Article
Reference
Evaluation of Disease Risk Comorbidity Index after Allogeneic Stem Cell Transplantation in a Cohort with Patients Undergoing Transplantation with In Vitro Partially T Cell Depleted Grafts
BEAUVERD, Yan, et al .
Abstract
Outcomes of hematopoietic stem cell transplantation (HSCT) are influenced by comorbidities, disease type, and status at transplantation. Several prognostic scores can be used, such as the disease risk index (DRI) or the hematopoietic cell transplantation-specific comorbidity index (HCT-CI). Recently, a new prognostic tool, the disease risk comorbidity index (DRCI), combining the DRI and the HCT-CI, was published. The DRCI determines 6 patient groups (very low risk [VLR], low risk [LR], intermediate risk 1 [IR-1], intermediate risk 2 [IR-2], high risk [HR], and very high risk [VHR]) with a significant predictive value for overall survival (OS), disease-free survival (DFS), relapse incidence (RI), and graft-versus-host disease-free/relapse-free survival (GRFS). However, the DRCI has not been evaluated for patients allografted with partially in vitro T cell depleted (pTDEP) grafts. In our center, we offer pTDEP to reduce graft-versus-host disease for patients in complete remission at transplant time. In this retrospective study, we investigated the DRCI in 404 adult patients (including 37.6% pTDEP) undergoing a first HSCT [...]
BEAUVERD, Yan, et al . Evaluation of Disease Risk Comorbidity Index after Allogeneic Stem Cell Transplantation in a Cohort with Patients Undergoing Transplantation with In Vitro Partially T Cell Depleted Grafts. Biology of Blood and Marrow Transplantation , 2020
DOI : 10.1016/j.bbmt.2020.09.022 PMID : 32980547
Available at:
http://archive-ouverte.unige.ch/unige:143929
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Evaluation of Disease Risk Comorbidity Index after Allogeneic Stem Cell Transplantation in a Cohort with Patients Undergoing Transplantation with In Vitro Partially T Cell Depleted Grafts
Q1
X X D1X X Yan Beauverd D2X X
1,*, D3X X Sarah Morin D4X X
1, D5X X Mitja Nabergoj D6X X
1, D7X X Caroline Stephan D8X X
1, D9X X Carmen De Ramon Ortiz D10X X
1,
D11X X
Anne-Claire Mamez D12X X
1, D13X X Elif Mahne D14X X
1, D15X X Anna Petropoulou D16X X
1, D17X X Federica Giannotti D18X X
1, D19X X Christian Ayer D20X X
1, D21X X
Benjamin Bruno D22X X
1, D23X X Laura Bounaix D24X X
1, D25X X Maria Anastasiou D26X X
1, D27X X Maria Mappoura D28X X
1, D29X X Thien-An Tran D30X X
1, D31X X
Stavroula Masouridi-Levrat D32X X
1, D33X X Yves Chalandon D34X X
1,21Hematology Division, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland
2Faculty of Medicine, University of Geneva, Geneva, Switzerland
Article history:
Received 15 May 2020 Accepted 17 September 2020
A B S T R A C T Outcomes
Q2 X Xof hematopoietic stem cell transplantation (HSCT) are influenced by comorbidities, disease type, and status at transplantation. Several prognostic scores can be used, such as the disease risk index (DRI) or the hematopoietic cell transplantation-specific comorbidity index (HCT-CI). Recently, a new prognostic tool, the disease risk comorbidity index (DRCI), combining the DRI and the HCT-CI, was published. The DRCI determines 6 patient groups (very low risk [VLR], low risk [LR], intermediate risk 1 [IR-1], intermediate risk 2 [IR-2], high risk [HR], and very high risk [VHR]) with a significant predictive value for overall survival (OS), disease-free survival (DFS), relapse incidence (RI), and graft-versus-host disease-free/relapse-free survival (GRFS). However, the DRCI has not been evaluated for patients allografted with partially in vitro T cell depleted (pTDEP) grafts. In our center, we offer pTDEP to reduce graft-versus- host disease for patients in complete remission at transplant time. In this retrospective study, we investigated the DRCI in 404 adult patients (including 37.6% pTDEP) undergoing afirst HSCT for hematological malignancies from 2008 to 2018. Because of the small number of patients in LR, VLR and LR were combined for analysis. In the entire cohort, 2-year OS was 84.4% (95% CI, 71.6% to 97.2%) for LR, 61.6% (54.8% to 68.4%) for IR-1, 45.7% (33.3% to 58.1%) for IR-2, 31% (19.4% to 42.6%) for HR, and 30.9% (14.5% to 47.3%) for VHR (P<.001). In addition, the DRCI was predictive of DFS, RI, and GRFS but not of nonrelapsed mortality and graft-versus-host disease. Our study confirms similar results with the original publication but gives less accurate prognosis information than the DRI and HCT-CI when used separately. In conclusion, the DRCI does not seem to offer more relevant information than the DRI and HCT-CI to help physicians and patients for the HSCT decision.
