El Sawy 2016

Bone Marrow Transplantation (2016), 1–18
© 2016 Macmillan Publishers Limited All rights reserved 0268-3369/16

www.nature.com/bmt
REVIEW
Up-to-date tools for risk assessment before allogeneic
hematopoietic cell transplantation
M Elsawy1,2 and ML Sorror1,3
Cure of malignant and non-malignant hematological diseases is potentially possible after allogeneic hematopoietic stem cell
transplantation (HCT). Accurate evaluation of the risk–benefit ratio for an individual patient could improve the decision-making
process about transplant, which ultimately would increase the likelihood of success. Several transplant-related models were
designed in an effort to optimize decision-making about suitable candidates for allogeneic HCT. In 1998, The European Society for
Blood and Marrow Transplantation (EBMT) developed a five-component pretransplantation risk scoring system for patients with
CML. The EBMT score was later tested in patients with various hematological disorders, and it was shown to stratify risks of mortality
after allogeneic HCT. More recent research efforts focused on models that assess health status before HCT. A HCT-specific
comorbidity index was designed to assign weights to 17 relevant comorbidities that were shown to independently predict non-
relapse mortality. Performance status scales and comprehensive geriatric assessment tools might uncover additional overall health
limitations that affect long-term survival among older recipients of allogeneic HCT. Other models include the pretransplantation
assessment of mortality score that summarizes the impacts of eight different pretransplantation patient- and disease-specific
variables into a 50-point model that predicts survival. The disease-risk index captures the impact of primary diagnoses and disease
status on relapse and survival following allogeneic HCT. The values and limitations of each model are discussed herein. We also
provide insight on how to use these models in the clinic to decide about offering allogeneic HCT with the most suitable
conditioning regimen intensity.
Bone Marrow Transplantation advance online publication, 6 June 2016; doi:10.1038/bmt.2016.141
INTRODUCTION and (3) future directions to improve our abilities to predict HCT
Allogeneic hematopoietic cell transplantation (HCT) is a potentially outcomes.
curative treatment for various malignant and non-malignant
hematological disorders. The rate of utilization of this treatment
modality is unremitting. However, this comes at a price. Allogeneic PATIENT-SPECIFIC RISK-ASSESSMENT MODELS
HCT could lead to significant transplant-related mortality. As a HCT-CI
result, decision-making about referral to allogeneic HCT is a Development. To enhance our ability to evaluate comorbidities
challenging task, both for physicians and patients. Therefore, before allogeneic HCT, an HCT-CI was developed by modifying
there is a great need for robust tools to help physicians identify another non-transplant index, the Charlson comorbidity index
which patients should be treated with high-dose conditioning (CCI),5 in three different ways.1 First, laboratory data, pulmonary
regimens, which are best suited for reduced-intensity conditioning function tests, ejection fraction, and values of bilirubin and hepatic
(RIC) regimens, and which patients should not be offered transaminases were introduced into the definitions of pulmonary,
allogeneic HCT. cardiac and hepatic comorbidities, respectively. Second, all
Currently, there is a number of risk-assessment models that are comorbidities encountered in the studied population of HCT
used by clinicians and investigators. Some of these models use recipients were included in a risk-assessment analysis. New
variables of patients’ health status, for example, the HCT-specific weights were then generated for the impacts of comorbidities
comorbidity index (HCT-CI),1 some focus on cancer-related on non-relapse mortality (NRM).
variables, for example, the disease-risk index (DRI),2 whereas The study included 1055 patients with different hematologic
others incorporate a number of patient- and disease-specific risk diseases who were given allogeneic HCT after nonmyeloablative
variables into combined models, for example, the European (n = 294) or high-dose (n = 761) conditioning regimens. Patients
Society for Blood and Marrow Transplantation (EBMT)3 and were randomly divided into a training (n = 708) and a validation
pretransplantation assessment of mortality (PAM)4 risk scores. set (n = 347). Integer weights of comorbidities were calculated
Here we discuss (1) the stages of development and validation of based on adjusted hazard ratios (HRs) from Cox proportional
the currently available models with emphasis on their relative hazard models of NRM. The new HCT-CI included 17 comorbidities
strengths and potential limitations; (2) the use of these models in acquiring scores from 1 to 3 (Table 1). In the validation set,
an integrated approach to guide decisions about allogeneic HCT; the HCT-CI scores captured more patients with comorbidities
1
Transplantation Biology Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Department of Medical Oncology, National Cancer Institute,
Cairo University, Cairo, Egypt and 3Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA. Correspondence:
Dr ML Sorror, Transplantation Biology Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA.
E-mail: msorror@fhcrc.org
Received 23 July 2015; revised 13 March 2016; accepted 11 April 2016
Risk assessment models prior allogeneic HCT
M Elsawy and ML Sorror
2
Table 1. Definitions of comorbidities included in the HCT-CI and the augmented HCT-CI and their corresponding scores
The HCT-CI
Comorbidity Definition Score
Arrhythmia Any type of arrhythmia that has necessitated the delivery of a specific anti-arrhythmia treatment at any 1
time point in the patient’s past medical history.
Cardiac Coronary artery disease,a congestive heart failure, myocardial infarction or EF ⩽ 50%. 1
Inflammatory bowel disease Crohn’s disease or ulcerative colitis requiring treatment at any time point in patient’s past medical history 1
Diabetes Requiring treatment with insulin or oral hypoglycemic agents continuously for 4 weeks before the start of 1
conditioning.
Cerebrovascular disease Transient ischemic attack or cerebrovascular accident. 1
Psychiatric disturbance Any disorder requiring continuous treatments for 4 weeks before the start of conditioning. 1
Hepatic, mild Chronic hepatitis, bilirubin4ULN to 1.5 × ULN or AST/ALT4ULN to 2.5 × ULN; at least two values of each 1
within 2 or 4 weeks before the start of conditioning.
Obesity Patients with a BMI 435 kg/m2 for patients 418 years or a BMI for age of ⩾ 95th percentile for patients of 1
⩽ 18 years of age.
Infection Requiring antimicrobial treatment starting from before conditioning and continued beyond day 0. 1
Rheumatologic Requiring specific treatment at any time point in the patient’s past medical history. 2
Peptic ulcer On the basis of prior endoscopic or radiologic diagnosis. 2
Moderate/severe renal Serum creatinine 42 mg/dL (at least two values within 2 or 4 weeks before the start of conditioning), on 2
dialysis or prior renal transplantation.
Moderate pulmonary Corrected DLco (via Dinakara equation) and/or FEV1 of 66-80% or dyspnea on slight activity. 2
Prior malignancy Treated at any time point in the patient’s past history, excluding non-melanoma skin cancer. 3
Heart valve disease Of at least moderate severity, prosthetic valve or symptomatic mitral valve prolapse as detected by 3
echocardiogram.
Severe pulmonary Corrected DLco (via Dinakara equation) and/or FEV1 ⩽ 65% or dyspnea at rest or requiring oxygen. 3
Moderate/severe hepatic Liver cirrhosis, bilirubin41.5 × ULN or AST/ALT42.5 × ULN; at least two values of each within 2 or 4 weeks 3
before the start of conditioning.
Augmented HCT-CI: all of the above plus

