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Validation of the Disease Risk Index for Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation after T Cell Depletion
Biol Blood Marrow Transplant xxx (2014) 1e7
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Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org
Validation of the Disease Risk Index for Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation after T Cell Depletion Yan Beauverd, Eddy Roosnek, Yordanka Tirefort, Monika Nagy-Hulliger, Michael Bernimoulin, Olga Tsopra, Marc Ansari, Carole Dantin, Alessandro Casini, Anne-Pascale Grandjean, Ekaterina Chigrinova, Stavroula Masouridi-Levrat, Yves Chalandon* Stem Cell Transplant Team, Division of Hematology, Geneva’s University Hospitals and University of Geneva Faculty of Medicine, Geneva, Switzerland
Article history: Received 24 December 2013 Accepted 18 April 2014 Key Words: Disease Risk Index Hematopoietic stem cell transplantation Prognosis Overall survival
a b s t r a c t Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may underrate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva’s University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T celledepleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n ¼ 3) for meaningful analysis. For nonTDEP patients, the 4-year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients. Ó 2014 American Society for Blood and Marrow Transplantation.
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many hematologic malignancies [1,2], particularly for patients with high-risk disease. Unfortunately, treatment is associated with a non-negligible morbidity and mortality, mainly due to infections and graftversus-host disease (GVHD) [3]. The success of HSCT depends on patient-related factors, such as age and comorbidities [4]; transplantation-related factors, such as donor type (matched or mismatched, related or unrelated) and donor-recipient sex combination; and the time interval from diagnosis to transplantation [5]. Importantly, the type of disease and its status at transplantation significantly affect graft success [6-10].
Financial disclosure: See Acknowledgments on page 7. * Correspondence and reprint requests: Professor Yves Chalandon, Division of Hematology, Geneva’s University Hospitals, 4 Rue Gabrielle PerretGentil, 1205 Geneva, Switzerland. E-mail address: [email protected] (Y. Chalandon).
Identifying pretransplantation risk factors is important to determine the risk of HSCT in terms of overall survival (OS), progression-free survival (PFS), relapse incidence (RI), and transplantation-related mortality (TRM). Current scoring schemes that estimate the risk of HSCT and help transplantation teams choose between different treatment modalities are The European Group for Blood and Marrow Transplantation (EBMT) risk score [5] and the Hematopoietic Cell TransplantationeSpecific Comorbidity Index (HCT-CI) [4]. However, they do not allow a particular focus on disease and disease status at the time of transplantation. Recently, Armand et al. [11] proposed a Disease Risk Index (DRI), which specifically investigates these characteristics. The DRI defines 3 risk groups for diseases (low, intermediate, high), and disease status is classified into 2 risk groups (low, high) [11]. The 6 possible combinations yield 4 distinct groups with different outcomes in term of OS, PFS, and RI. However, the cohort studied by Armand et al. included very few patients who underwent transplantation with T celledepleted grafts (TDEP) and, to our knowledge, the DRI has not been tested in
1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.04.023
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this patient population. The present observational study aims to determine whether the DRI is also valid for use at our center where 64% of patients undergo transplantation with TDEP. METHODS
Patients We analyzed a cohort of 409 consecutive patients who underwent their first HSCT at the stem cell transplantation center at Geneva’s University Hospitals, Geneva, Switzerland, during a 14-year period (from January 1998 to October 2012). Patients who underwent transplantation for nonmalignant diseases and with syngeneic donors were excluded from the study. We retrospectively collected pre-HSCT, HSCT, and post-HSCT data from our transplantation database. Medical charts were reviewed for cytogenetic data to stratify the risk for acute myeloid leukemia (AML) [12] and myelodysplastic syndrome (MDS) [13] in different risk groups. Fifteen patients (11%) with AML and 13 (20%) with MDS, for whom cytogenetic data were missing, were classified as intermediate risk. Five patients with biphenotypic acute leukemia (4 with normal cytogenetics, 1 with missing data) were classified in the same disease group as AML intermediate risk. All 409 patients were stratified into the 3 risk groups for disease (low, intermediate, high) and 2 risk groups for disease status (low, high) to determine their DRI [11].
Transplantation Patients underwent transplantation with different conditioning regimens. Myeloablative conditioning usually consisted of cyclophosphamide (120 mg/kg) with either total body irradiation (10 to 12 Gy) or busulfan (16 mg/kg oral or 12.8 mg/kg intravenously) with (in the case of in vitro T cell depletion) or without methylprednisolone (1000 mg/m2). Reduced-intensity conditioning (RIC) consisted mostly of fludarabine (120 mg/m2) with busulfan low dose (8 mg/kg oral or 6.4 mg/kg intravenously) with or without antithymocyte globulin (7.5 mg/kg with Thymoglobulin or 25 mg/kg with ATG-Fresenius) with (in the case of in vitro T cell depletion) or without 2 Q 1 methylprednisolone (1000 mg/m ) (Table 1). We used in vitro T cell depletion with alemtuzumab (CAMPATH-1H) Q 2 [14,15] mainly for patients in complete remission at transplantation. TDEP were given on day þ0 followed by an add-back of 100 106 donor T cells on day þ1. RIC patients without GVHD received donor lymphocyte infusions (DLI) from day þ100 in incremental doses starting with 5 105 CD3/kg for unrelated and 1 106/kg for related donor transplantations. DLI could be used also in the case of mixed chimerism or relapse.
Definitions We defined relapse as the recurrence of disease after complete remission (CR) or partial remission (PR) and induction failure as persistent disease without achieving remission of any type (CR or PR). PR was only used for lymphoma. Chronic lymphocytic leukemia or multiple myelomas not in CR after treatment at the time of transplantation were considered induction failure. Myeloproliferative neoplasms previously treated with drugs without intent to achieve CR, such as interferon, hydroxyurea, etc., were considered as untreated. Matched related donors, matched unrelated donors, and mismatched donors were considered to be (mis)matched based on HLA typing for HLA-A, -B, -C, -DRB1, and DQB1 alleles.
Outcomes Primary outcomes were 4-year OS, PFS, RI, and TRM for each of the 4 DRI groups, for all patients, TDEP, and non-TDEP patients. Secondary outcomes were the effects of TDEP on acute and chronic GVHD.
Statistical Analysis Baseline characteristics were reported descriptively and compared using the chi-square test or Fisher exact test. OS and PFS were calculated using the Kaplan-Meier estimator [16], with surviving patients censored in December 2012. Cumulative incidence estimates of GVHD, RI, and TRM were calculated with death from other causes defined as competitive events. Cox regression models of OS were constructed and included age, donorrecipient sex combination, cytomegalovirus donor-recipient status, donor type, DRI, TDEP, source of stem cells, and conditioning regimen as covariates for their association with OS. All calculations were done using SPSS version 21.0 (IBM Corp. Armonk, NY) and R version 3.0.1 (the Comprehensive R Archive Network [CRAN] project [http://cran.us.r-project.org]).