© 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Allogeneic stem cell transplantation (HSCT) is the only curative treatment for most hD35X Xematological malignancies. Out- comes of HSCT mainly depend on disease characteristics and patient conditions. Tools that help physicians to predict out- comes are important to determine which patient would most likely benefitD36X Xfrom HSCT. Over theD37X Xpast decades, several prog- nostic scores have been developed. The disease risk index (DRI) [1,D38X X2],D39X Xwhich includes type and status of disease at trans- plant time, is predictive of overall survival (OS)D40X Xbut does not
integrate patient’s comorbidities and overall conditions. Simi- larly, the hematopoietic cell transplantation-specific comor- bidity index (HCT-CI) [3-5] is also predictive of outcome but only includes comorbidities. Interpretation of results given by currently available prognostic tools [1,D41X X3,D42X X6,D43X X7] is not easy in the standard practice of care and can be challenging for physicians.
For this reason, a comprehensive new prognostic tool, the dis- ease risk comorbidity index (DRCI), encompassing both DRI and HCT-CI, was recently published by Bejanyan et al. [8]. The DRCI includesD44X X3 DRI groups (low risk, intermediate risk, and high/very high risk), as published by Armand et al. [1], andD45X X2 HCT-CI groups (0D46X Xto 2 points, D47X X3 points), as previously described by Sorror et al. [3]. Combination of theseD48X X3 DRI andD49X X2 HCT-CI groups yields six different groups with statistically dif- ferent probability of 2-yearD50X XOS. In addition, the DRCI is also Financial disclosure:See Acknowledgments on page XX.
*Correspondence and reprint requests
Q3 X X: Yan Beauverd, Hematology Division,
Department of Oncology, Geneva University Hospitals, Rue Gabrielle-Perret- Gentil 4, CH12011 Geneva, Switzerland.
E-mail address:[email protected](Y. Beauverd).
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1083-8791/© 2020 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
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predictive of relapse incidence (RI), disease-free survival (DFS), and graft-versus-host/relapse-free survival (GRFS). However, this new tool is not predictiveD51X Xof nonD52X XrelapseD53X Xmortality (NRM) and graft-versus-host-disease (D54X XGVHD).
Moreover, the cohort in the study published by Bejanyan et al.[8] did not include patients who underwent allograft with partially in vitro T-cell depleted graft (pTDEP). pTDEP is a graft manipulation consisting of inD55X Xvitro TD56X Xcell depletion with alemtuzumab. TD57X Xcell depleted graft is infused at day 0 followed with an addback of TD58X Xcells (100£106cells) on day +1 with the objective to reduce the morbidity associated with acute and chronicD59X XGVHD. In ourD60X Xcenter, we generally offer pTDEP HSCT to patients in complete remission at transplant time. We have previously demonstrated that pTDEP significantly improves D61X X
GVHD and GRFS without harming OS, DFS, or RID62X Xin selected patients [9-11].
In this retrospective study, we hypothesized that the DRCI can be applicable in a cohort of patients with pTDEP HSCT and can help physicians in making transplant decisions.
METHOD Patients
All consecutive18D63X X-yearD64X X-old patients who underwent afirst HSCT from a nonD65X Xhaploidentical or syngeneic donor for a hD66X Xematological malignancy at the Stem Cell Transplantation Centre of the Geneva University Hospitals from 2008 to 2018 were included andD67X Xanalyzed. Data were extracted from our transplantation database, and a review of individual medical records was performed for additional data not recorded in our database. HCT-CI and Kar- nofsky index were assessed at day 0 of HSCT. DRI was assessed at the nearest disease evaluation from HSCT.
Transplantation
Myeloablative conditioning (MAC) usually consisted of cyclophospha- mide (120 mg/kg) with either total body irradiation (10D68X Xto 12 Gy) or busulfan (16 mg/kg)D69X X,fludarabine (160 mg/m2) with busulfan (390D70X Xto 520 mg/m2), or treosulfan (42 mg/m2) [12,D71X X13]. Reduced-intensity conditioning (RIC) con- sisted mostly offludarabine (150 mg/m2) with low-D72X Xdose busulfan (8 mg/kg oral or 6.4 mg/kg intravenously) or melphalan (140 mg/m2) [12,D73X X13]. Patients received anti-thymocyte globulin (usually 7.5 mg/kg with ThymoglobulinD74X Xor 25 mg/kg with ATG-FreseniusD75X X/D76X XGrafalon
Q4 X XD77X X) as part as their conditioning regimen
when stem cell source was from an unrelated donor. Patients also received methylprednisolone (1000 mg/m2) as part as their conditioning in the case of pTDEP graft.