High ferritin Values of ⩾ 2500 as measured the closest before the start of conditioning. 1
Mild hypoalbuminemia Values of o 3.5–3.0 as measured the closest before the start of conditioning. 1
Thrombocytopenia Values of o 100 000 as measured the closest before the start of conditioning. 1
Moderate hypoalbuminemia Values of o 3.0 as measured the closest before the start of conditioning. 2
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; DLco = diffusion capacity of carbon monoxide;
EF = ejection fraction; FEV1 = forced expiratory volume in 1 s; HCT-CI = hematopoietic stem cell transplantation-specific comorbidity index; ULN = upper limit
of normal. aOne or more vessel-coronary artery stenosis requiring medical treatment, stent, or bypass graft.
compared with the CCI. HCT-CI scores of 1–2 and ⩾ 3 were found The index could potentially be used to guide selection of
in 34% and 28% of patients, whereas only 10% and 3% of patients conditioning regimens. For example, HCT-CI scores of 43
had CCI scores of 1 and ⩾ 2, respectively. HCT-CI scores of 0, were used as a stratification criterion to randomize patients
1–2 and ⩾ 3 predicted NRM incidences of 14%, 21% and 41%, with myelodysplastic syndromes (MDS) or AML between
respectively, and survival rates of 71%, 60% and 34%, respectively receiving high-dose versus RIC regimens before allogeneic HCT
(Figure 1). The HCT-CI scores showed higher discriminative power (NCT00322101).
than the CCI scores both for NRM (c-statistic estimate of 0.692 The HCT-CI was also used in retrospective studies to guide
versus 0.546, P o 0.001) and survival (c-statistic estimate of 0.661 decision-making before allogeneic HCT for a given hematologic
versus 0.561, P o 0.001), respectively. malignancy as detailed in Table 3.
In addition, the HCT-CI score could predict risks of development
Validation. The HCT-CI score has been extensively validated in of certain post-transplant complications. A recent analysis of
several retrospective and prospective multi-center studies. Some data from 2985 allogeneic HCT recipients form five different US
of these studies were performed in large data sets with various institutions demonstrated a strong association between higher
hematological disorders,6–8 whereas others were performed in HCT-CI scores and development of grades III and IV acute GvHD
single disease series.9–11 Overall, 25 studies could prove the
(Table 4), and subsequent mortality following diagnosis of grade II
validity of HCT-CI score as an independent predictor of outcomes.
(HR = 1.24; P o 0.0001) or grades III and IV acute GvHD (HR = 1.19;
Results of these studies are summarized in Table 2.6–30 All of these
studies used NRM and overall survival (OS) as the outcomes of Po 0.0001).39 In another study of 1775 adult survivors 3–18 years
interest to validate the index. In addition, five studies utilized after allogeneic HCT, higher pretransplant HCT-CI scores were
concordance probability estimates, such as c-statistic index, to associated with impaired physical health, increased depression,
measure the discriminative power of the HCT-CI.7,8,11,20,29 On the increased distress and diminished social support among
other hand, only eight studies found the HCT-CI not to provide long-term survivors.40 Thus, the HCT-CI can be used to guide
prognostic information due to several reasons that are discussed intervention studies aimed at improving the quality of life among
under the section ‘Limitations’.31–38 long-term survivors.
The index can best be used in combination with other variables
Advantages. The HCT-CI summarizes the impact of relevant covering other patient- and disease-specific risks (Table 5):
comorbidities on HCT outcomes into an unified model. The index
contains objective laboratory data to define certain comorbidities, ● A composite HCT-CI score and Karnofsky performance status14
allowing for more accurate measurement of comorbidities burden ● A combined comorbidity/relapse model41
compared with non-transplant-specific indices. ● A composite HCT-CI score and EBMT risk score42
Bone Marrow Transplantation (2016), 1 – 18 © 2016 Macmillan Publishers Limited

3
a HCT-CI b CCI
100 100
80 80 CCI 0
CCI 1
Percent NRM
Percent NRM
60 60 CCI ≥2
HCT-CI ≥3
40 40
HCT-CI 1-2
20 20
HCT-CI 0
0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months after HCT Months after HCT
c HCT-CI d CCI
100 100
80 80
HCT-CI 0
Percent survival
Percent survival
CCI 0
60 60
HCT-CI 1-2
40 40
CCI 1-2
20 HCT-CI ≥3 20
CCI ≥3
0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months after HCT Months after HCT
Figure 1. The HCT-CI compared with CCI. Cumulative incidence of NRM as stratified by (a) HCT-CI compared with (b) the original CCI and
Kaplan–Meier estimates of survival as stratified by (c) the HCT-CI compared with (d) the original CCI. CCI = Charlson comorbidity index;
HCT-CI = hematopoietic cell transplantation-specific comorbidity index; NRM = non-relapse mortality. This research was originally published in
Blood, Sorror et al.1 © American Society of Hematology.
● A combined HCT-CI score and the instrumental activities of Some studies did not show differences in outcomes among
daily living (IADL) for HCT recipients of 50 years of age or patients with scores 0, 1 and 2, suggesting that the HCT-CI only
older.43 performs as a binary categorizer.20 The definitions of low,
intermediate and high risks for HCT-CI are meant to be relative
and not absolute categorizations, as the increasing scores of the
Limitations. Although 25 out of 33 studies proved the discrimi- HCT-CI were meant to capture a general trend for increases in risks
native validity of the HCT-CI, eight studies did not (Table 2).31–38 of NRM. The range of these increases would differ based on the
Limited sample size was evident in most of the disagreeing intensity of transplant conditioning, disease status and other
studies. Lack of full agreement on the validity of the index was factors. For example, patients with scores of 1–2 could have
thought to limit its worldwide applicability. However, in two comparable NRM with patients with scores of 0 if they are given a
recent large prospective studies, the HCT-CI was shown to predict reduced-intensity regimen, but higher NRM if the conditioning
both NRM and OS after allogeneic HCT given to patients in Italy or regimen is higher in intensity. Therefore, the best way to define
United States.6,8 Another large retrospective study showed the HCT-CI risk groups would probably rely on stratifying patients into
index to be a valid prognostic factor across different conditioning roughly equally distributed subgroups. Alternatively, HCT-CI scores
regimens, ages and centers.7 In the latter study, investigators could be employed in multivariate models as a continuous
calculated a sample size of at least 200 patients to be required for variable.
appropriate validation of the HCT-CI. There have been questions whether exact instead of integer
Another potential limitation of the index was the weak weights of comorbidities would improve the model performance
agreement on comorbidity coding by evaluators at different or whether new weights need to be developed for different
institutions.34 To ensure accuracy and consistency of comorbidity transplant settings. One study looked at recalibrating the relative
coding among investigators, a systematic methodology for scores of the individual components of the HCT-CI by replacing
reviewing medical charts (Figure 2) and consistent guidelines for the integer weights, with the exact HRs of different comorbidities.
comorbidity coding were summarized in a web-based calculator Authors concluded that six comorbidities are no longer contribut-
(www.hctci.org).44 This brief training program resulted in ing to the total score.12 However, these results could not be
improvement of inter-rater reliability among different evaluators validated in a separate independent cohort. In fact, the HCT-CI
from 0.433 to 40.90 as measured by weighted kappa statistic score in its original structure was superior to the modified index in
estimates. prognostication of NRM and survival.45
© 2016 Macmillan Publishers Limited Bone Marrow Transplantation (2016), 1 – 18

4
Table 2. Performance of the HCT-CI as a prognostic factor in single and multi-center; retrospective and prospective studies
Study Number of Types of donors Types of conditioning Outcomes Comments Statistical Methods used
patients intensity for validation
Predicted by the Not predicted by Rates Multivariate C-statistic

HCT-CI the HCT-CI HRs estimates
Kerbauy 43 HLA matched MA (n = 37) NMA 4-year NRM and OS — Small sample size. Diagnosis: chronic √ — —
et al.13 (n = 35) HLA-MM (n = 6) myelomonocytic leukemia.
(n = 8)
Maruyama 132 Related (n = 70) MA (n = 52) RIC 2-year NRM and OS 2-year NRM and Diagnoses: leukemia/lymphoma in √ √ —
et al.9 Unrelated (n = 62) (n = 80) in MA patients OS in RIC nonremission.
patients
Kerbauy 104 Related (n = 58) MA (n = 95) NMA 5-year NRM and OS — Diagnoses: idiopathic myelofibrosis, √ √ —
Bone Marrow Transplantation (2016), 1 – 18

