies have shown that the HCT-CI fails to predict NRM [ 15 , 16 ] or overall survival (OS) [ 16 , 17 ] in CBT recipients. However, the HCT-CI was validated in a large cohort of CBT recipients in our previous research [ 18 ]. Attempts to validate the HCT-CI in the setting of CBT have yielded mixed results. Nonetheless, the prognostic significance of the original CHARM score remains unexplored in adults receiving unrelated single-unit CBT. To address this gap, we conducted a retrospective analysis to assess whether the CHARM score influences posttransplant outcomes in adults who underwent CBT at our institution.

Materials and Methods

Study Design and Participants

This was a retrospective study conducted at a single center in Japan. The analysis entailed a retrospective review of adult patients who underwent single-unit CBT at the Institute of Medical Science, the University of Tokyo from August 1998 to December 2023. Clinical data were acquired retrospectively from medical records. During the period in question, we conducted single-unit CBT as the initial allogeneic HCT process for 341 adult patients at our hospital. Nineteen patients unable to be assessed for the HCT-CI and one patient unable to be evaluated for alterations in body weight were eliminated from the retrospective analysis as their CHARM scores could not be computed. A total of 321 patients were ultimately included in the study. All cord blood units were sourced from the Cord Blood Bank of Japan.

The conditioning regimen and graft-versus-host disease (GVHD) prevention protocol were established by the patients’ physicians according to the characteristics of the patient and the disease [ 19 , 20 , 21 ], and the majority of patients received comparable supportive care [ 22 ] and transfusion delivery [ 23 ]. This retrospective study was performed in compliance with the Declaration of Helsinki. The Institutional Review Board of the University of Tokyo's Institute of Science approved this retrospective study (decision no: 2024-32-0823, date: September 2, 2024) and the implementation of an opt-out consent system.

Study Endpoints

The primary endpoint was the effect of the CHARM score on OS after CBT. The secondary endpoints included the influence of the CHARM score on relapse, NRM, hematological recovery, and both acute and chronic GVHD following CBT.

Definitions

The CHARM score was retrospectively computed using the following formula: 0.15310 x (HCT-CI) + 0.13247 x (LOG(CRP)) - 0.71227 x (albumin) + 0.00119 x (% weight) 2 , derived from medical records as per the original report [ 9 ]. Serum C-reactive protein (CRP) and albumin levels were measured within 3 days preceding the beginning of the conditioning regimen.

Neutrophil and platelet recovery were defined as an absolute neutrophil count surpassing 0.5x10 9 /L and a platelet count above 20x10 9 /L without the necessity of platelet transfusions on the first day of 3 and 7 consecutive days, respectively. The diagnosis and severity of acute and chronic GVHD were assessed according to published standard criteria [ 24 , 25 ].

OS was defined as the interval between the date of CBT and the date of death or the most recent follow-up. Relapse was characterized by morphological indications of hematological disease. NRM was characterized as mortality occurring during remission. The HCT-CI [ 1 ] and the refined Disease Risk Index (DRI) [ 26 ] were categorized based on established criteria. The number of human leukocyte antigen (HLA) discrepancies was ascertained using low-resolution typing for HLA-A, HLA-B, and HLA-DR in the graft-versus-host direction.

Statistical Analysis

Comparisons of baseline characteristics between two CHARM score groups (lower versus higher) were conducted using the Mann-Whitney U test for continuous variables and the chi-square or Fisher exact test for categorical variables. The analysis of hematopoietic recovery, GVHD, relapse, and NRM between the two CHARM score groups was conducted using the cumulative incidence method, which takes into account competing risks, and Gray’s test. The Kaplan-Meier method and log-rank test were employed to analyze the difference in OS between the two CHARM score groups.

The Fine-Gray proportional hazards model was employed in multivariate analysis to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for hematopoietic recovery, GVHD, relapse, and NRM, whereas the Cox proportional hazards regression model was applied for OS. The adjusted HRs and 95% CIs for the CHARM score (lower versus higher) were calculated, accounting for all covariates, including age at the time of CBT (<45 years versus ≥45 years), recipient’s sex (male versus female), refined DRI score (low/intermediate versus high/very high), conditioning regimen (total body irradiation [TBI] of 10-12 Gy versus TBI of 2-4 Gy), cryopreserved cord blood total nucleated cell count (<2.5x10 7 /kg versus ≥2.5x10 7 /kg), and HLA disparities (0 or 1 versus 2 or 3).

EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria), was used for statistical analyses [ 27 ]. Statistically significant p values were less than 0.05 as determined using a two-sided test.

Results

Patient Characteristics

Among the entire cohort, the median CHARM score was -3.31 (range: -7.45 to 3.81). To assess the impact of the CHARM score on posttransplant outcomes, patients were categorized into three groups based on similar cut-off values from the original report [ 9 ] (<-2.50149 versus -2.50149 to -2.01456 versus ≥-2.01456) ( Supplementary Figure 1 ). Based on these data, for further univariate and multivariate analyses, the patients were divided into two groups according to the original report [ 9 ] (lower group: values less than -2.01; higher group: values greater than or equal to -2.01). The lower CHARM score group consisted of 223 patients (69.5%) and the higher CHARM score group included 98 patients (30.5%). The patient and CBT characteristics of the two CHARM score groups are shown in Table 1 . The median follow-up for survivors in the total group was 121 months, ranging from 4 to 287 months.

Patients with higher CHARM scores were older and more likely to have a high or very high refined DRI score compared to those with lower CHARM scores. In contrast, patients with lower CHARM scores were more likely to receive TBI-based myeloablative conditioning regimens and GVHD prophylaxis based on cyclosporine and methotrexate. Disease types varied between the two CHARM score groups. The median follow-up for survivors was 120 months (range: 4-273 months) in the group with lower CHARM scores and 103 months (range: 9-287 months) in the group with higher CHARM scores (p=0.315) ( Table 1 ).

Neutrophil and Platelet Recovery

In univariate analysis, the cumulative incidence of neutrophil recovery was comparable between the two CHARM score groups (90.7% for the lower group and 87.6% for the higher group at 30 days, p=0.162) ( Supplementary Figure 2A ). The cumulative incidence of platelet recovery was also similar between the two groups (83.1% for the lower group and 77.6% for the higher group at 60 days, p=0.069) ( Supplementary Figure 2B ). In multivariate analysis, the CHARM score was not associated with neutrophil recovery (HR: 0.88, 95% CI: 0.69-1.12, p=0.320) or platelet recovery (HR: 0.82, 95% CI: 0.64-1.04, p=0.110) ( Supplementary Table 1 ).

GVHD

In univariate analysis, the cumulative incidence of grades II to IV acute GVHD (p=0.253) and grades III to IV acute GVHD (p=0.640) was similar between the two CHARM score groups ( Supplementary Figures 3A and 3B ). In multivariate analysis, the CHARM score was not associated with grades II to IV acute GVHD (HR: 0.75, 95% CI: 0.54-1.04, p=0.091) or grades III to IV acute GVHD (HR: 0.76, 95% CI: 0.36-1.58, p=0.470) ( Supplementary Table 2 ).

In univariate analysis, the cumulative incidence of extensive chronic GVHD was also similar between the two CHARM score groups (p=0.235) ( Supplementary Figure 3C ). In multivariate analysis, the CHARM score was not associated with extensive chronic GVHD (HR: 0.73, 95% CI: 0.42-1.28, p=0.280) ( Supplementary Table 2 ).

OS, Relapse, and NRM

In univariate analysis, OS was significantly worse in the higher CHARM score group compared to the lower CHARM score group (65.4% for the higher group and 79.1% for the lower group at 2 years, p<0.001) ( Figure 1A ). In multivariate analysis, a higher CHARM score was significantly associated with increased overall mortality (HR: 1.56, 95% CI: 1.06-2.29, p=0.022) ( Table 2 ).

In univariate analysis, the cumulative incidence of relapse was significantly worse in the higher CHARM score group compared to the lower CHARM score group (29.5% for the higher group and 18.2% for the lower group at 2 years, p=0.007) ( Figure 1B ). In multivariate analysis, a higher CHARM score was significantly associated with higher relapse rates (HR: 1.71, 95% CI: 1.09-2.69, p=0.020) ( Table 2 ).