GVHD prophylaxis consisted mainly of a calcineurin inhibitor and methotD78X Xrexate for MAC, or a calcineurin inhibitor and mycophenolate mofetil for RIC. InD79X Xvitro pTDEP was performed using alemtuzumab (Campath;
D80X X
Genzyme Corporation, Cambridge, MAD81X X) as previously described [14,D82X X15D83X X] for patients in complete remission at transplantation as part of GVHD prophy- laxis. pTDEP grafts were given on day 0 followed by an addD84X Xback of 100£106 donor T cells on day +1.
Endpoints andD85X XDefinitions
The primary endpoint was 2-year OS after HSCT. Secondary endpoints were 2-year DFS, GRFS, gradeD86X XIID87X XtoD88X XIV acuteD89X XGVHD (aD90X XGVHD) and 2-year allD91X X- grade chronic GVHD (cD92X XGVHD). These endpoints wereD93X Xanalyzed for the whole cohort, pTDEP patients, and non-TDEP patients separately. DRI was applied as described by Armand et al. [1] and HCT-CI as published by Sorror et al. [3].
We used the Glucksberg et al.[16]classification for aD94X XGVHD gradingD95X Xand the National Institutes of HealthD96X Xconsensus criteria for cGVHD grading [17]. GRFS was estimated as previously published by HoltanD97X Xet al. [18].
Statistics
Statistics were performed according to EBMT
Q5 X Xguidelines [19]. Baseline
characteristics were reported descriptively and compared using the chi- square test or Fisher exact test. We used the Kaplan-Meier method [20] to estimate the probability of OS, DFS, and GRFS and the cumulative incidence estimator as defined by Fine and Gray [21] to calculate probabilities of GVHD (with relapse as competing events), RI (with NRM as competing event), and NRM (with RI as competing event). In this analysis, very low-risk (VLR) and low-risk (LR) groups were combined because of the small number of patients within the LR group. For pTDEP HSCT, high risk (HR) and very high risk (VHR) were combined because of a low number of patients in individual groups.
Influence of Karnofsky index (80D98X Xversus>80), age (50 yearsD99X Xversus>50 years), conditioning regimen (RICD100X Xversus MAC), donor/recipient sex combina- tion (donor female/recipient maleD101X Xversus otherD102X Xcombinations), time from diag- nosis to transplantation (1 anD103X Xversus>1 an
Q6 X X), inD104X Xvitro graft manipulation
(pTDEP D105X Xversus non pTDEP), donor matching (matched donorD106X Xversus mis- matched donor), and stem cell source (peripheral blood stem cellD107X XD108X Xversus bone marrowD109X X) were investigated in univariate analysis (Cox proportionalD110X Xhazards model) for all endpoints. All variables with aD111X XP<D112X X.1 in univariate analysis were integrated in a multivariable analysis (Cox proportionalD113X Xhazards model).
All calculations were done using SPSS version 23.0 (IBM Corp., Armonk, NY) and R version 3.6.2 (the Comprehensive R Archive Network [CRAN] projectD114X XX X). Q7 Ethics
This study was performed according to international ethical standards and was conducted in accordance with the Declaration of Helsinki.
RESULTS Patients
In total, 404 adult patients with hD115X XematologicD116X Xmalignancies were included. Baseline characteristics are shown inTable 1.
Median follow-up was 1.9 years (D117X Xrange, 0 D118X Xto 11.7) for all patients and 4.9 years (D119X Xrange, 0.6D120X Xto 11.7) for living patients.
Median age at transplant time was 53 years (D121X Xrange, 18D122X Xto 74), 39.6% were female, and median Karnofsky index was 90
(D123X Xrange, 80D124X Xto 100). Of the grafts, 38.1% D125X Xwere from siblings,
52.5% from matchedD126X Xrelated donors, and 9.4% from mis- matched unrelated donors. Stem cell source was peripheral blood stem cellsD127X Xin 93.8% and bone marrowD128X Xin 6.2%. RIC and MAC conditioning were performed in 53.7% and 46.3%, respec- tively. pTDEP was performed in 37.6% of HSCTs. According to the DRCI, 30 patients (7.4%) were assignedD129X Xto the VLR group, 2 (0.5%)D130X Xto the LR group, 209 (51.7%)D131X Xto the intermediate 1 (IR-1) group, 67 (16.6%) D132X Xto the intermediate 2 (IR-2) group, 64 (15.8%) D133X Xto the HR group, and 32 (7.3%) D134X Xto the VHR group.