RESULTS Patients Baseline characteristics of the 409 patients in our cohort are shown in Table 1. Classification of patients based on disease and disease status risk according to the DRI proposed by Armand et al. [11] resulted in low, intermediate, high, and very high DRI groups comprising 45, 240, 110, and 14 patients, of whom 37, 177, 44, and 3 had received a TDEP and 8, 63, 66 and 11 had not received TDEP. Outcomes and DRI Relevance The 4-year OS and PFS for all patients were 49% (95% confidence interval [CI], 44% to 54%) and 41% (95% CI, 35% to 46%), respectively. The 4-year RI was 38% (95% CI, 33% to 43%) and TRM was 21% (95% CI, 17% to 25%). Using the DRI, the 4year OS for low, intermediate, high, and very high groups was 82% (95% CI, 70% to 93%), 53% (95% CI, 46% to 60%), 27% (95% CI, 17% to 37%), and 31% (95% CI, 2% to 59%), respectively; P < .0001 (Figure 1A). Four-year PFS for low, intermediate, high, and very high DRI groups was 75% (95% CI, 61% to 88%), 43% (95% CI, 36% to 50%), 22% (95% CI, 13% to 31%), and 20% (95%, CI 0 to 43%), respectively (P < .0001) (Figure 2A). As expected, the patient’s DRI score predicted the OS and PFS. Four-year RI for low, intermediate, high, and very high DRI groups was 9% (95% CI, 3% to 20%), 36% (95% CI, 30% to 43%), 50% (95% CI, 37% to 60%), and 61% (95% CI, 28% to 82%), respectively; P < .0001 (Figure 3A). By contrast, 4-year TRM was similar for low (18%; 95% CI, 8% to 30%), intermediate (19%; 95% CI, 14% to 25%), high (27%; 95% CI, 18% to 36%), and very high (18%; 95% CI, 19% to 48%) DRI groups; P ¼ .59 (Figure 3A). Outcomes by DRI and TDEP We analyzed also OS, PFS, RI, and TRM for TDEP patients. Four-year OS for low, intermediate, and high DRI groups (n ¼ 258; the 3 patients with a very high DRI were not included in the analysis) was 86% (95% CI, 74% to 98%), 53% (95% CI, 45% to 60%), and 33% (95% CI, 18% to 48%), respectively; P < .0001 (Figure 1B). Four-year PFS for low, intermediate, and high DRI groups was 81% (95% CI, 67% to 94%), 41% (95% CI, 34% to 49%), and 26% (95% CI, 12% to 39%), respectively; P < .0001 (Figure 2B). Four-year RI for low, intermediate, and high DRI groups was 11% (95% CI, 3% to 25%), 38% (95% CI, 31% to 46%), and 57% (95% CI, 41% to 71%), respectively; P < .0001 (Figure 3B). We found no significant differences in the 4-year TRM among low, intermediate, and high DRI groups; 14% (95% CI, 4% to 30%), 20% (95% CI, 15% to 27%), and 17% (95% CI, 7% to 30%), respectively; P ¼ .34 (Figure 3B). Outcomes by DRI and non-TDEP OS, PFS, RI, and TRM was analyzed for non-TDEP patients. Four-year OS for low, intermediate, high, and very high DRI groups was 63% (95% CI, 28% to 97%), 54% (95% CI, 40% to 67%), 23% (95% CI, 8% to 35%), and 18% (95% CI, 0 to 47%), respectively; P ¼ .0003 (Figure 1C). Four-year PFS for low, intermediate, high, and very high DRI groups was 47% (95% CI, 10% to 84%), 49% (95% CI, 35% to 63%), 20% (95% CI, 7% to 32%), and 15 (95% CI, 0 to 42%), respectively; P ¼ .0002 (Figure 2C). Four-year RI for low, intermediate, high and very high DRI groups was 14% (95% CI, 4% to 50%), 31% (95% CI, 19% to 44%), 47% (95% CI, 31% to 61%), and 61% (95% CI, 28% to 82%) respectively; P ¼ .001 (Figure 3C). Regarding the entire
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Table 1 Patient Characteristics Characteristic
TDEP
%
Non TDEP
%
Total
%
P Value
No. patients Age, median (range), yr Gender Male Female Disease CML CLL AML Favorable cytogenetic* Intermediate cytogenetic*,y,z Adverse cytogenetic* MDS Intermediate cytogeneticx,k Adverse cytogeneticx ALL Myeloproliferative neoplasms Multiple myeloma Hodgkin lymphoma Non-Hodgkin lymphoma Indolent B-NHL Aggressive B-NHL Mantle cell lymphoma T cell lymphoma, nodal T cell lymphoma, extranodal Stage at transplantation CR 1 CR >1 Untreated Induction failure Active relapse PR 1 PR >1 (RIC) CP AP or BC Disease risk Low Intermediate High Stage risk Low High DRI Low Intermediate High Very high Donor match Identical sibling donor Matched unrelated donor Mismatched unrelated donor Mismatched relative Matched other relative Graft source PBSC BM CB PBSCþBM Conditioning MAC RIC
261 43 (2-70)
63.8
148 43 (3-70)
36.2
409 43 (2-70)
149 112
57.1 42.9
92 56
62.2 37.8
241 168
58.9 41.1
.31
33 9 95 0 83 12 40 34 6 39 9 12 6 19 5 5 5 2 2
12.6 3.4 36.4 .0 31.8 4.6 15.3 13.0 2.3 14.9 3.4 4.6 2.3 7.3 1.9 1.9 1.9 .8 .8
9 3 46 0 35 11 25 18 7 20 5 15 8 16 2 5 6 2 1
6.1 2.0 31.1 .0 23.6 7.4 16.9 12.2 4.7 13.5 3.4 10.1 5.4 10.8 1.4 3.4 4.1 1.4 .7
42 12 141 0 118 23 65 52 13 59 14 27 14 35 7 10 11 4 3
10.3 2.9 34.5 .0 28.9 5.6 15.9 12.7 3.2 14.4 3.4 6.6 3.4 8.6 1.7 2.4 2.7 1.0 .7
<.05 .41 .28
109 46 28 24 15 1 5 31 2
41.8 17.6 10.7 9.2 5.7 .4 1.9 11.9 .8
34 24 5 47 26 0 3 8 1
23.0 16.2 3.4 31.8 17.6 .0 2.0 5.4 .7
143 70 33 71 41 1 8 39 3
35.0 17.1 8.1 17.4 10.0 .2 2.0 9.5 .7
<.05 .72 <.05 <.05 <.05 .64 .94 <.05 .70
47 195 19
18.0 74.7 7.3
14 114 20
9.5 77.0 13.5
61 309 39
14.9 75.6 9.5
<.05 .60 <.05
220 41
84.3 15.7
74 74
50.0 50.0
294 115
71.9 28.1
<.05 <.05
37 177 44 3
14.2 67.8 16.9 1.1
8 63 66 11
5.4 42.6 44.6 7.4
45 240 110 14
11.0 58.7 26.9 3.4
<.05 <.05 <.05 <.05
129 79 37 16 0
49.4 30.3 14.2 6.1 .0
73 61 13 0 1
49.3 41.2 8.8 .0 .7
202 140 50 16 1
49.4 34.2 12.2 3.9 .2
.98 <.05 .11 <.05 .36
242 18 0 1
92.7 6.9 .0 .4
113 28 7 0
76.4 18.9 4.7 .0
355 46 7 1
86.8 11.2 1.7 .2
<.05 <.05 <.05 .64
192 69
73.6 26.4
74 74
50.0 50.0
266 143
65.0 35.0
<.05
No Yes GVHD prophylaxis Cyclosporine Tacrolimus MTX MMF CST
144 117
55.2 44.8
125 23
84.5 15.5
269 140
65.8 34.2
<.05
260 0 115 57 1
99.6 .0 44.1 21.8 .4
145 2 71 66 2
98.0 1.4 48.0 44.6 1.4
405 2 186 123 3
99.0 .5 45.5 30.1 .7
.14 .13 .45 <.05 .30
.68
.69 .97 <.05 .10 .22
CML indicates chronic myelogenous leukemia; CLL, chronic lymphocytic leukemia; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; CP, chronic phase; AP, accelerated phase; BC, blast crisis; PBSC, peripheral blood stem cell; BM, bone marrow; CB, cord blood; MAC, myeloablative conditioning. * Classified according to Armand et al. [12]. y Included 5 patients with biphenotypic leukemia. z Included 15 patients with missing cytogenetic data. x Classified according to Armand et al. [13]. k Q6 ---.