In univariate analysis, the cumulative incidence of NRM was significantly worse in the group with higher CHARM scores compared to the group with lower CHARM scores (15.5% for the higher group and 9.1% for the lower group at 2 years, p=0.048) ( Figure 1C ). In multivariate analysis, the CHARM score was not associated with NRM (HR: 1.17, 95% CI: 0.68-1.99, p=0.560) ( Table 2 ).

Subgroup Analysis According to Disease Type, Disease Risk, and Conditioning Regimen

Because disease type, disease status, or conditioning regimen could affect the posttransplant outcomes in adults who have undergone CBT, we also analyzed the effects of CHARM score stratification according to disease type (acute myeloid leukemia/myelodysplastic syndrome [AML/MDS] or acute lymphoblastic leukemia/non-Hodgkin’s lymphoma [ALL/NHL]), refined DRI score (low/intermediate or high/very high), and conditioning regimen (TBI of 12 Gy).

In univariate analysis, the beneficial effects of lower CHARM scores on OS compared to higher CHARM scores were observed in the subgroups of patients with AML/MDS (78.6% versus 64.8% at 2 years, p=0.002), high and very high risk according to the refined DRI (68.8% versus 52.1% at 2 years, p<0.001), and TBI conditioning regimens based on 12 Gy (80.1% versus 68.7% at 2 years, p=0.011), but not in the subgroups of patients with ALL/NHL or low and intermediate risk according to the refined DRI ( Figures 2A , 3A , and 4A ).

In univariate analysis, the beneficial effects of lower CHARM scores on relapse compared to higher CHARM scores were also observed in the subgroups of patients with AML/MDS (17.8% versus 28.4% at 2 years, p=0.022), high and very high risk according to the refined DRI (28.5% versus 40.4% at 2 years, p=0.045), and TBI conditioning regimens based on 12 Gy (18.9% versus 27.0% at 2 years, p=0.040), but not in the subgroups of patients with ALL/NHL or low and intermediate risk according to the refined DRI ( Figures 2B , 3B , and 4B ). The cumulative incidence of NRM was comparable between the two CHARM score groups irrespective of disease type, disease risk, or TBI conditioning regimen based on 12 Gy ( Figures 2C , 3C , and 4C ). When restricted to patients who received TBI conditioning regimens based on 12 Gy, the CHARM score was not associated with the incidence of acute or chronic GVHD in univariate analysis ( Figures 4D , 4E , and 4F ).

Impact of Serum CRP and Albumin Levels on Relapse and NRM

We further evaluated whether serum CRP and albumin levels affected relapse and NRM. When patients were divided into two groups according to approximate median values of serum CRP (<0.15 mg/dL versus ≥0.15 mg/dL) and albumin(<3.9 g/dL versus ≥3.9 g/dL), the cumulative incidence of relapse was significantly worse in the group with higher CRP levels compared to the group with lower CRP (26.5% versus 16.4% at 2 years, p=0.021) ( Supplementary Figure 4A ), but the cumulative incidence of NRM was comparable between the two CRP groups ( Supplementary Figure 4B ). In contrast, the group with lower albumin levels had significantly higher rates of relapse (28.6% versus 16.2% at 2 years, p=0.002) and NRM (16.1% versus 7.2% at 2 years, p=0.044) compared to the group with higher albumin ( Supplementary Figures 4A and 4B ). Age-adjusted HCT-CI scores [ 28 ] did not affect OS, relapse, or NRM in univariate analysis ( Supplementary Figure 5 ).

Discussion

We evaluated the impact of the CHARM score on posttransplant outcomes in adults undergoing unrelated single-unit CBT. In this study, the CHARM score significantly influenced overall mortality and relapse, but not NRM, which is inconsistent with the original report [ 9 ]. Interestingly, these effects were maintained only in the subgroups of patients with AML/MDS, high and very high risk as determined by the refined DRI, and TBI conditioning regimens based on 12 Gy. Thus, our data indicate that the CHARM score predicts mortality through the stratification of relapse risk among both the entire cohort and several subgroup cohorts following unrelated single-unit CBT.