Among the 152 pTDEPs, 19 (12.5%) were assignedD135X Xto the VLR group, 1 (0.7%)D136X Xto the LR group, 82 (53.9%)D137X Xto the IR-1 group, 37 (24.3%)D138X Xto the IR-2 group, 7 (4.6%)D139X Xto the HR group, and 6 (3.9%)D140X Xto the VHR group. Among the 252 non-TDEPs, 11 (4.4%), 1 (0.7%), 127 (50.4%), 30 (11.9%), 57 (22.6%), and 26 (10.3%) were assignedD141X Xto the VLR, LR, IR-1, IR-2, HR, and VHR groups, respectively.
OS
The 2-yearD142X XOS for the entire cohort was 54.3% (D143X X95% confi- dence interval [CI], 49.3%D144X Xto 59.3%). The 2-yearD145X XOS by risk group for the entire cohort, the pTDEP cohort, and non-pTDEP cohortD146X Xis described inTable 2and presented inFigure 1D147X XAD148X X-C. In the univariate D149X XCox regression model, Karnofsky index 80 (HRX X: 2.0 [D150X X95% CI, 1.4D151X Xto 3],D152X XP<D153X X.001D154X X), RIC (D155X XHR: 1.38 [D156X X95% CI, 1.1D157X X Q8 to 1.8],p= 0.022), and pTDEP (D158X XHR: 0.64 [D159X X95% CI, 0.5D160X Xto 0.8],D161X X
P=D162X X.003) had a significant impact on OS. In the multivariable
D163X X
Cox regression model including those significant variables and DRCI, only DRCI (LR:D164X Xreference, IR-1: HR 2.49 [D165X X95% CI, 1.1D166X Xto 5.7],P= .D167X X031; IR-2: HR 3.82 [1.6D168X Xto 9.1],P= .D169X X002;D170X XHR: HR 6.1
[D171X X95% CI, 2.6D172X Xto 14.6],P<.D173X X001; VHR: HR 5.9 [D174X X95% CI, 2.4D175X Xto 14.6],
P<.D176X X001)D177X Xand Karnofsky index80 (HR 1.5 [D178X X95% CI, 1.1D179X Xto 2.3],
P= .D180X X039) remain statistically significant.
DFS
For all patients, 2-yearD181X Xprobability of DFS was 44.7% (D182X X95% CI, 39.7%D183X Xto 49.7%). The 2-yearD184X XDFS by risk group for the entire cohort, the pTDEP cohort, and the non-pTDEP cohortD185X Xis pre- sented inTable 2. In the univariateD186X XCox regression model for DFS, Karnofsky index80 (HR 2.0 [1.3D187X Xto 2.9],P= .D188X X001), RIC
(D189X XHR, 1.4 [D190X X95% CI, 1.1D191X Xto 1.8],P= .D192X X027D193X X), and pTDEP (D194X XHR, 0.64 [D195X X95%
CI, 0.5D196X Xto 0.9],P= .D197X X03) had a significant impact. In the multivari-
ableD198X XCox regression model including those significant variables
and DRCI, only DRCI (LR:D199X Xreference, IR-1: HR 2.52 [D200X X95% CI, 1.1D201X X to 5.8],P= .D202X X029; IR-2: HR 3.67 [1.5D203X Xto 8.7],P= .D204X X003; HR: HR 6.7
[D205X X95% CI, 2.8D206X Xto 15.8],P<.D207X X001; VHR: HR 5.8 [D208X X95% CI, 2.3D209X Xto 14.3],
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Table 1
Patient’s Characteristics
Characteristic All Patients pTDEP Non-pTDEP PValue
No. % No. % No. %
No. of patients 404 152 252
Age, median (range), yr 52.5 (18-74) 51 (18-69) 56 (18-74)
Female sex 160 39.6 64 42.1 96 38.1 .425
Disease type
AML .258
Favorable cytogenetic* 8 2.0 5 3.3 3 1.2 .159
Intermediate cytogenetic* 146 36.1 64 42.1 82 32.5 .055
Adverse cytogenetic* 35 8.7 8 5.3 27 10.7 .068
MDS .540
Low risky 14 3.5 7 4.6 7 2.8 .402
High risky 38 9.4 10 6.6 28 11.1 .160
CML 13 3.2 9 5.9 4 1.6 .021
MPN 38 9.4 9 5.9 29 11.5 .078
ALL 37 9.2 18 11.8 19 7.5 .157
CLL 7 1.7 5 3.3 2 0.8 .109
HL 10 2.5 1 0.7 9 3.6 .098
B-NHL 0.0 .781