et al.10 Unrelated (n = 45) (n = 9) advanced polycythemia vera and
essential thrombocythemia.
Sorror et al.11 244 HLA matched MA (n = 202) NMA 2-year NRM and OS — Diagnosis: AML in 1st CR. √ √ √
(n = 220) HLA-MM (n = 18) RIC (n = 24)
(n = 24)
Sorror et al.30 577 HLA matched MA (n = 425) NMA 2-year NRM and OS — Adding disease status improved √ √ —
(n = 523) HLA-MM (n = 125) prediction. Diagnosis: AML/MDS.
(n = 54)
Sorror et al.14 341 Related (n = 160) NMA (n = 341) 2-year NRM and OS — Adding KPS improved prediction √ √ —
Unrelated (n = 181) Diagnosis: malignant and benign
hematological disorders.
Artz et al.15 112 HLA matched RIC 1-year OS 1-year NRM Small sample size. Diagnosis: malignant √ √ —
(n = 103) HLA-MM and benign hematological disorders.
(n = 9)
Sorror et al.16 220 HLA matched MA (n = 68) NMA 3-year NRM and OS — Diagnoses: chronic lymphocytic leukemia √ √ —
(n = 205) HLA-MM (n = 152) and lymphoma.
(n = 15)
Xhaard et al.31 286 Related (n = 149) MA (n = 167) NMA — 2-year NRM and Lack of information on PFT. Diagnosis: √ √ √
Unrelated (n = 63) (n = 119) OS malignant and benign hematological
Other (n = 74) disorders.
Majhail 373 HLA matched MA (n = 150) NMA 2-year NRM and OS 2-year NRM and Small number of patients in subgroups √ √ —
et al.12 (n = 184) UCB (n = 223) in overall cohort OS in subgroup Diagnosis: malignant and benign
(n = 189) analysis hematological disorders.
Farina et al.17 203 Related (n = 121) RIC (n = 154) NMA 2-year NRM,OS and — Diagnosis Lymphoma and myeloma. √ √ —
Unrelated (n = 82) (n = 49) PFS,
Guilfoyle 187 Related (n = 138) MA (n = 177) NMA — 2-year NRM and (1) High incidence of pulmonary √ √ —
et al.37 Unrelated (n = 49) (n = 10) OS comorbidities (2) Small sample size (3)
Data collected from 1990–2005
(significant heterogeneity in treatment
protocols and supportive care). Diagnosis:
malignant and benign hematological
disorders.
Kataoka 187 HLA matched MA (n = 170) NMA (1) 3-year NRM and OS in high-risk Small number of patients in subgroups. √ √ —
et al.18 (n = 143) HLA-MM (n = 17) OS disease Diagnosis: malignant and benign
(n = 44) (2) OS in low-risk subgroup hematological disorders.
disease subgroup
Lim et al.19 128 HLA matched RIC 3-year NRM, OS and — Diagnosis: AML/MDS. √ √ —
(n = 94) HLA-MM DFS
(n = 34)
Barba et al.20 194 RIC 2-year NRM and OS — Diagnosis: malignant and benign √ √ √
© 2016 Macmillan Publishers Limited

Table 2. (Continued )
Study Number of Types of donors Types of conditioning Outcomes Comments Statistical Methods used
patients intensity for validation
Predicted by the Not predicted by Rates Multivariate C-statistic

HCT-CI the HCT-CI HRs estimates
Related (n = 153)
Unrelated or MM
(n = 41)
Terwey et al.32 151 HLA matched MA (n = 138) RIC — 2-year NRM and High frequency of intermediate and high- √ √ —

(n = 134) HLA-MM (n = 13) OS risk patients (71%). Diagnosis: ALL.
(n = 17)
DeFor et al.33 444 HLA matched MA (n = 169) NMA — 2-year NRM and Using exact HRs rather integer weights of √ √ √
(n = 211) UCB (n = 275) OS comorbidities for scores calculation.
(n = 233)
Birninger 340 Related (n = 116) MA (n = 133) NMA — 3-year NRM and (1) Unbalanced score categories (2) √ √ —
et al.34 Other (n = 224) (n = 207) OS Possible over-scoring of some
comorbidities Diagnosis: high-risk AML.
Smith et al.21 252 HLA matched MA (n = 189) RIC/ 1-year NRM and OS — Pediatric population based study √ √ —
(n = 149) HLA-MM NMA (n = 61) None Diagnosis: malignant and benign
(n = 55) UCB (n = 48) (n = 2) hematological disorders.
Castagna 63 HLA matched RIC — 1-year TRM and Small sample size, patients 460 years. √ — —
et al.35 (n = 59) HLA-MM 2-year OS Diagnosis: malignant and benign
(n = 2) UCB (n = 2) hematological disorders.
Williams 96 Related (n = 34) MA (n = 33) RIC ─ 1-year NRM and Small-sized heterogeneous sample. √ √ —
et al.36 Unrelated (n = 62) (n = 63) OS Diagnosis: malignant and benign
Bokhari 121 Related (n = 57) RIC 2-year NRM and OS 2-year NRM and Diagnosis: AML/MDS. √ √ —
et al.22 Unrelated (n = 64) when combined with OS
age and disease
status
Raimondi 1937 Related (n = 958) MA (n = 1083) RIC 2-year NRM and OS — A large multi-center prospective study. √ √ √
et al.8 Unrelated (n = 979) (n = 854) Diagnosis: malignant and benign
Mo et al.23 526 PMRD MA 2-year NRM, OS and — Diagnosis: malignant and benign √ √ —
relapse risk hematological disorders.

24
Le et al. 79 HLA matched MA 5-year NRM and OS — Diagnosis: malignant and benign √ √ —
Ratan et al.25 218 HLA matched and MA 5-year NRM,OS and — Diagnosis: AML/MDS. √ √ —
other RFS
Hashmi 103 Related (n = 45) RIC 1-year OS — Diagnosis: malignant and benign √ √ —
et al.,26 Unrelated (n = 58) hematological disorders.
Bayraktar 377 HLA matched MA (n = 199) NMA Mortality and 1-year — Diagnosis: patients admitted to ICU post √ √ —
et al.27 (n = 277) HLA-MM (n = 178) OS in patients allo-HCT.

(n = 100) admitted to ICU
Chemnitz 245 Related (n = 87) MA/RIC (n = 167) 5-year NRM and OS — Diagnosis: malignant and benign √ √ —
et al.28 Unrelated (n = 158) NMA (n = 35) Other hematological disorders.
(n = 43)
Nakaya 243 Related (n = 68) MA (n = 166) RIC — 2-year NRM and A multi-center prospective study. √ √ —
et al.38 Unrelated (n = 175) (n = 77) OS Diagnosis: malignant and benign
hematological disorders. HCT-CI was
predictive of 2-year NRM and OS using
new cutoffs for risk groups (low risk for

scores of 0–3 and high risk for scores ⩾ 4).
5
6
Modifications. Two recent modifications were introduced to the
MA = myeloablative; MDS = myelodysplastic syndromes; MM = mismatched; NMA = nonmyeloablative; NRM = non-relapse mortality; OS = overall survival; PFTs = pulmonary function tests; PMRD = partially
Abbreviations: DFS = disease-free survival; HCT-CI = hematopoietic cell transplantation-specific comorbidity index; HRs = hazard ratios; ICU = intensive care unit; KPS = Karnofsky performance status;
C-statistic
estimates
HCT-CI to improve its discriminative power. In a study of 3033
—
√
√
recipients of allogeneic HCT, who were randomly divided into a
Statistical Methods used training set (n = 1853) and a validation set (n = 1180), an age of
for validation ⩾ 40 years was found to have an impact on NRM that is equivalent
to a single comorbidity with a score of 1. A score of 1 was assigned
Multivariate to age of ⩾ 40 years to form a composite comorbidity/age index.
HRs
√
In the validation cohort, the composite model had a statistically
matched related donor; RFS = relapse-free survival; RIC = reduced-intensity conditioning; TRM = transplant-related mortality; UCB = umbilical cord blood. aRecipients of allogeneic HCT.
significant higher discriminative capacity for NRM (c-statistic
estimates of 0.664 versus 0.556; P o 0.001) and survival (c-statistic
estimates of 0.682 versus 0.560; P o0.001) compared with age
Rates
√
alone, respectively. In the same validation cohort, the composite
comorbidity/age index stratified patients according to outcomes
donors. Diagnosis: malignant and benign
A large multi-center prospective study. into four distinct groups compared with three groups for the
HCT-CI.46
The HCT-CI scores could be used to
patients with no suitable matched

optimize graft source selection for
In another study, weights were developed for low albumin,