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Figure 1. Overall survival stratified by Disease Risk Index group. (A) All patients. (B) T celledepleted patients. (C) NoneT celledepleted patients.
Figure 2. Progression-free survival stratified by Disease Risk Index group. (A) All patients. (B) T celledepleted patients. (C) NoneT celledepleted patients.
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Table 2 Patient Outcomes A. All Patients OR
n
OS (95% CI) (P < .0001)
PFS (95% CI) (P < .0001)
RI (95% CI) (P < .0001)
TRM (95% CI) (P ¼ .59)
L I H VH
45 240 110 14
82 53 27 31
71 43 22 20
9 36 50 61
18 19 27 18
(70-93) (46-60) (17-37) (2-59)
(58-85) (36-50) (13-32) (0-43)
(3-20) (30-43) (37-60) (28-82)
(8-30) (14-25) (18-36) (19-48)
B. TDEP Patients OR
n
OS (95% CI) (P < .0001)
PFS (95% CI) (P < .0001)
RI (95% CI) (P < .0001)
TRM (95% CI) (P ¼ .34)
L I H VH
37 177 44 3
86 (74-98) 53 (45-60) 33 (18-48) NA
81 (67-94) 41 (34-49) 26 (12-39) NA
11 (3-25) 38 (31-46) 57 (41-71) NA
14 (4-30) 20 (15-27) 17 (7-30) NA
OS (95% CI) (P < .0003)
PFS (95% CI) (P < .0002)
RI (95% CI) (P < .0001)
TRM (95% CI) (P ¼ .85)
63 54 22 18
47 49 20 15
14 31 47 69
44 17 32 10
C. Non-TDEP Patients OR L I H VH
n 8 63 66 11
(28-97) (40-67) (8-35) (0-47)
(10-84) (35-63) (7-32) (0-42)
(4-50) (19-44) (31-61) (26-90)
(12-73) (9-28) (20-44) (3-41)
OR indicates overall risk; L, low; I, intermediate; H, high; VH, very high; NA, not available.
group, no significant differences was found in the 4-year TRM among low, intermediate, high DRI, and very high DRI groups (44% [95% CI, 12% to 73%]; 17% [95% CI, 9% to 28%], 32% [95% CI, 20% to 44%], and 10% [95% CI, 3% to 41%], respectively; P ¼ .085) (Figure 3C). All results are summarized in Table 2. The impact of the DRI on OS was confirmed by multivariate analysis (Table 3). Infusion of DLI One hundred forty patients (117 TDEP patients) received a DLI. Seventy-six DLI were given for relapse (2 for increased paraprotein, 3 for decreasing donor chimerism, 17 for molecular relapse, and 54 for hematological relapse). In addition, 64 TDEP patients received DLI as dictated by our transplantation protocol. Patients received a median of 2 (range, 1 to 7) DLI with a median dose of 1.6 106 CD3/kg (range, .1 to 257 106/kg). Comparison of DRI Outcomes with the Study by Armand et al. Table 4 shows that the OS and PFS in the low-risk group were somewhat higher than those reported by Armand et al. [11], although the impact of being ranked in a particular DRI group was similar. This was true for the entire cohort, including TDEP patients.
web 4C=FPO
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Figure 3. Transplantation-related mortality and relapse incidence stratified by Disease Risk Index group. (A) All patients. (B) T celledepleted patients. (C) NoneT celledepleted patients.
DISCUSSION Risk stratification to predict HSCT patient outcomes is essential and several scoring schemes have already been tested, such as the EBMT score [5] or the HCT-CI [4]. Armand et al. [11] have proposed a new tool, the DRI, which gives prominence to disease and disease status at time of transplantation, including the high impact cytogenetic classifications for AML and MDS [17]. However, to the best of our knowledge, the DRI has not been tested yet for TDEP HSCT patients. In this retrospective study, we confirm the feasibility and validity of the DRI score in the specific setting of TDEP HSCT. The 4-year OS, PFS, and RI were statistically
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Table 3 Multivariate Analysis for Overall Survival Variable
HR
Age, yr <20 20-40 >40 Donor-recipient sex combination Others Female donor-male recipient CMV donor-recipient combination Donor negative-recipient negative Donor positive-recipient negative Donor negative-recipient positive Donor positive-recipient positive Donor type MRD MUD MMD DRI Low Intermediate High Very high T celledepleted graft No TDEP TDEP Stem cell source PBSC BM CB Conditioning regimen MAC RIC
Lower Higher P Value 95% CI 95% CI
Ref 1.435 1.667
.819 .969
2.514 2.866
.207 .065
Ref 1.030
.733
1.448
.866
Ref 1.049 .655 1.491 1.006 1.066 .734
1.681 2.209 1.549
. .842 .047 .735
Ref 1.658 1.188 2.989 1.985
2.315 4.505
.003 .000
Ref 3.352 1.611 5.434 2.536 7.883 2.835
6.976 11.643 21.896
.001 .000 .000
.528
1.048
.090
Ref 1.597 1.021 .781 .222
2.496 2.742
.040 .700
Ref .934
1.294
.686
Ref .744
.676
HR indicates hazard ratio; Ref, reference group; CMV, cytomegalovirus; MRD, matched related donor; MUD, matched unrelated donor; MMD, mismatched donor.