Indolent 1 0.2 1 0.7 0 0.0 .376
Aggressive 13 3.2 6 3.9 7 2.8 .567
BL 1 0.2 0 0.0 1 0.4 1.00
MCL 4 1.0 1 0.7 3 1.2 1.00
T-NHL 13 3.2 5 3.3 8 3.2 1.00
MM 26 6.4 3 2.0 23 9.1 .005
Disease status
CR/earlyz 287 71.0 128 84.2 159 63.1 .000
PR 12 3.0 3 2.0 9 3.6 .547
Advancedx 54 13.4 3 2.0 51 20.2 .000
NA║ 51 12.6 18 11.8 33 13.1 .759
Graft source .005
PBSC 379 93.8 149 98 230 91.3
BM 25 6.2 3 2 22 8.7
Donor match .016
MRD 154 38.1 65 42.8 89 35.3
MUD 212 52.5 67 44.1 145 57.5
MMUD 38 9.4 20 13.2 18 7.1
Conditioning .000
RIC 217 53.7 51 33.6 166 65.9
MAC 187 46.3 101 66.4 86 34.1
DRI .000
Low 32 7.9 20 13.2 12 4.8
Intermediate 276 68.3 119 78.3 157 62.3
High 76 18.8 13 8.6 63 25
Very high 20 5 0 0 20 7.9
DRCI .000
Very low 30 7.4 19 12.5 11 4.4
Low 2 0.5 1 0.7 1 0.7
Intermediate 1 209 51.7 82 53.9 127 50.4
Intermediate 2 67 16.6 37 24.3 30 11.9
High 64 15.8 7 4.6 57 22.6
Very high 32 7.9 6 3.9 26 10.3
Values are presented as number (%) unless otherwise indicated.
AML indicates acute myeloid leukemia; MDS, myelodysplastic syndrome; CML, chronic myelogenous leukemia; MPN, myeloproliferative neoplasm; ALL, acute lym- phoblastic leukemia; CLL, chronic lymphocytic leukemia; HL, Hodgkin lymphoma; B-NHL, B cell non-Hodgkin lymphoma; BL, Burkitt lymphoma; MCL, mantle cell lymphoma; T-NHL, T cell non-Hodgkin lymphoma; MM, multiple myeloma; CR, complete remission; PR, partial remission; NA, not applicable; PBSC, peripheral blood stem cell; BM, bone marrow; MRD, matched related donor; MUD, matched unrelated donor; MMUD, mismatched unrelated donor.
* Favorable: t(8;21), inv(16), t(15;17); adverse: complex karyotype (4 anomalies) ; intermediate: other.
y Low-risk MDS:5% blasts; high-risk MDS:>5% blasts.
z Early: for MDS only, means CR or untreated.
x Advanced stage refers to active relapse or induction failure, including progressive disease for CLL, HL, and NHL.
║ Applicable for CML or MPN only.
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P<.D210X X001) and Karnofsky index80 (HR 1.5 [D211X X95% CI, 1.1D212X Xto 2.3],
P= .D213X X036) remain significant.
GRFS
The 2-yearD214X Xprobability of GRFS for the whole cohort was 32.6% (D215X X95% CI, 27.8%D216X Xto 42.2%). The 2-yearD217X XGRFS by risk group for the entire cohort, the pTDEP cohort, and the non-pTDEP cohortD218X Xis described inTable 2and presented inFigure 2D219X XAD220X X-C. In univariate analysis, Karnofsky index80 (HR: 2.0 [95%D221X XCI, 1.4D222X X to 2.8],P<.D223X X001), RIC (HR: 1.39 [95%D224X XCI, 1.1D225X Xto 1.8],P= .D226X X005), and pTDEP (HR: 0.55 [95%D227X XCI, 0.4D228X Xto 0.7],P<.D229X X001) were signifi- cant. In a multivariable analysis, including these variables and DRCI, Karnofsky index 80 (HR: 1.68 [D230X X95% CI, 1.2D231X Xto 2.4],
P= .D232X X005), pTDEP (HR: 0.72 [95%D233X XCI, 0.5D234X Xto 0.9],P= .D235X X018), and
DRCI (LR:D236X Xreference, IR-1: HR 1.56 [D237X X95% CI, 0.9D238X Xto 2.6],P= .D239X X088;
IR-2: HR 1.49 [0.9D240X Xto 2.9],P= .D241X X160; HR: HR 2.86 [D242X X95% CI, 1.6D243X Xto 5.0],P <.D244X X001; VHR: HR 3.01 [D245X X95% CI, 1.6D246X Xto 5.6],p<.0001) remain significant.