Diagnosis: malignant and benign
Diagnosis: malignant and benign low platelets and high ferritin values. Adding scores for these
laboratory values to the HCT-CI resulted in an augmented index
that possessed higher c-statistic estimate for predicting NRM
compared with the HCT-CI alone (P = 0.0007).47
CGA
Use in HCT Recipients. The prognostic role of Comprehensive
Comments
Geriatric Assesment (CGA) has been shown in patients treated

with chemotherapy.48,49 However, the feasibility of CGA in the
setting of HCT is yet to be better defined.
In a single institution prospective study, investigators explored
the prognostic role of CGA in 203 patients with ages between 50
Not predicted by
and 73 years (median age = 58 years), who received allogeneic

HCT for various hematological disorders.43 In multivariate analysis,
the HCT-CI
the authors identified IADL, slow gait, high HCT-CI scores, low
mental health by short-form 36 medical component summary and
—
elevated CRP blood levels to be associated with significantly worse

Outcomes
OS. IADL limitation was the most predictive factor of OS (HR = 2.28;
2-year NRM and OS
2-year NRM and OS
Po 0.001) among all CGA domains. This impact was even more
1 and 3-year NRM
noticeable among patients of 460 years of age (HR = 3.25;

Predicted by the
Po 0.001). The authors then combined IADL with the HCT-CI in a

single three-point model (Table 5). None of the patients aged ⩾ 60
years with a combined score of 2 survived 42 years.43
and OS
HCT-CI
Another prospective study reached a different conclusion. In a

group of 126 patients with newly diagnosed AML given allogeneic
HCT (median age = 74 years, range 60–90), investigators explored
Types of conditioning
MA (62%) RIC (18%)

MA (n = 308) NMA/
the impact of CGA domains on OS. After adjusting for age

MA (67%) aNMA/
and cytogenetic risks in multivariate models, only self-reported

cardiac history was an independent prognostic factor for survival
RIC (n = 184)
NMA (20%)
(HR = 2.290), whereas the remaining CGA tools were not.50 Clearly,
RIC (33%)
intensity
we need more discovery and validation studies before CGA is

introduced in transplant clinics.
a
Advantages. The use of a shortened and relevant GCA battery

might reveal additional vulnerabilities to those captured by
HLA-MM (n = 254)
Autologous (58%)
Unrelated (23%)
Unrelated (44%)
comorbidities or performance status that are specific to older

Types of donors
Related (19%)
Related (56%)
UCB (n = 238)
patients. Therefore, CGA could further refine pre-HCT risk

assessment when considered with other risk factors. Geriatric
health limitations might be potentially modifiable in the
peri-transplant period to improve HCT outcomes.
Limitations. The use of CGA in the setting of allogeneic HCT is

Number of
patients
hampered by a number of limitations. A full CGA is probably time-

19 767
2523
consuming, particularly for sick patients. Some of these patients

(Continued )
Elsawy et al.29 492
might not be able to complete the assessment. The assessment

could also be time-consuming for the medical staff. A consider-
Elsawy et al.7
Sorror et al.6
able amount of learning needs to be done to encourage patients

and physicians on the use of GA models. Moreover, identifying the
most relevant components of CGA would further simplify its
Table 2.
Study
usage. This is particularly true for the functional components that

are uniquely assessed by the CGA. For example, in an analysis of

Table 3. Role of HCT-CI scores in optimizing treatment selection for specific hematological disorders
Study Number of Disease category Conditioning intensity Risk stratification Comments

patients
Sorror 577 AML (n = 391) MDS MA (n = 452) NMA HCT-CI Disease risk 2-yr NRM and OS (%) Increasing HCT-CI scores and higher disease risk were the two
et al.30 (n = 186) (n = 125) score MA NMA most predictors of mortality. Thus, combined HCT-CI score and
NRM OS NRM OS disease-risk status stratified patients into 4 groups with distinct

0–2 Low 11 78 4 70 outcomes. Patients with HCT-CI scores = 0–2 had comparable
0–2 Intermediate and 24 51 3 57 risks of 2-year NRM, following high-dose or nonmyeloablative
high conditioning regimens regardless of their disease status,
⩾3 Low 32 45 27 41 suggesting their suitability for prospective randomized studies
⩾3 Intermediate and 46 24 29 29 comparing both regimens. On the other hand, those with HCT-CI
high scores ⩾ 3 and high-risk diseases experienced higher rates of
NRM, but similar survival following high-dose versus
nonmyeloablative conditioning regimens, respectively. Novel
conditioning regimens with some anti-tumor effect, but
potentially tolerable toxicity profile could be explored in this
group of patients to improve their survival.82
Sorror 82 CLL 2-Gy TBI (n = 13) 2-Gy HCT-CI LN size 5-yr OS (%) Combined HCT-CI scores and LN size were the two most
et al.83 TBI+fludarabine score predictive factors of outcomes.
(n = 69)
0 o5 cm 78
0 ⩾ 5 cm 43
⩾1 o5 cm 60
⩾1 ⩾ 5 cm 27
Sorror 220 CLL and lymphoma MA (n = 68) NMA HCT-CI Conditioning 3-yr 3-yr OS (%) Patients with HCT-CI score = 0 had no statistically significant
et al.16 (n = 152) score intensity NRM differences in outcomes, whereas patients with HCT-CI scores ⩾ 1
(%) had statistically significant better outcomes with NMA versus MA
conditioning regimens, respectively.
0 NMA 18 68
0 MA 15 60
⩾1 NMA 28 47
⩾1 MA 50 35
Pavlu 271 Imatinib-resistant MA HCT-CI 5-yr NRM (%) 5-year OS (%) CML patients with low HCT-CI scores and low CRP values are
et al.84 CML score better candidates for early MA HCT after imatinib failure.
0 5.3 69.6
⩾1 18.5 55.5
CRP (mL/L) 5-yr OS (%)

⩽9 70
49 40
Abbreviations: HCT-CI = hematopoietic cell transplantation-specific comorbidity index; LN = lymph node; MA = myelobalative; MDS = myelodysplastic syndromes; NMA = nonmyeloablative; NRM = non-relapse
mortality; OS = overall survival; yr = year.

7
8
data from nine studies enrolling a total of 34 485 adults aged 65 currently used models such as the HCT-CI or Karnofsky
years or older, a walk test as a measure of gait speed has been performance status. One study is evaluating these components
shown to be associated with outcome of elderly patients.51 In a prospectively to determine feasibility of allogeneic HCT and
more recent study, a six-minute walking test (MWT) and a hand compare its outcomes to those after non-transplant therapies in
grip strength (HGS) test were the best predictors of mortality patients with AML (NCT01929408).
among 310 hospitalized patients 460 years.52 In a prospective
study, analyzing data from 2273 visits of allogeneic HCT recipients
diagnosed with chronic GvHD, both the 2MWT and HGS DISEASE-SPECIFIC RISK-ASSESSMENT MODELS
were significantly associated with global chronic GvHD severity. DRI
In multivariable analysis, 2MWT was significantly associated with Development. The underlying primary hematologic disease and
OS, NRM and failure-free survival; meanwhile no association was its response to initial chemotherapy are major determinants of
observed for HGS.53 Well-designed and appropriately powered outcomes following allogeneic HCT.54–56 Investigators from the
studies are still needed to identify the additional magnitude of Dana Farber Cancer Institute and Fred Hutchinson Cancer
prognostic value that some unique CGA components could add to Research Center (FHCRC) designed a study to develop and
validate a novel and comprehensive model that captures the
impact of primary diagnosis, disease status, histologic subtypes
Table 4. Association between HCT-CI scores and development of
(for lymphomas)56–58 and chromosomal aberrations (for AML, ALL
acute GvHD
and MDS59,60) on outcomes. The study included a group of 1539
HCT-CI score Incidence of grades III-IV acute GVHD* consecutive patients, who received their first allogeneic HCT
between 2000 and 2009 after nonmyeloablative/RIC (n = 727) or
0 13% high-dose (n = 812) conditioning regimens.2 The DRI was derived
1–4 18% from Cox proportional hazards models with OS as the main
⩾5 24% outcome of interest for each diagnosis and disease status. The DRI
*Po0.0001. comprises three disease grouping categories and two status
grouping categories resulting in six possibilities of diagnosis/
Table 5. Augmentation of HCT-CI predictability by combining with other models85
Composite model Risk groups Outcomes at 2 years Outcomes at 4 or 5 years
HCT-CI KPS NRM (%) OS (%) NRM (%) OS (%)
Comorbidity/PS 14
0–2 480% 16 68
0–2 ⩽ 80% 17 58
⩾3 480% 30 41
⩾3 ⩽ 80% 39 32
Comorbidity/age score46 (nonmyeloablative versus RIC) HCT-CI/age