different for each DRI group, whereas only TRM did not reach statistical significance. In our transplantation center, we use TDEP mostly in patients in CR or in the chronic phase of chronic myeloid leukemia to avoid severe acute and chronic GVHD [18,19] that would increase the risk of infection [20], impair functional status, and decrease the patient’s quality of life [21,22]. In most of these patients, we infused a TDEP followed by a dose of 100 106 T cells/kg the day after. Depending on the conditioning regimen, escalated doses of DLI were given after tapering immunosuppression (usually starting on day þ100 for RIC). DLI was not given automatically for myeloablative conditioning. Four-year OS, PFS, RI, and TRM for TDEP were not statistically significant different from the results in our entire cohort. The DRI correlated well with OS, PFS, and RI in TDEP patients, but not with TRM. The latter is not surprising because disease and disease status at the time of transplantation and the related risk of relapse should be at least as important in TDEP patients as in non-TDEP patients, whereas the opposite is true for TRM. We consider that the strength of the new scoring tool is the stronger emphasis on disease and disease status to predict HSCT outcomes. Moreover, it is easy to apply because of the low number of disease risk groups (only 3), disease status groups (only 2), and the relatively simple cytogenetic classifications of AML [12] and MDS [13]. The DRI score could be used to assess the determinants associated with the risk of HSCT together with other tools, such as the EBMT or HCT-CI risk scores. However, its simplicity may also render the score less precise, as molecular markers of disease status, recently described as independent prognostic factors, are not included [23-26]. For instance, mutations of NPM1 [23] or
Table 4 Comparison of Disease Risk Index Outcomes with Study Results of Armand et al. Overall Survival (95% CI) OR
Study Cohort All Patients (P < .0001)
Study Cohort T Celledepleted Patients (P < .0001)
Study Cohort NoneT Celledepleted Patients (P ¼ .003)
Armand et al. (P < .001)
L I H VH
82% 53% 27% 31%
86% (74%-98%) 53% (45%-60%) 33% (18%-48%) NA
63% 54% 22% 18%
64% 46% 26% 6%
(70%-93%) (46%-60%) (17%-37%) (2%-59%)
(28%-97%) (40%-67%) (8%-35%) (0-47%)
(56%-70%) (42%-50%) (21%-31%) (0-21%)
Progression-free Survival (95% CI) OR
Study Cohort All patients (P < .0001)
Study Cohort T Celledepleted Patients (P < .0001)
Study Cohort NoneT Celledepleted Patients (P ¼ .003)
Armand et al. (P < .001)
L I H VH
75% 43% 22% 20%
81% (67%-94%) 41% (34%-49%) 26% (12%-39%) NA
47% 49% 20% 15%
56% 40% 18% 6%
(61%-88%) (36%-50%) (13%-31%) (0-43%)
(10%-83%) (35%-63%) (7%-32%) (0-42%)
(48%-63%) (36%-43%) (14%-22%) (0-21%)
Relapse Incidence (95% CI)
Q7
OR
Study Cohort All Patients (P < .0001)
Study Cohort T Celledepleted Patients (P < .0001)
Study Cohort NoneT Celledepleted Patients (P ¼ .001)
Armand et al. (P < .001)
L I H VH
9% 36% 50% 61%
11% (3%-25%) 38% (31%-46%) 57% (41%-71%) NA
14% 31% 47% 69%
19% 36% 55% 63%
(3%-20%) (30%-43%) (37%-60%) (28%-82%)
(4%-50%) (19%-44%) (31%-61%) (26%-90%)
(13%-24%) (33%-40%) (50%-60%) (44%-81%)
Transplantation-related Mortality (95% CI) OR
Study Cohort All Patients (P ¼ .59)
Study Cohort T Celledepleted Patients (P ¼ .34)
Study Cohort NoneT Celledepleted Patients (P ¼ .85)
Armand et al. (P ¼ .11)
L I H VH
18% 19% 27% 18%
14% (4%-30%) 20% (15%-27%) 17% (7%-30%) NA
44% 17% 32% 10%
26% 24% 27% 31%
(8%-30%) (14%-25%) (18%-36%) (19%-48%)
(12%-73%) (9%-28%) (20%-44%) (3%-41%)
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(19%-32%) (21%-27%) (22%-32%) (18%-45%)
712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776
Y. Beauverd et al. / Biol Blood Marrow Transplant xxx (2014) 1e7
777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 Q 9 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851
CEBPA [23] in AML are of good prognosis, whereas mutations of FLT3-ITD [24,25] and hyperexpression of EVI1 [26] are of poor prognosis. Thus, the DRI may have to be adapted by adding molecular markers to the current cytogenetic ones. Similarly, additional cytogenetic markers could be added for patients with myeloma where t(4;14) and del(17p) are associated with a worse prognosis [27]. The present study has some limitations. It was retrospective and covered a long period (14 years), during which supportive care and the efficacy of antifungal prophylaxis have evolved and improved over time. Despite these limitations, however, the data reported herein are informative. Our data confirm that patients undergoing HSCT can be stratified into 4 DRI groups with statistically significant different outcomes. In addition, this new scoring scheme can be applied also to TDEP HSCT patients with a lower incidence of acute GVHD and could serve as an additional tool to help physicians determine individual risks and benefits of HSCT. In conclusion, our data illustrate the prognostic value of the DRI in a cohort with a majority of TDEP patients. ACKNOWLEDGMENTS We acknowledge the valuable contribution of the medical and nursing staff of the 5FL ward of the Division of Hematology and the medical day care unit of the Division of Oncology of Geneva’s University Hospitals. We thank also Corinne Charrin and Colette Grand for their excellent technical assistance in the stem cell laboratory. Financial disclosure statement: The authors have no financial conflicts of interest to disclose. Conflict of interest statement: ---. Authorship statement: Y.B. and Y.C. designed the study. E.R., Y.T., M.N.H., M.B., O.T., M.A., C.D., A.C., A.P.G., E.C., and S.M.L. contributed data and reviewed the manuscript. Y.B., E.R., and Y.C. analyzed the data and wrote the manuscript. All authors read and approved the final manuscript. REFERENCES 1. Armitage JO. Bone marrow transplantation. New Engl J Med. 1994;330: 827-838. 2. Passweg JR, Halter J, Bucher C, et al. Hematopoietic stem cell transplantation: a review and recommendations for follow-up care for the general practitioner. Swiss Med Wkly. 2012;142:w13696. 3. Gratwohl A, Brand R, Frassoni F, et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005;36:757-769. 4. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912-2919. 5. Gratwohl A, Stern M, Brand R, et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115:4715-4726. 6. Hamilton BK, Copelan EA. Concise review: the role of hematopoietic stem cell transplantation in the treatment of acute myeloid leukemia. Stem Cells. 2012;30:1581-1586. 7. Parmar S, de Lima M, Deeg HJ, Champlin R. Hematopoietic stem cell transplantation for myelodysplastic syndrome: a review. Semin Oncol. 2011;38:693-704. 8. Kim SW, Yoon SS, Suzuki R, et al. Comparison of outcomes between autologous and allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphomas with central review of pathology. Leukemia. 2013;27:1394-1397.