Several prognostic models for allogeneic HCT have aimed to predict transplant outcomes through the stratification of NRM [ 1 , 2 , 3 , 4 , 5 , 6 , 29 ]. The CHARM score, for example, was originally developed to estimate 1-year NRM for older patients [ 9 ]. Each element of the CHARM, including HCT-CI score, CRP, albumin, and amount of weight loss, was derived using HRs for NRM [ 9 ]. Among the previous prognostic models, the HCT-CI [ 1 ], the PAM score [ 2 , 3 ], and the NRM-J index [ 5 ] include components of comorbidity, whereas the TRM score alone includes serum albumin levels [ 6 ]. Previous studies demonstrated that higher pretransplant CRP levels were associated with higher NRM [ 30 ] and worse OS [ 31 , 32 ] among allogeneic HCT recipients. Moreover, pretransplant hypoalbuminemia, which is a marker of nutritional status and systemic chronic inflammation, is predictive of NRM after allogeneic HCT [ 33 , 34 , 35 ]. The present study has clearly demonstrated that higher CRP levels are associated with a higher rate of relapse following CBT, whereas lower albumin levels are associated with higher rates of relapse and NRM following CBT. Our previous study also showed that several factors related to inflammatory and nutritional status, including serum albumin and CRP, affected NRM after unrelated single-unit CBT [ 36 ]. The present study showed that the CHARM score was significantly associated with NRM in univariate analysis, but that association did not hold in multivariate analysis. The difference between our results and those of the original CHARM study might be partly due to the lower frequency of patients older than 60 years (13%) in our CBT cohort, which could contribute to the lack of an association between the CHARM and NRM in our multivariate analysis.

Unexpectedly, our study revealed that the CHARM score predicted the relapse rate rather than NRM in adult cases of unrelated single-unit CBT. Furthermore, the CHARM score’s discriminative capacity for relapse was higher among higher-risk patients compared to lower-risk patients as defined by the refined DRI. Although the refined DRI has proven to be the most reliable and useful disease-specific predictor for relapse following allogeneic HCT [ 26 ], the CHARM score could stratify the relapse risk, particularly among higher-risk patients, in our study. Some components of the CHARM may also be associated with disease aggressiveness. CRP has been shown to predict leukemic relapse following allogeneic HCT [ 37 ]. Hypoalbuminemia is also a component of the prognostication for AML in the AML-Composite Model [ 38 , 39 ], which is consistent with our results showing that the CHARM score’s discriminative capacity for OS and relapse is higher in cases of myeloid malignancies compared to lymphoid malignancies. Moreover, weight reduction and serum albumin concentrations may be affected by rigorous treatment preceding allogeneic HCT, indicating that the CHARM score could influence disease recurrence following CBT. Therefore, the CHARM score could assist in selecting the best transplant strategy, such as determining the need for maintenance therapy in higher-risk patients undergoing unrelated single-unit CBT.

Study Limitations

We acknowledge several limitations of this study. First, this study was retrospective, was performed at a single institution in Japan, and involved a rather limited cohort of exclusively Japanese patients. Therefore, the association between the CHARM score and CBT outcomes requires further investigation in cohorts from other racial groups. Second, the original CHARM study focused on patients older than 60 years. However, the frequency of patients older than 60 years in our CBT cohort was only 13%. It is unclear whether the lower frequency of older patients contributed to the lack of association between the CHARM score and NRM in our cohort. Moreover, it remains uncertain whether our observed results are more applicable to CBT compared to adult-donor HCT. The BMT CTN 1704 prospective trial was conducted in different areas of the United States [ 9 ], and given the higher incidence and severity of GVHD in Caucasian patients compared to Japanese patients [ 40 ], both graft source and race could affect the incidence and severity of GVHD, which could contribute to the impact of the CHARM score on posttransplant outcomes.

Conclusion

Our data demonstrated that the CHARM score could predict OS through the stratification of relapse risk rather than NRM in adults undergoing unrelated single-unit CBT, which is not consistent with the original study on the CHARM score. Further validated research is needed to clarify the impact of the CHARM score on transplant outcomes in CBT.

Ethics

Ethics Committee Approval: This retrospective study was performed in compliance with the Declaration of Helsinki. The Institutional Review Board of the University of Tokyo's Institute of Science approved this retrospective study (decision no: 2024-32-0823, date: September 2, 2024).

Informed Consent: An informed consent protocol was used for the use or collection of participants’ data for research purposes.

Supplementary Materials

Unadjusted probability of overall survival (A) and cumulative incidences of relapse (B) and non-relapse mortality (C) following single-unit cord blood transplantation, stratified by the Composite Health Risk Assessment Model score.