0 5–12 81–87
1–2 9–18 66–67
3–4 17–36 47–54
⩾5 35–41 34–35
Comorbidity/relapse score (patients ⩾ 60 years old)41 HCT-CI Relapse risk score

0 Low 69
0 Standard 45
0 High 41
1–2 Low 56
1–2 Standard 44
1–2 High 15
⩾3 Low 56
⩾3 Standard 23
⩾3 High 23
HCT-CI/EBMT42 HCT-CI EBMT

0 o4 11 72
0 ⩾4 19 61
1–2 o4 16 63
1–2 ⩾4 28 48
⩾3 o4 31 40
⩾3 ⩾4 41 30
HCT-CI/IADL43 Scores
HCT-CI score of ⩾ 3 or IADL score o14 acquire a score 0 62
of 1. Both abnormalities get a score of 2
1 44
2 13
Abbreviations: EBMT = European bone marrow transplant; HCT-CI = hematopoietic cell transplantation comorbidity index; IADL = instrumental activities of
daily living; KPS = Karnofsky performance status; NRM = non-relapse mortality; OS = overall survival; PS = performance status. This research was originally
published in ASH Educational Book, Sorror and Estey85 © American Society of Hematology.

9
Three-step process (15 minutes)
Medical notes Labs/Tests Final assessment

8 min 6 min 1 min
Review Bilirubin Serum DLco Echo/ Double Total

Nutrition H&P Consults
of data /AST/ALT creatinine FEV1 MUGA checking score
0% 5% 20% 40% 45% 55% 60% 80% 90% 95% 100%

Cumulative data acquisition scale (%)
Figure 2. Three-step methodology for comorbidity coding. This research was originally published in Blood, Sorror.44 © American Society of
Hematology.
disease status combinations that were collapsed into four risk Table 6. Disease risk index2,61
groups. The DRI predicted excellent 4-year OS and PFS rates of Disease Disease risk
64% and 56%, respectively, for patients with low-risk, these figures
were 6% and 6%, respectively, among very high-risk patients AML favorable cytogenetics Low
(Table 6 and Figure 3). CLL
The investigators then validated the DRI in an independent CML
cohort of 672 patients from FHCRC. The DRI could successfully Indolent B-cell NHL
stratify rates of OS and PFS among patients in the validation ALL Intermediate
cohort (P o 0.001 for both; Figure 4). AML intermediate cytogenetics
MDS intermediate cytogenetics
MPN
Validation. Recently, DRI was further refined and validated in a Multiple myeloma
large study from the Center for International Blood and Marrow HL
Transplant Research comprising 13 131 patients given allogeneic DLBCL/transformed indolent B-cell
HCT between 2000 and 2010, following nonmyeloablative/RIC NHL
(47%) or high-dose (53%) conditioning regimens. Four risk Mantle cell lymphoma
categories were identified with 2-year OS ranging from 64 to T-cell lymphoma, nodal
24% (P o0.001) for low- and very high-risk categories, AML adverse cytogenetics High
respectively.61 The authors then attempted to further refine the MDS adverse cytogenetics
T-cell lymphoma, extranodal
DRI categories as described under the section ‘Modification’
below. Stage Stage risk
Three independent groups of investigators recently tested the
discriminative validity of the DRI in their own patient cohorts. Any CR Low
Results are summarized in Table 7. 1st PR
Untreated
Advantages. DRI provides a uniform model to measure the Chronic phase CML
impacts of various diagnoses/disease status/cytogenetic combina- 2nd or subsequent PR (if RIC)
2nd or subsequent PR (if MAC) High
tions on survivals, following allogeneic HCT. The DRI index can
Induction failure
prove to be a useful tool to compare or adjust results of studies Active relapse
that include heterogeneous hematological diseases. In addition, Accelerated or blast phase CML
the index can be useful in comparing outcomes across different
transplant centers that treat different diagnoses. Overall assignment
Limitations. DRI lacks essential data on molecular markers of Disease risk Stage risk DRI
some diseases, for example, FMS-like tyrosine kinase 3 (FLT3)
Low Low Low
internal tandem duplication status for AML. Low High Intermediate
As the DRI was developed from a large pool of various Intermediate Low
diagnoses and disease status, it is possible that the current Intermediate High High
categories of the DRI might not stratify risks of mortality well High Low
within a single disease. Like any other prognostic model, the use High High Very high
of the DRI has to be introduced in appropriately powered studies
Abbreviations: DLBCL = diffuse large B-cell lymphoma; HL = Hodgkin
with sufficient follow-up durations. In a recent study, the DRI was lymphoma; MAC = myeloablative conditioning; MDS = myelodysplastic
found to stratify risks only in samples of 450 patients with syndromes; MPN = myeloproliferative neoplasms; NHL = non-Hodgkin
440 months of follow-up duration.62 Additional refinements of lymphoma; RIC = reduced-intensity conditioning. This research was
the DRI might change these parameters. originally published in Blood. Armand et al.2 © American Society of
Hematology.
Modifications. The original developers of the model attempted to
modify it in a large Center for International Blood and Marrow
Transplant Research study.61 Changes included the following: than those in the original DRI based on the similarities in
(1) patients given RIC or high-dose regimens in 2nd or subsequent outcomes (Table 8). The refined DRI had c-statistic estimate of
PR were grouped together in the low risk category; (2) rare 0.643 for prediction of OS compared with 0.637 for the original
diseases such as Burkitt lymphoma were added; and (3) some DRI; no P-value was reported to allow for better quantification of
disease status combinations were assigned different risk groups the magnitude of this change.

10
a 100 b 100
Low risk Int risk Low risk Int risk
High risk Very high risk High risk Very high risk
80
Progression-free survival (%)

80
Overall survival (%)
60 60
40 40
20 20
P<0.0001 0 P<0.0001
0
0 12 24 36 48 60 0 12 24 36 48 60
Months from transplantation Months from transplantation
c 100 d 100
80 80
Non-relapse mortality (%)

Incidence of relapse (%)
60 60
40 40
20 20
0 P<0.0001 0 P<0.0001
0 12 24 36 48 60 0 12 24 36 48 60
Figure 3. Risk stratification by disease-risk index categories for (a) overall survival, (b) PFS, (c) cumulative incidence of relapse and
(d) cumulative incidence of non-relapse mortality. This research was originally published in Blood. Armand et al.2 © American Society of
Hematology.
a 100 b 100
80 80
Progression-free survival (%)
Overall survival (%)
60 60
40 40
20 20
P<0.0001 0 P<0.0001
0
0 12 24 36 48 60 0 12 24 36 48 60
Figure 4. Validation of the disease-risk index in an independent cohort of 672 patients. (a) Overall survival; and (b) PFS. This research was
originally published in Blood. Armand et al.2 © American Society of Hematology.
The refined index could not demonstrate significant difference the difference in conditioning intensity between the two
in OS between lymphoma patients, who received HCT in their first groups. Also, more recent evidence suggests that there is no
or second CR. However, their outcomes were better than those in association between achieving CR as assessed by pretransplant
18
any PR. This observation should be interpreted cautiously given F-fluorodeoxy glucose–positron emission tomography scan and

11
post-allogeneic HTC survival for patients with lymphoma.63 Prior
Abbreviations: CIR = cumulative incidences of relapse; DRI = disease-risk index; MA = myelobalative; mo = month; MPN = myeloproliferative; NMA = nonmyeloablative; NRM = non-relapse mortality; OS = overall
Diagnoses: malignant and non-malignant hematologic disorders.