7
9. Sureda A, Canals C, Arranz R, et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin’s lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Espanol de Linfomas/Trasplante de Medula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012;97:310-317. 10. Gahrton G, Iacobelli S, Bjorkstrand B, et al. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013;121:5055-5063. 11. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012;120: 905-913. 12. Armand P, Kim HT, Zhang MJ, et al. Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant. 2012;18:280-288. 13. Armand P, Deeg HJ, Kim HT, et al. Multicenter validation study of a transplantation-specific cytogenetics grouping scheme for patients with myelodysplastic syndromes. Bone Marrow Transplant. 2010;45:877-885. 14. Chakrabarti S, MacDonald D, Hale G, et al. T-cell depletion with Campath-1H "in the bag" for matched related allogeneic peripheral blood stem cell transplantation is associated with reduced graftversus-host disease, rapid immune constitution and improved survival. Brit J Haematol. 2003;121:109-118. 15. Chalandon Y, Roosnek E, Mermillod B, et al. Can only partial T-cell depletion of the graft before hematopoietic stem cell transplantation mitigate graft-versus-host disease while preserving a graft-versusleukemia reaction? A prospective phase II study. Biol Blood Marrow Transplant. 2006;12:102-110. 16. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 17. Armand P, Kim HT, DeAngelo DJ, et al. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant. 2007;13:655-664. 18. Wagner JE, Thompson JS, Carter SL, Kernan NA. Effect of graft-versushost disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multicentre, randomised phase II-III trial. Lancet. 2005;366:733-741. 19. Bayraktar UD, de Lima M, Saliba RM, et al. Ex vivo T cell-depleted versus unmodified allografts in patients with acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant. 2013;19: 898-903. 20. Socie G, Stone JV, Wingard JR, et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. New Engl J Med. 1999;341:14-21. 21. Pidala J, Kurland B, Chai X, et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood. 2011;117:4651-4657. 22. Pallua S, Giesinger J, Oberguggenberger A, et al. Impact of GvHD on quality of life in long-term survivors of haematopoietic transplantation. Bone Marrow Transplant. 2010;45:1534-1539. 23. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. New Engl J Med. 2008;358:1909-1918. 24. Mrozek K, Marcucci G, Paschka P, et al. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109:431-448. 25. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61: 7233-7239. 26. Lugthart S, van Drunen E, van Norden Y, et al. High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood. 2008;111:4329-4337. 27. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood. 2007;109:3489-3495.
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Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org
Validation of the Disease Risk Index for Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation after T Cell Depletion Yan Beauverd, Eddy Roosnek, Yordanka Tirefort, Monika Nagy-Hulliger, Michael Bernimoulin, Olga Tsopra, Marc Ansari, Carole Dantin, Alessandro Casini, Anne-Pascale Grandjean, Ekaterina Chigrinova, Stavroula Masouridi-Levrat, Yves Chalandon* Stem Cell Transplant Team, Division of Hematology, Geneva’s University Hospitals and University of Geneva Faculty of Medicine, Geneva, Switzerland
Article history: Received 24 December 2013 Accepted 18 April 2014 Key Words: Disease Risk Index Hematopoietic stem cell transplantation Prognosis Overall survival
a b s t r a c t Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may underrate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva’s University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T celledepleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n ¼ 3) for meaningful analysis. For nonTDEP patients, the 4-year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients. Ó 2014 American Society for Blood and Marrow Transplantation.
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many hematologic malignancies [1,2], particularly for patients with high-risk disease. Unfortunately, treatment is associated with a non-negligible morbidity and mortality, mainly due to infections and graftversus-host disease (GVHD) [3]. The success of HSCT depends on patient-related factors, such as age and comorbidities [4]; transplantation-related factors, such as donor type (matched or mismatched, related or unrelated) and donor-recipient sex combination; and the time interval from diagnosis to transplantation [5]. Importantly, the type of disease and its status at transplantation significantly affect graft success [6-10].
Financial disclosure: See Acknowledgments on page 7. * Correspondence and reprint requests: Professor Yves Chalandon, Division of Hematology, Geneva’s University Hospitals, 4 Rue Gabrielle PerretGentil, 1205 Geneva, Switzerland. E-mail address: [email protected] (Y. Chalandon).
Identifying pretransplantation risk factors is important to determine the risk of HSCT in terms of overall survival (OS), progression-free survival (PFS), relapse incidence (RI), and transplantation-related mortality (TRM). Current scoring schemes that estimate the risk of HSCT and help transplantation teams choose between different treatment modalities are The European Group for Blood and Marrow Transplantation (EBMT) risk score [5] and the Hematopoietic Cell TransplantationeSpecific Comorbidity Index (HCT-CI) [4]. However, they do not allow a particular focus on disease and disease status at the time of transplantation. Recently, Armand et al. [11] proposed a Disease Risk Index (DRI), which specifically investigates these characteristics. The DRI defines 3 risk groups for diseases (low, intermediate, high), and disease status is classified into 2 risk groups (low, high) [11]. The 6 possible combinations yield 4 distinct groups with different outcomes in term of OS, PFS, and RI. However, the cohort studied by Armand et al. included very few patients who underwent transplantation with T celledepleted grafts (TDEP) and, to our knowledge, the DRI has not been tested in
1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.04.023
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this patient population. The present observational study aims to determine whether the DRI is also valid for use at our center where 64% of patients undergo transplantation with TDEP. METHODS
Patients We analyzed a cohort of 409 consecutive patients who underwent their first HSCT at the stem cell transplantation center at Geneva’s University Hospitals, Geneva, Switzerland, during a 14-year period (from January 1998 to October 2012). Patients who underwent transplantation for nonmalignant diseases and with syngeneic donors were excluded from the study. We retrospectively collected pre-HSCT, HSCT, and post-HSCT data from our transplantation database. Medical charts were reviewed for cytogenetic data to stratify the risk for acute myeloid leukemia (AML) [12] and myelodysplastic syndrome (MDS) [13] in different risk groups. Fifteen patients (11%) with AML and 13 (20%) with MDS, for whom cytogenetic data were missing, were classified as intermediate risk. Five patients with biphenotypic acute leukemia (4 with normal cytogenetics, 1 with missing data) were classified in the same disease group as AML intermediate risk. All 409 patients were stratified into the 3 risk groups for disease (low, intermediate, high) and 2 risk groups for disease status (low, high) to determine their DRI [11].