CHARM: Composite Health Risk Assessment Model; CBT: cord blood transplantation.

Unadjusted cumulative incidences of neutrophil (A) and platelet (B) recovery following single-unit cord blood transplantation, stratified by the Composite Health Risk Assessment Model score.

CHARM: Composite Health Risk Assessment Model; CBT: cord blood transplantation.

Unadjusted cumulative incidences of grades II to IV acute graft-versus-host disease (GVHD) (A), grades III to IV acute GVHD (B), and extensive chronic GVHD (C) following single-unit cord blood transplantation, stratified by the Composite Health Risk Assessment Model score.

CHARM: Composite Health Risk Assessment Model; CBT: cord blood transplantation; GVHD: graft-versus-host disease.

Unadjusted cumulative incidences of relapse (A) and non-relapse mortality (B) following single-unit cord blood transplantation, stratified by serum C-reactive protein and albumin levels.

CBT: Cord blood transplantation; NRM: non-relapse mortality; CRP: C-reactive protein.

Unadjusted probability of overall survival (A) and cumulative incidences of relapse (B) and non-relapse mortality (C) following single-unit cord blood transplantation, stratified by the age-adjusted Hematopoietic Cell Transplantation-Specific Comorbidity Index score.

CBT: Cord blood transplantation; NRM: non-relapse mortality; HCT-CI: Hematopoietic Cell Transplantation-Specific Comorbidity Index.

The authors thank all the physicians and staff at our hospital for their help in this study.

Authorship Contributions: Surgical and Medical Practices: S.A., Y.O., Y.N., S.T.; Concept: T.K.; Design: T.K.; Data Collection or Processing: S.K., M.M.-O., T.K., S.A., Y.O., Y.N., S.T.; Analysis or Interpretation: S.K., T.K.; Literature Search: S.K., T.K.; Writing: S.K., T.K.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

1 Sorror ML Maris MB Storb R Baron F Sandmaier BM Maloney DG Storer B Hematopoietic cell transplantation (HCT)-Specific Comorbidity Index: a new tool for risk assessment before allogeneic HCT. Blood 2005 106 8 2912 2919 10.1182/blood-2005-05-2004 15994282 PMC1895304

2 Parimon T Au DH Martin PJ Chien JW A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med 2006 144 6 407 414 10.7326/0003-4819-144-6-200603210-00007 16549853

3 Au BK Gooley TA Armand P Fang M Madtes DK Sorror ML Boeckh MJ Gibson CJ Deeg HJ Storb R Appelbaum FR Chien JW Martin PJ Reevaluation of the pretransplant assessment of mortality score after allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2015 21 5 848 854 10.1016/j.bbmt.2015.01.011 25644959 PMC4408250

4 Gratwohl A The EBMT risk score. Bone marrow transplant 2012 47 6 749 756 10.1038/bmt.2011.110 21643021

5 Yanada M Konuma T Mizuno S Saburi M Shinohara A Tanaka M Marumo A Sawa M Uchida N Ozawa Y Onizuka M Yoshioka S Nakamae H Kondo T Kimura T Kanda J Fukuda T Atsuta Y Nakasone H Yano S Predicting non-relapse mortality following allogeneic hematopoietic cell transplantation during first remission of acute myeloid leukemia. Bone Marrow Transplant 2021 56 2 387 394 10.1038/s41409-020-01032-9 32796950

6 Zarling LC Othus M Sandmaier BM Milano F Schoch G Davis C Bleakley M Deeg HJ Appelbaum FR Storb R Walter RB Utility of the Treatment-Related Mortality (TRM) score to predict outcomes of adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Leukemia 2022 36 6 1563 1574 10.1038/s41375-022-01574-5 35440690 PMC9177780

7 Elsawy M Sorror ML Up-to-date tools for risk assessment before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2016 51 10 1283 1300 10.1038/bmt.2016.141 27272454

8 Sorror ML The use of prognostic models in allogeneic transplants: a perspective guide for clinicians and investigators. Blood 2023 141 18 2173 2186 10.1182/blood.2022017999 36800564 PMC10273168