diagnosed with myeloma and MPN compared with the original

study might have been responsible for the weaker association
autologous HCT for lymphoma had no significant influence on
The inclusion of children and the higher inclusion of patients
Failed in smaller samples ⩽ 50 patients and shorter follow-up

adapted DRI was developed by modifying original DRI could
survival in multivariate models (HR = 1.1; P = 0.2).
The authors suggested using the DRI with its four risk categories
in studies with a cohort size of 4300 patients, while collapsing it
into three categories (by merging high- and very high-risk groups
into one group) in studies with a cohort size of o 300 patients. A
group of investigators from Europe modified the DRI to resolve its
limited power of discrimination in their patient cohort. They
moved the diagnoses of myeloproliferative neoplasms (MPN) and
multiple myeloma from the intermediate-risk disease category
64% of grafts are T-cell depleted
and reassigned them to low- and high-risk groups, respectively, to

Building a new refined model
develop an adapted DRI (aDRI). This modification was based on

with outcomes. Accordingly,
observations from previous studies, where patients with MPN
predict relapse and PFS tended to have relatively favorable outcomes,10,64 although those
with myeloma were noted to have relatively poor outcomes
following allogeneic HCT.65 Risk groups of the aDRI could
periods ⩽ 40 mo. successfully stratify hazards of relapse (P o 0.05) and PFS for high-
and very high-risk groups, (P o0.05) but not OS (P40.09).
Comments
Compared with original DRI, aDRI had a higher discriminative

capacity for relapse (c-statistics = 0.563 versus 0.631; P = 0.005,
respectively) and, to a lesser extent, for PFS (c-statistics = 0.540
versus 0.572; P = 0.04, respectively).66 Lack of a benefit in
predicting OS brings the value of this adaption into question,
5-year OS, PFS and
particularly as OS was the outcome of interest in the original

relapse for other
study of DRI.
Not predicted
4-year TRM
COMBINED PATIENT- AND DISEASE-CENTERED RISK-

groups
NRM
ASSESSMENT MODELS
outcomes
EBMT score
survival; RIC = reduced-intensity conditioning; TRM = transplant-related mortality, UCB = umbilical cord blood.
4-year PFS, OS and CIR
Development. EBMT risk score is one of the earliest models that

was designed to provide assumptions about post-transplant risks
4-year OS, PFS and
5-year OS, PFS and

relapse incidence
of NRM, relapse and survival. Investigators from Europe analyzed

relapse for very
high-risk group
the impact of a number of pretransplant variables on HCT

outcomes among a cohort of 3142 patients diagnosed with CML,
2-year OS
Predicted
the most common diagnosis treated by HCT at that time.67

In multivariate models, investigators identified five different
variables to be statistically significantly associated with outcomes.
Results were used to build a five-component scoring model with a
MA (53%) NMA/RIC
MA = 266 RIC = 143
MA (n = 297) NMA/
total score ranging from 0 to 7 (Table 9).3

MA (n = 138) RIC
The new model was predictive of leukemia-free survival, OS and

transplant-related mortality (TRM) at 5 years among patients with
RIC (n = 169)
Conditioning
CML in the era before the discovery of tyrosine kinase inhibitors

intensities
(n = 304)
Validation of the DRI in single and multi-center studies
(TKIs). Rates of 5-year OS ranged between 72% and 22% for scores
(47%)
of 0 and 6, respectively.67
Validation. Multiple studies were conducted to validate the

Related (42%) Unrelated
Unrelated (n = 144) UCB
EBMT model. Results are summarized in Table 10.

(57%) Unknown (1%)
Unrelated (n = 190)
Unrelated (n = 164)
Advantages. The EBMT model is a relatively simple one. Its

Related (n = 219)
Related (n = 138)
Related (n = 306)
Number of Types of donors
components are well known and readily available to transplant

physicians. This simplicity allows for ease of use and widespread
applicability. Its development and validation were done in a
(n = 16)
number of studies that comprised large numbers of patients with

heterogeneous characteristics, allowing for generalizability of its
use. The model can be used equally well in patient cohorts with a
single diagnosis, as well as multiple ones. In addition, components
patients
Armand et al.61 13 131
of the model capture different aspects of a patient’s health, as well

409
442
466
as some disease-specific risk factors suggesting its suitability for

prediction of OS.
Servais et al.66
Limitations. Although the EBMT score is considered to be a

Lim et al.62
Beauverd
generalized model comprising a set of variable patient-, disease-

et al.86
Table 7.
and transplant-related factors, it has a relatively modest

Study
discriminative capacity with c-statistic estimate of 0.63.3 This

could be due to a number of reasons:

12
Table 8. Differences in diseases risk assignments between original and refined DRI
Disease Original DRI risk category Refined DRI risk category
HL in CR Intermediate Low
MCL in CR Intermediate Low
Advanced stage AML with favorable CG Intermediate High
Advanced stage high-risk MDS with intermediate CG Intermediate High
ALL in 2nd CR Intermediate High
ALL in 3rd CR Intermediate High
CML in blast phase Intermediate Very high
Early stage low-risk MDS with adverse CG High Intermediate
Advanced stage ALL High Very high
Advanced stage aggressive NHL High Very high
Advanced stage high-risk MDS with adverse CG Very high High
Advanced stage low-risk MDS with adverse CG Very high High
Abbreviations: CG = cytogenetics; DRI = disease-risk index; HL = Hodgkin’s lymphoma; MCL = mantle cell lymphoma; MDS = myelodysplastic syndromes;
NHL = non-Hodgkin lymphoma.
First, cutoffs for some of its components are arbitrary and

Table 9. Components of EBMT risk score87
outdated. For example, age cutoffs were set for an era when only
high-dose conditioning was offered to patients younger than Risk factor Score
50 years old. Hence, there is no age categorization beyond
40 years in the model. The unaccountability of some important Patient age (years)
prognostic factors such as comorbidity and performance status 420 0
might also be responsible for the modest prognostic power of the 20–40 1
440 2
EBMT score. Further, disease stage categorization in the EBMT
score is far less detailed than in the DRI classification. The EBMT Disease stagea
model does not account for the impacts of cytogenetics or Early 0
molecular markers. Although the EBMT model assigns a higher Intermediate 1
score for grafts from HLA-matched unrelated versus related Late 2
donors, this impact is limited to allogeneic HCT following high-
dose regimens and to an era when HLA matching was done using Time interval from diagnosis to transplant (months)b
six antigens tested by low-resolution techniques. Recent studies o12 0
412 1
have shown comparable outcomes between 10/10 HLA-unrelated
and identical siblings among recipients of RIC regimens.68 Donor typec
The relative importance of some components is also HLA-identical sibling 0
questionable. For example, scores of 0 versus 1 are assigned to Unrelated, other 1
an interval between diagnosis and HCT of less versus 412 months,
respectively. A long period between diagnosis and HCT could, Donor recipient sex combination
on one hand, reflect disease aggressiveness requiring more All other 0
Female donor, male recipient 1
chemotherapy to achieve remission before HCT or, on the other
hand, could represent a disease with an indolent course not Reprinted by permission from Gratwohl.3 aEarly disease stage includes:
requiring early HCT. Nevertheless, this may not be essentially true acute leukemia (AL) transplanted in first CR, myelodysplastic syndromes
for diseases such as acute leukemia in first CR, in which this factor (MDS) untreated or in first CR, CML in first chronic phase, and lymphoma
will be always set as 0. This factor could be further subdivided into and myeloma transplanted either untreated or in first CR. Intermediate
disease stage includes: AL in second CR, CML at all other stages than first
two separate periods with discordant impacts on survival. A longer
chronic phase or blast crisis, MDS in second CR or in PR, lymphoma and
time from diagnosis to achieving remission is usually associated myeloma in second CR, in PR or in stable disease. Late disease stage
with higher risk of relapse after HCT and hence lower OS. includes: AL in all other disease stages, and lymphoma and myeloma in all
In contrast, a longer time from remission to transplant could disease stages other than defined as early or intermediate. No applicable
be associated with lower relapse rates, lower risk of NRM and stage for aplastic anemia (score 0). bDoes not apply for patients
better OS.3,69 transplanted in first CR (score 0). cDoes not apply for autologous
transplantation.
Modifications. In an effort to address some of the limitations of
the model, a modified EBMT (mEBMT) score was developed. In the
mEBMT score, interval between diagnosis and HCT was omitted, cohort of 306 recipients of RIC HCT for prediction of 4-year OS
given its strong association with disease stage. Also, an extra point rates, P = 0.001 and 0.06, respectively.70
was given for patients 460 years, assuming their vulnerability to In a study of 502 leukemia patients who received haploidentical
higher mortality risks. In multivariate analysis, HR per score unit grafts, the donor type component was categorized according to
for OS, NRM and relapse mortality were 1.5 (P o 0.001), 1.36 the number of mismatched HLA loci, given the differences in
(P = 0.042) and 1.68 (P o0.001), respectively.32 These modifications incidence of NRM among different HLA mismatch categories.
remain arbitrary and not based on a well-designed analysis to A score of 0, 1 or 2 was assigned to grafts with either single,
explore their impacts on outcomes. For example, age was recently double or triple mismatched loci, respectively, to develop a
shown to have a limited impact on outcomes when comorbidities haplo-EBMT score. The EBMT score was significantly predictive
are accounted for, and that impact was restricted to those of 40 of incidences of NRM (P o0.001), leukemia-free survival
years or less versus older patients.46 Nevertheless, the mEBMT rates (P o0.001), incidences of relapse (P = 0.004) and OS rates
score performed better compared with the original score in a (P o 0.001), respectively.71