RI
For the entire cohort, 2-yearD247X Xcumulative incidence of RI was 34.4% (95%D248X XCI, 29.6%D249X Xto 39.2%). The 2-year probability of RI by risk group for the entire cohort, the pTDEP cohort, and the non-pTDEP cohortD250X Xis presented inTable 2. In a univariate anal- ysis, only Karnofsky index80 (HR: 1.76 [D251X X95% CI, 1.1D252X Xto 2.8],
P= .D253X X22D254X X) and pTDEP (HR: 0.66 [95%D255X XCI, 0.5D256X Xto 0.9],P= .D257X X014) had
an impact on RI. In a multivariable analysis, only DRCI (LR:
D258X X
reference, IR-1: HR 2.5 [D259X X95% CI, 1.1D260X Xto 5.8],P= .D261X X028; IR-2: HR 4.0 [1.7D262X Xto 9.4],P= .D263X X002; HR: HR 6.1 [D264X X95% CI, 2.5D265X Xto 14.4],
P<.D266X X001; VHR: HR 6.1 [D267X X95% CI, 2.4D268X Xto 15.1],P<.D269X X001) and Kar-
nofsky index80 (HR: 1.55 [D270X X95% CI, 1.1D271X Xto 2.4],P= .D272X X29) had an impact on RI.
NRM
The 2-year probability of NRM for all patients was 19.7%
(D273X X95% CI, 15.7%D274X Xto 23.7%). The 2-year probability of NRM by risk
group for the entire cohort, the pTDEP cohort, and the non- pTDEP cohortD275X Xis presented inTable 2. In a univariate analysis, only RIC had an impact on NRM (HR: 1.65 [95%D276X XCI, 1.1D277X Xto 2.5D278X X], D279X X
P=D280X X.22). In a multivariable analysis, there was no significant
impact of conditioning regimen (RIC D281X Xversus MAC) or DRCI on NRM.
GVHD
The 2-yearD282X Xprobability of gradeD283X XII to IV aGVHD was 44.3%
(D284X X95% CI, 39.3%D285X Xto 49.3%) in the entire cohort. Results by risk
group for the entire cohort, the pTDEP cohort, and the non- pTDEP cohort are presented inTable 2. In a univariate analysis, only pTDEP (HR: 0.57 [95%D286X XCI, 0.4D287X Xto 0.8],P<.D288X X001) and stem cell source from bone marrow (HR: 1.66 [95%D289X XCI, 1.0D290X Xto 2.7],
P= .D291X X46) had a significant impact. In a multivariable analysis
including pTDEP and stem cell source, only pTDEP remains sig- nificant (HR: 0.58 [95%D292X XCI, 0.4D293X Xto 0.8],P= .D294X X001).
The 2-yearD295X Xprobability of cGVHD was 19.9% (D296X X95% CI, 15.9%D297X X to 23.9%) in the entire cohort. Results by risk group for the entire cohort, the pTDEP cohort, and the non-pTDEP cohort are presented inTable 2. In a univariate analysis, only donor/recip- ient sex matching (donor female/recipient maleD298X X[dF/rMD299X X] [HR:
1.8 [D300X X95% CI, 1.1D301X Xto 3.1],P= .D302X X02) and pTDEP (HR: 0.59 [95%D303X XCI,
0.4D304X Xto 1.9],P= .D305X X042) had a significant impact. Impact of thoseD306X X2
variables D307X Xwas confirmed in a multivariable analysis (dF/rM;
HR: 1.9 [95%D308X XCI, 1.1D309X Xto 3.1],P= .D310X X016D311X X; pTDEP; HR: 0.58 [95%D312X XCI,
0.3D313X Xto 0.9],P= .D314X X035).