9 Artz A Logan BR Saber W Geller N Bellach A Kou J Wood W McCarty JM Knight TG Runaas L Johnston L Walston J Nakamura R Schuler T Mishra A Uberti J Dahi PB Saultz JN McCurdy SR Morris L Imus P Hogan WJ Nadiminti K Bhatt VR Mattila D Protz B Devine SM Horowitz MM Sorror M The Composite Health Risk Assessment Model (CHARM) to predict 1-year non-relapse mortality (NRM) among older recipients of allogeneic transplantation: a prospective BMT-CTN study 1704. Blood 2023 142 Suppl 1 109 10.1182/blood-2023-173855

10 Takahashi S Iseki T Ooi J Tomonari A Takasugi K Shimohakamada Y Yamada T Uchimaru K Tojo A Shirafuji N Kodo H Tani K Takahashi T Yamaguchi T Asano S Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood 2004 104 12 3813 3820 10.1182/blood-2004-03-1001 15280199

11 Takahashi S Ooi J Tomonari A Konuma T Tsukada N Oiwa-Monna M Fukuno K Uchiyama M Takasugi K Iseki T Tojo A Yamaguchi T Asano S Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood 2007 109 3 1322 1330 10.1182/blood-2006-04-020172 17038536

12 Eapen M Rocha V Sanz G Scaradavou A Zhang MJ Arcese W Sirvent A Champlin RE Chao N Gee AP Isola L Laughlin MJ Marks DI Nabhan S Ruggeri A Soiffer R Horowitz MM Gluckman E Wagner JE Center for International Blood and Marrow Transplant Research Acute Leukemia Working Party Eurocord (the European Group for Blood Marrow Transplantation) National Cord Blood Program of the New York Blood Center Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 2010 11 7 653 660 National Cord Blood Program of the New York Blood Center 10.1016/S1470-2045(10)70127-3 20558104 PMC3163510

13 Shouval R Fein JA Labopin M Kröger N Duarte RF Bader P Chabannon C Kuball J Basak GW Dufour C Galimard JE Polge E Lankester A Montoto S Snowden JA Styczynski J Yakoub-Agha I Mohty M Nagler A Outcomes of allogeneic haematopoietic stem cell transplantation from HLA-matched and alternative donors: a European Society for Blood and Marrow Transplantation registry retrospective analysis. Lancet Haematol 2019 6 11 e573 e584 10.1016/S2352-3026(19)30158-9 31477550

14 Konuma T Kanda J Inamoto Y Hayashi H Kobayashi S Uchida N Sugio Y Tanaka M Kobayashi H Kouzai Y Takahashi S Eto T Mukae J Matsuhashi Y Fukuda T Takanashi M Kanda Y Atsuta Y Kimura F Improvement of early mortality in single-unit cord blood transplantation for Japanese adults from 1998 to 2017. Am J Hematol 2020 95 4 343 353 10.1002/ajh.25705 31849102

15 Majhail NS Brunstein CG McAvoy S DeFor TE Al-Hazzouri A Setubal D Arora M Le CT Wagner JE Weisdorf DJ Does the hematopoietic cell transplantation Specific Comorbidity Index predict transplant outcomes? A validation study in a large cohort of umbilical cord blood and matched related donor transplants. Biol Blood Marrow Transplant 2008 14 9 985 992 10.1016/j.bbmt.2008.06.008 18721761

16 Adachi Y Ukai S Sagou K Fukushima N Ozeki K Kohno A Promising outcome of umbilical cord blood transplantation in patients with multiple comorbidities. Biol Blood Marrow Transplant 2018 24 7 1455 1462 10.1016/j.bbmt.2018.02.013 29476952

17 Salit RB Oliver DC Delaney C Sorror ML Milano F Prognostic value of the hematopoietic cell transplantation comorbidity index for patients undergoing reduced-intensity conditioning cord blood transplantation. Biol Blood Marrow Transplant 2017 23 4 654 658 10.1016/j.bbmt.2017.01.084 28189904

18 Konuma T Harada K Shinohara A Uchida N Shingai N Ito A Ozawa Y Tanaka M Sawa M Onizuka M Katayama Y Hiramoto N Nakano N Kimura T Kanda Y Fukuda T Atsuta Y Nakasone H Kanda J Association of individual comorbidities with outcomes in allogeneic hematopoietic cell transplantation from unrelated adult donors versus unrelated cord blood: a study on behalf of the Donor/Source and Transplant Complications Working Groups of the Japanese Society for Transplantation and Cellular Therapy. Am J Hematol 2024 99 263 273 38164974 10.1002/ajh.27174