Table 10. Validation of the EBMT risk score in single and multi-center retrospective studies
Study Number of Types of donors Conditioning intensities Outcomes Comments

patients
Predicted Not predicted
Passweg et al.88 3211 Related (75%) Unrelated MA 5-year OS — Diagnosis: CML.

(25%) Analysis of data reported by 234 centers worldwide to the
International Bone Marrow Transplantation Registry.
De Souza et al.89 1084 Related (95%) Unrelated MA (86%) Others (14) TRM, OS, DFS and RR — Diagnosis: CML.
(5%) for EBMT scores 5–6 Authors have shown that the EBMT model could help in selecting
candidates who could potentially benefit from allogeneic HCT
compared with TKIs.
Terwey et al.32 151 HLA matched (n = 134) MA (n = 138) RIC 5-year NRM, OS and — Diagnosis: ALL.
HLA-MM (n = 17) (n = 13) relapse mortality mEBMT score omitting time interval from diagnosis to transplant.
Gratwohl et al.87 56 505 Related (74%) Unrelated MA (86%) RIC (14%) 5-year TRM and OS — Diagnoses: malignant and non-malignant hematologic disorders.
(24%) The analysis aimed at exploring the prognostic value of the EBMT
model in diseases other than CML utilizing large registry data set
of patients with different hematological disorders, who received
their first allogeneic HCT at different centers in Europe. Results
supported expanding the use of EBMT risk score to
hematological disorders other than CML.
Lodewyck et al.90 327 T-cell depleted unrelated MA (n = 256) Others 5-year NRM and OS — Diagnosis: poor risk AML and MDS.
grafts (n = 71) Incorporation of high resolution HLA typing with EBMT scores
resulted in better prognostication.
Barba et al.70 306 Related (230) Unrelated (76) RIC 4-year NRM and OS — Diagnoses: malignant hematologic disorders.
mEBMT score provided better prediction compared with classical
EBMT score.
Rezvani et al.91 124 HLA matched (n = 107) MA (n = 72) RIC 5-year NRM and OS — Diagnoses: recipients of a second transplantation for malignant
HLA-MM (n = 17) (n = 52) and non-malignant hematologic disorders.
A combined model of EBMT scores and time from first to second
transplantation independently predicted outcomes.
Pitombeira et al.92 278 Related (n = 238) Unrelated MA (n = 241) RIC 5-year NRM and OS RR Diagnoses: malignant and non-malignant hematologic disorders.
(40) (n = 37)
93
Wallet et al. 136 UCB MA (n = 46) RIC 3-year TRM, OS and RR — Diagnoses: malignant and non-malignant hematologic disorders.
(n = 90)
Wang et al.71 502 Haploidentical grafts MA NRM, LFS and OS — Diagnoses: acute and chronic leukemia.
Adapted a modified Haplo-EBMT score based on number of MM
HLA loci.
Abbreviations: DFS = disease-free survival; EBMT = European Society for Blood and Marrow Transplantation; LFS = leukemia-free survival; MA = myelobalative; MDS = myelodysplastic syndromes; mEBMT
score = modified EBMT score; MM = mismatched; NRM = non-relapse mortality; OS = overall survival; RIC = reduced-intensity conditioning; RR = relapse rate; TKI = tyrosine kinase inhibitor; TRM = transplant-
related mortality; UCB = umbilical cord blood.

13
14
70 Category 1 Category 2 Category 3 Category 4
Table 11.Components and categories of pretransplantation (8-16) (17-23) (24-30) (31-50)
assessment of mortality score (PAM score)
Number of patients
Age (years) Score 50
o20 1
20–30 1
30–40 1 30
40–50 1
50–60 3
460 5 10
Donor type
Matched related 1 8 14 20 26 32 38 44 50
Unrelated 3 PAM score
Mismatched related 4
Figure 5. Histogram of distribution of PAM scores in 276 allogeneic
Disease risk HCT recipients. Majority of patients clustered in categories 2 and 3
Low 1 with very few patients in categories 1 and 2. Reprinted by
Intermediate 8 permission from Mori et al.72
High 12
account for the introduction of nonmyeloablative transplant
Conditioning regimen protocols.4 In multivariate analysis, eight risk factors were found
Nonmyeloablative 1 to significantly impact HCT outcome. Accordingly, the authors
Non-TBI 4 designed a 50-point model from those factors (Table 11). The
TBI with ⩽ 12 Gy 8
model stratified patients into four categories with scores ranging
TBI with 412 Gy 9
from 8 to 50 points with statistically significantly different 2-year
Serum creatinine level probabilities of mortality for risk categories of 1–4 ranging from 16
⩽ 1.2 mg/dL 1 to 81% in the early validation cohort and from 8 to 82% in the late
41.2 mg/dL 8 validation cohort, respectively (Po 0.001). Authors then per-
formed internal validation of the PAM score utilizing three
Serum ALT level subgroups from the same institution. These subgroups comprised
⩽49 U/L 1 the three most frequently observed diagnoses in the entire cohort:
449 U/L 2
CML (n = 1017) AML (n = 667) and MDS (n = 407). C-statistic
FEV1 estimates ranged between 0.69 and 0.76 for all validation
480% 1 cohorts.4
70-80% 3
o70% 6 Validation. In a group of 276 non-Caucasian patients, investiga-
tors attempted to validate the PAM model. There was an uneven
Corrected DLco distribution of patients in the different risk categories, with 16%
480% 1 and 66% of patients being assigned to categories 2 and 3,
70-80% 1
o70% 4
respectively (Figure 5). Thus, authors modified score categories to
allow a more even distribution of patients by slightly changing
Category Original score Modified score cutoff values between the different categories (Table 11). In the
1 9–16 8–19 modified model, categories 2 and 3 included 29% and 47% of
2 17–23 20–25 patients, respectively. Overall, c-statistics were slightly higher for
3 24–30 26–30 the modified compared with the original model (0.74 versus 0.70).
4 31–44 31–50 No P-value estimate for the difference between the two c-statistic
Abbreviations: ALT = alanine aminotransferase; DLco = diffusion capacity of estimates was provided.72
the lung for carbon monoxide; FEV1 = forced expiratory volume in 1 s. In another study, investigators failed to validate the prognostic
Low-risk diseases included: CML in chronic phase, refractory anemia, capacity of the PAM score in a cohort of 194 RIC HCT recipients.
aplastic anemia and the Blackfan–Diamond syndrome. Intermediate-risk The model was not predictive of rates of 2-year OS (P = 0.11) nor
diseases included: CML in accelerated phase or chronic phase after blastic incidences of NRM (P40.4).20 Similarly, the limited predictive
phase, acute leukemia or lymphoma in remission, refractory anemia with
power of the PAM score was demonstrated in a small study, where
excess blasts, chronic lymphocytic leukemia and paroxysmal nocturnal
hemoglobinuria. High-risk diseases included: CML in blastic phase,
the model failed to predict hazards of 2-year OS (P = 0.2) or
juvenile CML, acute leukemia or lymphoma in relapse, refractory 100- day TRM (P = 0.08) in a cohort of 63 HCT recipients who were
anemia with excess blasts in transformation, myeloma, solid tumors and 460 years of age.35
non-hematologic diseases.
Advantages. The PAM score incorporates some significant
comorbidities, as well as some disease - and HCT-specific features
PAM score to create a single model. This mix of variables allows for a global
Development. The PAM score was developed as a model to assessment of overall mortality.
predict all-cause mortality during the immediate 2-year period,
following allogeneic HCT in 2802 patients treated between 1990 Limitations. The external validity of the PAM score remains
and 2002 at FHCRC. Patients were randomly divided into two controversial with contradicting reports from different
equal cohorts for the model development and validation. The institutions.20,31 Another caveat is under-representation of older
validation cohort (n = 1401) was further subdivided into an early patients, with only 4% of patients being older than 60 years. In
subgroup (n = 853), for patients given HCT before 1 January 1998, addition, disease categories were not represented equally in the
and a late subgroup (n = 548), for patients given HCT thereafter, to cohort, with almost 75% of patients carrying only three diagnoses,