Table2 OutcomesofHSCTAccordingtoDRCIfortheEntireCohort,pTDEPCohort,andNon-pTDEPCohort 2-yrOS,%(95%CI)2-yrDFS,%(95%CI)2-yrGRFS,%(95%CI)2-yrRI,%(95%CI) DRCIEntireCohort, P<.001 pTDEPCohort, P<.001 Non-pTDEPCohort, P<.001 EntireCohort, P<.001 pTDEPCohort, P<.001 Non-pTDEPCohort, P<.001 EntireCohort, P<.001 pTDEPCohort, P<.001 Non-pTDEPCohort, P=.001 EntireCohort, P<.001 pTDEPCohort, P=.179
Non-pTDEPCohort, P<.001 LR84.4(71.6-97.2)90(76.6-90)75(50-100)74.7(59.3-90.1)80(62.2-97.8)65.6(37.6-93.6)68.6(52.2-85)74.7(55.1-94.3)48.6(20-79.2)12.5(0.6-24.4)15(0-31.4)8.3(0-25.1) IR-161.6(54.8-68.4)63.8(53-74.6)59.2(50.2-68.2)50.1(43.1-57.1)55.5(44.3-66.7)46.6(37.6-55.6)35.9(29.1-42.7)47(35.8-58.2)28.7(50.2-68.2)28.9(22.6-35.3)26.9(17.1-36.7)29.4(21.2-37.6) IR-245.7(33.3-58.1)48.2(31.6-64.8)42.7(24.5-60.7)38.3(26.3-50.3)40.2(24-56.4)36.1(18.3-53.9)35.9(23.9-47.5)37.4(21.4-53.4)29.3(12.5-46.1)30(18.6-41.3)27.0(12.0-42.0)34(16-52) HR31(19.4-42.6)38.5(11.5-65.5)27.7(15.7-39.7)23.4(12.8-34)15.4(0-35.4)24.6(13.2-36)12.5(4.3-20.7)7.7(0-22.5)12.3(3.7-20.9)61.2(48.6-73.9)49(17.6-80.4)61.6(48.2-75) VHR30.9(14.5-47.3)NA34.2(15.4-53)27.8(11.8-43.8)NA30.3(12.2-48.5)9.4(0-19.8)NA11.5(0-24.1)49(30.1-67.9)NA47.9(26.9-68.9) 2-yrNRM,%(95%CI)2-yrGradeII-IVaGVHD,%(95%CI)2-yrAll-GradecGVHD,%(95%CI) DRCIEntireCohort, P=.027
pTDEPCohort, P=.024 Non-pTDEPCohort, P=.22 EntireCohort, P=.435 pTDEPCohort, P=.854 Non-pTDEPCohort, P=.31 EntireCohort, P=.23 pTDEPCohort, P=.631
Non-pTDEPCohort, P=.27 LR9.4(0-19.9)5(0-15.0)16.7(0-39.3)31.5(14.7-48.3)25.0(5.0-45.0)42.9(11.9-73.9)13.6(0.6-26.6)10.7(0-25.5),19.3(0-45.5) IR-120.5(14.9-26.2)17.6(9-26.2)22.5(14.9-30.1)41.9(35.1-48.7)23.2(13.8-32.6)54.3(45.3-63.3)24.7(18.4-31.2)15.0(7.0-23.0),32(22.8-41.2) IR-228.5(17.3-39.6)29.7(14.3-45.1)26.7(10.1-43.3)32.1(20.5-43.7)27.8(12.6-43.0)37.3(19.1-55-5)11.4(2.4-20.4)12.9(0.6-25.0)10.70-25.7) HR13(4.3-21.6)25.0(0-52.2)11(2.4-19.6)35.2(22.6-47.8)16.1(0-38.1)39.7(25.9-53.5)18.1(7.6-28.8)020.4(8.6-32-2) VHR20(4.9-35.1)NA20(3.4-36.6)44.4(25.2-63.6)NA46.8(25-68.6)19.6(2.8-36.8)NA23.8(3.8-43.8)
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DISCUSSION
Risk stratification is essential to predict outcomes of HSCT patients and guide physicians in evaluation of HSCT eligibility.
Different robust and validated scores have already been pub- lished. DRI, based on disease type and status at transplant time, is prognostic for OS, DFS, and RI [1,D315X X2].D316X XOn the other hand, HCT-CI, which investigates comorbid conditions before HSCT, is prognostic for OS, NRM [3], and GVHD [22]. TheseD317X X2 scores, investigating patient and disease characteristics, are able to predict not only relevant outcomes such as OSD318X Xbut also risks of NRM, GVHD, and relapse. TheseD319X X2 prognostic models investi- gating preD320X Xtransplant conditionsD321X Xprovide a broad vision of risks and benefits that a specific patient can expect with HSCT.
Recently, the DRCI score, which combines DRI and HCT-CI, was published and has demonstrated a significant impact in terms of OS, RI, DFS, and GRFS [8].