19 Konuma T Kato S Ooi J Oiwa-Monna M Ebihara Y Mochizuki S Yuji K Ohno N Kawamata T Jo N Yokoyama K Uchimaru K Asano S Tojo A Takahashi S Single-unit cord blood transplantation after granulocyte colony-stimulating factor-combined myeloablative conditioning for myeloid malignancies not in remission. Biol Blood Marrow Transplant 2014 20 3 396 401 10.1016/j.bbmt.2013.12.555 24333750

20 Konuma T Kato S Oiwa-Monna M Tojo A Takahashi S Single-unit cord blood transplant for acute lymphoblastic leukemia and lymphoma using an intensified conditioning regimen of total body irradiation, high-dose cytarabine and cyclophosphamide. Leuk Lymphoma 2015 56 4 1148 1150 10.3109/10428194.2014.949261 25093379

21 Konuma T Kato S Isobe M Mizusawa M Oiwa-Monna M Takahashi S Tojo A Reduced-toxicity myeloablative conditioning consisting of fludarabine/busulfan/low-dose total body irradiation/granulocyte colony-stimulating factor-combined cytarabine in single cord blood transplantation for elderly patients with nonremission myeloid malignancies. Biol Blood Marrow Transplant 2019 25 4 764 770 10.1016/j.bbmt.2018.12.004 30529460

22 Mizusawa M Konuma T Kato S Isobe M Shibata H Suzuki M Takahashi O Oiwa-Monna M Takahashi S Tojo A Clinical outcomes of persistent colonization with multidrug-resistant Gram-negative rods in adult patients undergoing single cord blood transplantation. Int J Hematol 2020 111 6 858 868 10.1007/s12185-020-02854-5 32172445

23 Tanoue S Konuma T Kato S Oiwa-Monna M Isobe M Jimbo K Takahashi S Tojo A Platelet transfusion refractoriness in single-unit cord blood transplantation for adults: risk factors and clinical outcomes. Biol Blood Marrow Transplant 2018 24 9 1873 1880 10.1016/j.bbmt.2018.05.006 29753839

24 Przepiorka D Weisdorf D Martin P Klingemann HG Beatty P Hows J Thomas ED 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995 15 6 825 828 7581076

25 Sullivan KM Agura E Anasetti C Appelbaum F Badger C Bearman S Erickson K Flowers M Hansen J Loughran T Martin P Matthews D Petersdorf E Radich J Riddell S Rovira D Sanders J Schuening F Siadak M Storb R Witherspoon RP Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991 28 250 259 1887253

26 Armand P Kim HT Logan BR Wang Z Alyea EP Kalaycio ME Maziarz RT Antin JH Soiffer RJ Weisdorf DJ Rizzo JD Horowitz MM Saber W Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014 123 23 3664 3671 10.1182/blood-2014-01-552984 24744269 PMC4047501

27 Kanda Y Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013 48 3 452 458 10.1038/bmt.2012.244 23208313 PMC3590441

28 Sorror ML Storb RF Sandmaier BM Maziarz RT Pulsipher MA Maris MB Bhatia S Ostronoff F Deeg HJ Syrjala KL Estey E Maloney DG Appelbaum FR Martin PJ Storer BE Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 2014 32 29 3249 3256 10.1200/JCO.2013.53.8157 25154831 PMC4178523

29 Shouval R Fein JA Shouval A Danylesko I Shem-Tov N Zlotnik M Yerushalmi R Shimoni A Nagler A External validation and comparison of multiple prognostic scores in allogeneic hematopoietic stem cell transplantation. Blood Adv 2019 3 12 1881 1890 10.1182/bloodadvances.2019032268 31221661 PMC6595255

30 Sato M Nakasone H Oshima K Ishihara Y Wada H Sakamoto K Kawamura K Ashizawa M Machishima T Terasako K Kimura S Kikuchi M Okuda S Tanihara A Yamazaki R Tanaka Y Kanda J Kako S Nishida J Kanda Y Prediction of transplant-related complications by C-reactive protein levels before hematopoietic SCT. Bone Marrow Transplant 2013 48 5 698 702 10.1038/bmt.2012.193 23042494