Transplantation Patients underwent transplantation with different conditioning regimens. Myeloablative conditioning usually consisted of cyclophosphamide (120 mg/kg) with either total body irradiation (10 to 12 Gy) or busulfan (16 mg/kg oral or 12.8 mg/kg intravenously) with (in the case of in vitro T cell depletion) or without methylprednisolone (1000 mg/m2). Reduced-intensity conditioning (RIC) consisted mostly of fludarabine (120 mg/m2) with busulfan low dose (8 mg/kg oral or 6.4 mg/kg intravenously) with or without antithymocyte globulin (7.5 mg/kg with Thymoglobulin or 25 mg/kg with ATG-Fresenius) with (in the case of in vitro T cell depletion) or without 2 Q 1 methylprednisolone (1000 mg/m ) (Table 1). We used in vitro T cell depletion with alemtuzumab (CAMPATH-1H) Q 2 [14,15] mainly for patients in complete remission at transplantation. TDEP were given on day þ0 followed by an add-back of 100 106 donor T cells on day þ1. RIC patients without GVHD received donor lymphocyte infusions (DLI) from day þ100 in incremental doses starting with 5 105 CD3/kg for unrelated and 1 106/kg for related donor transplantations. DLI could be used also in the case of mixed chimerism or relapse.
Definitions We defined relapse as the recurrence of disease after complete remission (CR) or partial remission (PR) and induction failure as persistent disease without achieving remission of any type (CR or PR). PR was only used for lymphoma. Chronic lymphocytic leukemia or multiple myelomas not in CR after treatment at the time of transplantation were considered induction failure. Myeloproliferative neoplasms previously treated with drugs without intent to achieve CR, such as interferon, hydroxyurea, etc., were considered as untreated. Matched related donors, matched unrelated donors, and mismatched donors were considered to be (mis)matched based on HLA typing for HLA-A, -B, -C, -DRB1, and DQB1 alleles.
Outcomes Primary outcomes were 4-year OS, PFS, RI, and TRM for each of the 4 DRI groups, for all patients, TDEP, and non-TDEP patients. Secondary outcomes were the effects of TDEP on acute and chronic GVHD.
Statistical Analysis Baseline characteristics were reported descriptively and compared using the chi-square test or Fisher exact test. OS and PFS were calculated using the Kaplan-Meier estimator [16], with surviving patients censored in December 2012. Cumulative incidence estimates of GVHD, RI, and TRM were calculated with death from other causes defined as competitive events. Cox regression models of OS were constructed and included age, donorrecipient sex combination, cytomegalovirus donor-recipient status, donor type, DRI, TDEP, source of stem cells, and conditioning regimen as covariates for their association with OS. All calculations were done using SPSS version 21.0 (IBM Corp. Armonk, NY) and R version 3.0.1 (the Comprehensive R Archive Network [CRAN] project [http://cran.us.r-project.org]).
RESULTS Patients Baseline characteristics of the 409 patients in our cohort are shown in Table 1. Classification of patients based on disease and disease status risk according to the DRI proposed by Armand et al. [11] resulted in low, intermediate, high, and very high DRI groups comprising 45, 240, 110, and 14 patients, of whom 37, 177, 44, and 3 had received a TDEP and 8, 63, 66 and 11 had not received TDEP. Outcomes and DRI Relevance The 4-year OS and PFS for all patients were 49% (95% confidence interval [CI], 44% to 54%) and 41% (95% CI, 35% to 46%), respectively. The 4-year RI was 38% (95% CI, 33% to 43%) and TRM was 21% (95% CI, 17% to 25%). Using the DRI, the 4year OS for low, intermediate, high, and very high groups was 82% (95% CI, 70% to 93%), 53% (95% CI, 46% to 60%), 27% (95% CI, 17% to 37%), and 31% (95% CI, 2% to 59%), respectively; P < .0001 (Figure 1A). Four-year PFS for low, intermediate, high, and very high DRI groups was 75% (95% CI, 61% to 88%), 43% (95% CI, 36% to 50%), 22% (95% CI, 13% to 31%), and 20% (95%, CI 0 to 43%), respectively (P < .0001) (Figure 2A). As expected, the patient’s DRI score predicted the OS and PFS. Four-year RI for low, intermediate, high, and very high DRI groups was 9% (95% CI, 3% to 20%), 36% (95% CI, 30% to 43%), 50% (95% CI, 37% to 60%), and 61% (95% CI, 28% to 82%), respectively; P < .0001 (Figure 3A). By contrast, 4-year TRM was similar for low (18%; 95% CI, 8% to 30%), intermediate (19%; 95% CI, 14% to 25%), high (27%; 95% CI, 18% to 36%), and very high (18%; 95% CI, 19% to 48%) DRI groups; P ¼ .59 (Figure 3A). Outcomes by DRI and TDEP We analyzed also OS, PFS, RI, and TRM for TDEP patients. Four-year OS for low, intermediate, and high DRI groups (n ¼ 258; the 3 patients with a very high DRI were not included in the analysis) was 86% (95% CI, 74% to 98%), 53% (95% CI, 45% to 60%), and 33% (95% CI, 18% to 48%), respectively; P < .0001 (Figure 1B). Four-year PFS for low, intermediate, and high DRI groups was 81% (95% CI, 67% to 94%), 41% (95% CI, 34% to 49%), and 26% (95% CI, 12% to 39%), respectively; P < .0001 (Figure 2B). Four-year RI for low, intermediate, and high DRI groups was 11% (95% CI, 3% to 25%), 38% (95% CI, 31% to 46%), and 57% (95% CI, 41% to 71%), respectively; P < .0001 (Figure 3B). We found no significant differences in the 4-year TRM among low, intermediate, and high DRI groups; 14% (95% CI, 4% to 30%), 