In our monocentric retrospective study, including 404 con- secutive patients, the proportion of patients attributed in each risk group was relatively similar, except for the LR group, when compared with the original publication. In the entire
cohort, we had only 2 patients in the LR group (0.5%D322X Xversus 6%
in the original publication). For this reason, we had to combine VLR and HR for analysis. As previously demonstrated by Bejan- yan et al.[8], we confirm the prognostic impact of LR, IR-1, IR-2, and HR group on OS. Unfortunately, in the entire cohort, OS for HR and VHR was similar, making the distinction of these D323X X
2 groups unnecessary for prognosis.
In the same way as the original publication, we also con- firmed that DRCI has a prognostic impact on DFS for LR, IR-1, IR-2, and HR. Similar to OS, HR and VHR stratificationD324X Xis not helpful for prognosis of DFS. In addition, DCRI can differentiate probability of GRFS (LRD325X Xversus IR-1/IR-2 D326X Xversus HR/VHR). In our cohort, we also noticed that DRCI stratification is not prog- nostic for NRM, gradeD327X XIII to IV aGVHD, and cGVHD and corre- sponds withD328X Xresults published by Bejanyan et al.[8].
The main limitation of our study is the low number of patients included, with patients in the VLR and LRD329X Xanalyzed together. Despite this limitation, we have demonstrated results similar D330X Xto the original publication with prognostic impact of OS, DFS, and RI (especially for patients in LR, IR-2,
(a) (b)
(c)
Figure 1.(A) Two-year OS for the entire cohort. (B) Two-year OS for pTDEP patients. (C) Two-year OS for non-pTDEP patients.
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IR-2, and HR) and GRFS. Similarly, we confirm the absence of a prognostic impact of DRCI of NRM, aGVHD
Q9 X X. Prognosis of DRCI
for pTDEP patients D331X Xis similar D332X Xto the entire cohort. Goals of pTDEPD333X Xare to reduce acute and chronicD334X XGVHD, but the DRCI does not D335X Xhelp to recognize patients who can benefit D336X Xfrom pTDEP grafts. Indeed, as previously published, DRI isD337X Xnot prog- nostic of GVHD in unmanipulated graftsD338X XD339X Xor in pTDEP patients
[1,D340X X2,D341X X9,D342X X10]. Although HCT-CI is prognostic ofD343X XGVHD, prognostic
impact on pTDEP patients has not beenD344X Xinvestigated. More- over, combining DRI and HCT-CI probably weakens the weight of HCT-CI inD345X XGVHD prognostication.
Despite results substantially similarD346X Xto the original publica- tion, our resultsD347X Xhighlight the intrinsic limitations of the DRCI model. FirstD348X X, the fact that HR and VHR cannot discriminate dif- ferences for OS and DFS is not useful for clinicians and patients to help D349X Xin making a transplant choice for these groups of patients. This also suggests that this prognostic model cannot be transposed in other transplantD350X Xcenters. SecondD351X X, DRCI is not prognostic for NRM and GVHD. Estimation of these outcomes
D352X X
is of main importance when discussing risks and benefits of HSCT with patients. In the clinical practice of transplant physi- cians, those data are very important for HSCT choice. Third, the DRCI combines validates prognostic modelX Xthat predicts spe- Q10 cifically different outcomes, relapse for DRI and NRM for HCT- CT. In these circumstances, combining thoseD353X X2 models in the DRCI probably dilutes the weight ofD354X Xcomorbidity conditions in NRM prognostication. Moreover, from a statistical point of view, relapse is a competing event for NRM that can also con- tribute to the absence of a predictive role for NRM. Fourth, the DRCI does not giveD355X Xan advantage in terms of speed or ease of
useD356X Xsince it is mandatory to have results of the DRI and HCT-CI
separately to determineD357X Xtheir prognostic impact.
In conclusion, although our data confirmD358X XresultsD359X Xsimilar to the original publication and give useful information on OS, DFS, RI, and GRFS,D360X Xthey also confirmD361X Xthe inherent limitations associated with this model with the absence of prognosis for NRM and GVHD that are necessary to assess transplant eligibil- ity. In accordance with the results of our study and the initial
(a) (b)
(c)
Figure 2.(A) Two-year GRFS for the entire cohort. (B) Two-year GRFS for pTDEP patients. (C) Two-year GRFS for non-pTDEP patients.
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702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766
publication, for the physician and patient point of view, we recommendD362X Xusing the DRI and HCT-CI separately to obtain more accurate and relevant information to guideD363X Xtransplant choice.
ACKNOWLEDGMENTS
Financial disclosure:The authors have nothing to disclose.
Conflict of interest statement:There are no conflicts of inter- est to report.
Authorship statement:Y.B. and Y.C. designed the study and wrote the manuscript. Y.B. analyzed the data. All authors con- tributed data and reviewed the manuscript.
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