31 Patel A Szydlo RM Auner HW Kanfer EJ MacDonald DH Milojkovic D Altaf S Innes A Gabriel I Rahemtulla A Chaidos A Karadimitris A Olavarria E Apperley JF Pavlů J C-reactive protein prior to myeloablative allogeneic haematopoietic cell transplantation identifies patients at risk of early- and long-term mortality. Br J Haematol 2018 180 6 889 892 10.1111/bjh.14454 27897310

32 Pavlů J Kew AK Taylor-Roberts B Auner HW Marin D Olavarria E Kanfer EJ MacDonald DH Milojkovic D Rahemtulla A Rezvani K Goldman JM Apperley JF Szydlo RM Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase. Blood 2010 115 20 4018 4020 10.1182/blood-2010-01-263624 20304808 PMC6143151

33 Vaughn JE Storer BE Armand P Raimondi R Gibson C Rambaldi A Ciceri F Oneto R Bruno B Martin PJ Sandmaier BM Storb R Sorror ML Design and validation of an augmented hematopoietic cell transplantation-comorbidity index comprising pretransplant ferritin, albumin, and platelet count for prediction of outcomes after allogeneic transplantation. Biol Blood Marrow Transplant 2015 21 8 1418 1424 10.1016/j.bbmt.2015.04.002 25862589 PMC4506728

34 Shouval R de Jong CN Fein J Broers AEC Danylesko I Shimoni A Reurs MR Baars AE van der Schaft N Nagler A Cornelissen JJ Baseline renal function and albumin are powerful predictors for allogeneic transplantation-related mortality. Biol Blood Marrow Transplant 2018 24 8 1685 1691 10.1016/j.bbmt.2018.05.005 29753163

35 Fein JA Shimoni A Labopin M Shem-Tov N Yerushalmi R Magen H Furie N Kopel E Danylesko I Nagler A Shouval R The impact of individual comorbidities on non-relapse mortality following allogeneic hematopoietic stem cell transplantation. Leukemia 2018 32 8 1787 1794 10.1038/s41375-018-0185-y 29950692

36 Miyashita E Konuma T Kataoka J Oiwa-Monna M Mizusawa M Isobe M Kato S Sato T Takahashi S Tojo A The prognostic impact of pretransplantation inflammatory and nutritional status in adult patients after myeloablative single cord blood transplantation. Biol Blood Marrow Transplant 2019 25 5 981 988 10.1016/j.bbmt.2019.01.006 30639818

37 Min CK Kim SY Eom KS Kim YJ Kim HJ Lee S Kim DW Lee JW Min WS Kim CC Patterns of C-reactive protein release following allogeneic stem cell transplantation are correlated with leukemic relapse. Bone Marrow Transplant 2006 37 5 493 498 10.1038/sj.bmt.1705276 16435015

38 Sorror ML Storer BE Fathi AT Gerds AT Medeiros BC Shami P Brunner AM Sekeres MA Mukherjee S Peña E Elsawy M Wardyn S Whitten J Moore R Becker PS McCune JS Appelbaum FR Estey EH Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality. JAMA Oncol 2017 3 12 1675 1682 10.1001/jamaoncol.2017.2714 28880971 PMC5824273

39 Sorror ML Storer BE Nyland J Estey EH Revised acute myeloid leukemia composite model using the 2017 European LeukemiaNet Risk Classification. JAMA Oncol 2019 5 7 1062 1064 10.1001/jamaoncol.2019.0902 31095246 PMC6537840

40 Kanda J Brazauskas R Hu ZH Kuwatsuka Y Nagafuji K Kanamori H Kanda Y Miyamura K Murata M Fukuda T Sakamaki H Kimura F Seo S Aljurf M Yoshimi A Milone G Wood WA Ustun C Hashimi S Pasquini M Bonfim C Dalal J Hahn T Atsuta Y Saber W Graft-versus-host disease after HLA-matched sibling bone marrow or peripheral blood stem cell transplantation: comparison of North American Caucasian and Japanese populations. Biol Blood Marrow Transplant 2016 22 4 744 751 10.1016/j.bbmt.2015.12.027 26762681 PMC4801761