15
CML, AML and MDS. This finding could limit reproducibility of markers of the primary malignancy could be incorporated in the
results when encountering a more heterogeneous population future to further improve the predictive power of the DRI.
of HCT recipients. Although PAM score included conditioning Global risk models such as PAM or EBMT target OS as the
intensity as a variable, growing evidence suggests its minor primary assessed outcome. These models could provide a second
impact on HCT outcomes.2,61 layer of evaluation to support conclusions made by the combined
Recently, the PAM score has been shown to be a better use of specific models for NRM and relapse. The newly modified
predictor of 2-year post-transplant mortality among recipients of PAM model is made specifically for recipients of high-dose
high-dose compared with RIC allogeneic HCT. Each point increase conditioning regimens. EBMT could be combined with HCT-CI to
in the PAM score correlated with 10% versus 6% increase in risks enhance prediction of survival.42
of 2-year mortality following high-dose versus RIC allogeneic HCT, The future of risk stratification will increasingly rely on objective
respectively (P = 0.002). C-statistics estimates were higher among and more advanced data. Whole-genome sequencing, gene
recipients of high-dose compared with RIC allogeneic HCT, expression profiling75 and expression of micro-RNAs76,77 are likely
0.64 and 0.57, respectively.73 This significantly precludes the to be used in prediction of relapse. Similarly, information on
model usefulness for predicting outcomes for the rapidly growing single-nucleotide polymorphisms78 non-HLA genetic variants79
population of RIC allogeneic HCT recipients. and biomarkers for acute GvHD80,81 could be used to stratify risks
of NRM. These potential future changes promise an individualized
Modifications. To allow more even distribution of patients, the
approach in decision-making and patient care before and
cutoff values for PAM risk categories were modified (Table 11).72
after HCT.
The original developers of the model showed some variables to
lose their prognostic association with 2-year mortality rate over
time in a cohort of 1549 recipients of allogeneic HCT between CONFLICT OF INTEREST
2003 and 2009. As a result, The authors declare no conflict of interest.
● Diffusion capacity of the lungs for carbon monoxide, serum

alanine aminotransferase and serum creatinine levels were ACKNOWLEDGEMENTS
omitted. We are grateful to the help by Bonnie Larson and Helen Crawford in manuscript
● Patient and donor CMV serostatus combinations were added. preparation. MLS was supported by funding from Pathway to Independence
● Disease risk was reorganized as per the DRI risk classification Grant HL088021 from the National Institutes of Health; Research Scholar Grant
system.2 #RSG-13-084-01-CPHPS from the American Cancer Society and a Patient-Centered
● Degree of HLA matching was used to re-categorize the Outcome Research Institute contract #CE-1304-7451. ME was supported by Grant
unrelated donor group. JS2865 from the Egyptian Ministry of Higher Education.
These modifications resulted in a revised PAM score.73 The

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Bone Marrow Transplantation (2016), 1–18

© 2016 Macmillan Publishers Limited All rights reserved 0268-3369/16

Bone Marrow Transplantation advance online publication, 6 June 2016; doi:10.1038/bmt.2016.141

Comorbidity Deﬁnition Score

Augmented HCT-CI: all of the above plus

Bone Marrow Transplantation (2016), 1 – 18 © 2016 Macmillan Publishers Limited

© 2016 Macmillan Publishers Limited Bone Marrow Transplantation (2016), 1 – 18

Predicted by the Not predicted by Rates Multivariate C-statistic

Bone Marrow Transplantation (2016), 1 – 18

© 2016 Macmillan Publishers Limited

Predicted by the Not predicted by Rates Multivariate C-statistic

© 2016 Macmillan Publishers Limited

relapse risk hematological disorders.

et al.27 (n = 277) HLA-MM (n = 178) OS in patients allo-HCT.

Bone Marrow Transplantation (2016), 1 – 18

patients with no suitable matched

In another study, weights were developed for low albumin,

compared with the HCT-CI alone (P = 0.0007).47

Geriatric Assesment (CGA) has been shown in patients treated

and 73 years (median age = 58 years), who received allogeneic

elevated CRP blood levels to be associated with signiﬁcantly worse

2-year NRM and OS

noticeable among patients of 460 years of age (HR = 3.25;

Po 0.001). The authors then combined IADL with the HCT-CI in a

Another prospective study reached a different conclusion. In a

MA (62%) RIC (18%)

the impact of CGA domains on OS. After adjusting for age

and cytogenetic risks in multivariate models, only self-reported

we need more discovery and validation studies before CGA is

Advantages. The use of a shortened and relevant GCA battery

comorbidities or performance status that are speciﬁc to older

patients. Therefore, CGA could further reﬁne pre-HCT risk

Limitations. The use of CGA in the setting of allogeneic HCT is

hampered by a number of limitations. A full CGA is probably time-

consuming, particularly for sick patients. Some of these patients

Elsawy et al.29 492

might not be able to complete the assessment. The assessment

able amount of learning needs to be done to encourage patients

usage. This is particularly true for the functional components that

Bone Marrow Transplantation (2016), 1 – 18 © 2016 Macmillan Publishers Limited

Study Number of Disease category Conditioning intensity Risk stratiﬁcation Comments

© 2016 Macmillan Publishers Limited

CRP (mL/L) 5-yr OS (%)

Bone Marrow Transplantation (2016), 1 – 18

Table 5. Augmentation of HCT-CI predictability by combining with other models85

Composite model Risk groups Outcomes at 2 years Outcomes at 4 or 5 years

HCT-CI KPS NRM (%) OS (%) NRM (%) OS (%)

Comorbidity/age score46 (nonmyeloablative versus RIC) HCT-CI/age

Comorbidity/relapse score (patients ⩾ 60 years old)41 HCT-CI Relapse risk score

HCT-CI/EBMT42 HCT-CI EBMT

Bone Marrow Transplantation (2016), 1 – 18 © 2016 Macmillan Publishers Limited

Medical notes Labs/Tests Final assessment

Review Bilirubin Serum DLco Echo/ Double Total

0% 5% 20% 40% 45% 55% 60% 80% 90% 95% 100%

© 2016 Macmillan Publishers Limited Bone Marrow Transplantation (2016), 1 – 18

Progression-free survival (%)

Non-relapse mortality (%)

Bone Marrow Transplantation (2016), 1 – 18 © 2016 Macmillan Publishers Limited

Diagnoses: malignant and non-malignant hematologic disorders.

Diagnoses: malignant and non-malignant hematologic disorders.