20% (95% CI, 15% to 27%), and 17% (95% CI, 7% to 30%), respectively; P ¼ .34 (Figure 3B). Outcomes by DRI and non-TDEP OS, PFS, RI, and TRM was analyzed for non-TDEP patients. Four-year OS for low, intermediate, high, and very high DRI groups was 63% (95% CI, 28% to 97%), 54% (95% CI, 40% to 67%), 23% (95% CI, 8% to 35%), and 18% (95% CI, 0 to 47%), respectively; P ¼ .0003 (Figure 1C). Four-year PFS for low, intermediate, high, and very high DRI groups was 47% (95% CI, 10% to 84%), 49% (95% CI, 35% to 63%), 20% (95% CI, 7% to 32%), and 15 (95% CI, 0 to 42%), respectively; P ¼ .0002 (Figure 2C). Four-year RI for low, intermediate, high and very high DRI groups was 14% (95% CI, 4% to 50%), 31% (95% CI, 19% to 44%), 47% (95% CI, 31% to 61%), and 61% (95% CI, 28% to 82%) respectively; P ¼ .001 (Figure 3C). Regarding the entire
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257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 Q 3 310 311 312 313 314 315 316 317 318 Q 4 Q5 319 320 321
3
Table 1 Patient Characteristics Characteristic
TDEP
%
Non TDEP
%
Total
%
P Value
No. patients Age, median (range), yr Gender Male Female Disease CML CLL AML Favorable cytogenetic* Intermediate cytogenetic*,y,z Adverse cytogenetic* MDS Intermediate cytogeneticx,k Adverse cytogeneticx ALL Myeloproliferative neoplasms Multiple myeloma Hodgkin lymphoma Non-Hodgkin lymphoma Indolent B-NHL Aggressive B-NHL Mantle cell lymphoma T cell lymphoma, nodal T cell lymphoma, extranodal Stage at transplantation CR 1 CR >1 Untreated Induction failure Active relapse PR 1 PR >1 (RIC) CP AP or BC Disease risk Low Intermediate High Stage risk Low High DRI Low Intermediate High Very high Donor match Identical sibling donor Matched unrelated donor Mismatched unrelated donor Mismatched relative Matched other relative Graft source PBSC BM CB PBSCþBM Conditioning MAC RIC
261 43 (2-70)
63.8
148 43 (3-70)
36.2
409 43 (2-70)
149 112
57.1 42.9
92 56
62.2 37.8
241 168
58.9 41.1
.31
33 9 95 0 83 12 40 34 6 39 9 12 6 19 5 5 5 2 2
12.6 3.4 36.4 .0 31.8 4.6 15.3 13.0 2.3 14.9 3.4 4.6 2.3 7.3 1.9 1.9 1.9 .8 .8
9 3 46 0 35 11 25 18 7 20 5 15 8 16 2 5 6 2 1
6.1 2.0 31.1 .0 23.6 7.4 16.9 12.2 4.7 13.5 3.4 10.1 5.4 10.8 1.4 3.4 4.1 1.4 .7
42 12 141 0 118 23 65 52 13 59 14 27 14 35 7 10 11 4 3
10.3 2.9 34.5 .0 28.9 5.6 15.9 12.7 3.2 14.4 3.4 6.6 3.4 8.6 1.7 2.4 2.7 1.0 .7
<.05 .41 .28
109 46 28 24 15 1 5 31 2
41.8 17.6 10.7 9.2 5.7 .4 1.9 11.9 .8
34 24 5 47 26 0 3 8 1
23.0 16.2 3.4 31.8 17.6 .0 2.0 5.4 .7
143 70 33 71 41 1 8 39 3
35.0 17.1 8.1 17.4 10.0 .2 2.0 9.5 .7
<.05 .72 <.05 <.05 <.05 .64 .94 <.05 .70
47 195 19
18.0 74.7 7.3
14 114 20
9.5 77.0 13.5
61 309 39
14.9 75.6 9.5
<.05 .60 <.05
220 41
84.3 15.7
74 74
50.0 50.0
294 115
71.9 28.1
<.05 <.05
37 177 44 3
14.2 67.8 16.9 1.1
8 63 66 11
5.4 42.6 44.6 7.4
45 240 110 14
11.0 58.7 26.9 3.4
<.05 <.05 <.05 <.05
129 79 37 16 0
49.4 30.3 14.2 6.1 .0
73 61 13 0 1
49.3 41.2 8.8 .0 .7
202 140 50 16 1
49.4 34.2 12.2 3.9 .2
.98 <.05 .11 <.05 .36
242 18 0 1
92.7 6.9 .0 .4
113 28 7 0
76.4 18.9 4.7 .0
355 46 7 1
86.8 11.2 1.7 .2
<.05 <.05 <.05 .64
192 69
73.6 26.4
74 74
50.0 50.0
266 143
65.0 35.0
<.05
No Yes GVHD prophylaxis Cyclosporine Tacrolimus MTX MMF CST
144 117
55.2 44.8
125 23
84.5 15.5
269 140
65.8 34.2
<.05
260 0 115 57 1
99.6 .0 44.1 21.8 .4
145 2 71 66 2
98.0 1.4 48.0 44.6 1.4
405 2 186 123 3
99.0 .5 45.5 30.1 .7
.14 .13 .45 <.05 .30
.68
.69 .97 <.05 .10 .22
CML indicates chronic myelogenous leukemia; CLL, chronic lymphocytic leukemia; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; CP, chronic phase; AP, accelerated phase; BC, blast crisis; PBSC, peripheral blood stem cell; BM, bone marrow; CB, cord blood; MAC, myeloablative conditioning. * Classified according to Armand et al. [12]. y Included 5 patients with biphenotypic leukemia. z Included 15 patients with missing cytogenetic data. x Classified according to Armand et al. [13]. k Q6 ---.
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Figure 1. Overall survival stratified by Disease Risk Index group. (A) All patients. (B) T celledepleted patients. (C) NoneT celledepleted patients.
Figure 2. Progression-free survival stratified by Disease Risk Index group. (A) All patients. (B) T celledepleted patients. (C) NoneT celledepleted patients.
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Table 2 Patient Outcomes A. All Patients OR
n
OS (95% CI) (P < .0001)
PFS (95% CI) (P < .0001)
RI (95% CI) (P < .0001)
TRM (95% CI) (P ¼ .59)
L I H VH
45 240 110 14
82 53 27 31
71 43 22 20
9 36 50 61
18 19 27 18
(70-93) (46-60) (17-37) (2-59)
(58-85) (36-50) (13-32) (0-43)
(3-20) (30-43) (37-60) (28-82)
(8-30) (14-25) (18-36) (19-48)
B. TDEP Patients OR
n
OS (95% CI) (P < .0001)
PFS (95% CI) (P < .0001)
RI (95% CI) (P < .0001)
TRM (95% CI) (P ¼ .34)
L I H VH
37 177 44 3
86 (74-98) 53 (45-60) 33 (18-48) NA
81 (67-94) 41 (34-49) 26 (12-39) NA
11 (3-25) 38 (31-46) 57 (41-71) NA
14 (4-30) 20 (15-27) 17 (7-30) NA
OS (95% CI) (P < .0003)
PFS (95% CI) (P < .0002)
RI (95% CI) (P < .0001)
TRM (95% CI) (P ¼ .85)
63 54 22 18
47 49 20 15
14 31 47 69
44 17 32 10
C. Non-TDEP Patients OR L I H VH
n 8 63 66 11
(28-97) (40-67) (8-35) (0-47)
(10-84) (35-63) (7-32) (0-42)
(4-50) (19-44) (31-61) (26-90)
(12-73) (9-28) (20-44) (3-41)
OR indicates overall risk; L, low; I, intermediate; H, high; VH, very high; NA, not available.
group, no significant differences was found in the 4-year TRM among low, intermediate, high DRI, and very high DRI groups (44% [95% CI, 12% to 73%]; 17% [95% CI, 9% to 28%], 32% [95% CI, 20% to 44%], and 10% [95% CI, 3% to 41%], respectively; P ¼ .085) (Figure 3C). All results are summarized in Table 2. The impact of the DRI on OS was confirmed by multivariate analysis (Table 3). Infusion of DLI One hundred forty patients (117 TDEP patients) received a DLI. Seventy-six DLI were given for relapse (2 for increased paraprotein, 3 for decreasing donor chimerism, 17 for molecular relapse, and 54 for hematological relapse). In addition, 64 TDEP patients received DLI as dictated by our transplantation protocol. Patients received a median of 2 (range, 1 to 7) DLI with a median dose of 1.6 106 CD3/kg (range, .1 to 257 106/kg). Comparison of DRI Outcomes with the Study by Armand et al. Table 4 shows that the OS and PFS in the low-risk group were somewhat higher than those reported by Armand et al. [11], although the impact of being ranked in a particular DRI group was similar. This was true for the entire cohort, including TDEP patients.
web 4C=FPO
517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581
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Figure 3. Transplantation-related mortality and relapse incidence stratified by Disease Risk Index group. (A) All patients. (B) T celledepleted patients. (C) NoneT celledepleted patients.
DISCUSSION Risk stratification to predict HSCT patient outcomes is essential and several scoring schemes have already been tested, such as the EBMT score [5] or the HCT-CI [4]. Armand et al. [11] have proposed a new tool, the DRI, which gives prominence to disease and disease status at time of transplantation, including the high impact cytogenetic classifications for AML and MDS [17]. However, to the best of our knowledge, the DRI has not been tested yet for TDEP HSCT patients. In this retrospective study, we confirm the feasibility and validity of the DRI score in the specific setting of TDEP HSCT. The 4-year OS, PFS, and RI were statistically
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6
647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711
Y. Beauverd et al. / Biol Blood Marrow Transplant xxx (2014) 1e7
Table 3 Multivariate Analysis for Overall Survival Variable
HR
Age, yr <20 20-40 >40 Donor-recipient sex combination Others Female donor-male recipient CMV donor-recipient combination Donor negative-recipient negative Donor positive-recipient negative Donor negative-recipient positive Donor positive-recipient positive Donor type MRD MUD MMD DRI Low Intermediate High Very high T celledepleted graft No TDEP TDEP Stem cell source PBSC BM CB Conditioning regimen MAC RIC
Lower Higher P Value 95% CI 95% CI
Ref 1.435 1.667
.819 .969
2.514 2.866
.207 .065
Ref 1.030
.733
1.448
.866
Ref 1.049 .655 1.491 1.006 1.066 .734
1.681 2.209 1.549
. .842 .047 .735
Ref 1.658 1.188 2.989 1.985
2.315 4.505
.003 .000
Ref 3.352 1.611 5.434 2.536 7.883 2.835
6.976 11.643 21.896
.001 .000 .000
.528
1.048
.090
Ref 1.597 1.021 .781 .222
2.496 2.742
.040 .700
Ref .934
1.294
.686
Ref .744
.676
HR indicates hazard ratio; Ref, reference group; CMV, cytomegalovirus; MRD, matched related donor; MUD, matched unrelated donor; MMD, mismatched donor.
different for each DRI group, whereas only TRM did not reach statistical significance. In our transplantation center, we use TDEP mostly in patients in CR or in the chronic phase of chronic myeloid leukemia to avoid severe acute and chronic GVHD [18,19] that would increase the risk of infection [20], impair functional status, and decrease the patient’s quality of life [21,22]. In most of these patients, we infused a TDEP followed by a dose of 100 106 T cells/kg the day after. Depending on the conditioning regimen, escalated doses of DLI were given after tapering immunosuppression (usually starting on day þ100 for RIC). DLI was not given automatically for myeloablative conditioning. Four-year OS, PFS, RI, and TRM for TDEP were not statistically significant different from the results in our entire cohort. The DRI correlated well with OS, PFS, and RI in TDEP patients, but not with TRM. The latter is not surprising because disease and disease status at the time of transplantation and the related risk of relapse should be at least as important in TDEP patients as in non-TDEP patients, whereas the opposite is true for TRM. We consider that the strength of the new scoring tool is the stronger emphasis on disease and disease status to predict HSCT outcomes. Moreover, it is easy to apply because of the low number of disease risk groups (only 3), disease status groups (only 2), and the relatively simple cytogenetic classifications of AML [12] and MDS [13]. The DRI score could be used to assess the determinants associated with the risk of HSCT together with other tools, such as the EBMT or HCT-CI risk scores. However, its simplicity may also render the score less precise, as molecular markers of disease status, recently described as independent prognostic factors, are not included [23-26]. For instance, mutations of NPM1 [23] or
Table 4 Comparison of Disease Risk Index Outcomes with Study Results of Armand et al. Overall Survival (95% CI) OR
Study Cohort All Patients (P < .0001)
Study Cohort T Celledepleted Patients (P < .0001)
Study Cohort NoneT Celledepleted Patients (P ¼ .003)
Armand et al. (P < .001)
L I H VH
82% 53% 27% 31%
86% (74%-98%) 53% (45%-60%) 33% (18%-48%) NA
63% 54% 22% 18%
64% 46% 26% 6%
(70%-93%) (46%-60%) (17%-37%) (2%-59%)
(28%-97%) (40%-67%) (8%-35%) (0-47%)
(56%-70%) (42%-50%) (21%-31%) (0-21%)
Progression-free Survival (95% CI) OR
Study Cohort All patients (P < .0001)
Study Cohort T Celledepleted Patients (P < .0001)
Study Cohort NoneT Celledepleted Patients (P ¼ .003)
Armand et al. (P < .001)
L I H VH
75% 43% 22% 20%
81% (67%-94%) 41% (34%-49%) 26% (12%-39%) NA
47% 49% 20% 15%
56% 40% 18% 6%
(61%-88%) (36%-50%) (13%-31%) (0-43%)
(10%-83%) (35%-63%) (7%-32%) (0-42%)
(48%-63%) (36%-43%) (14%-22%) (0-21%)
Relapse Incidence (95% CI)
Q7
OR
Study Cohort All Patients (P < .0001)
Study Cohort T Celledepleted Patients (P < .0001)
Study Cohort NoneT Celledepleted Patients (P ¼ .001)
Armand et al. (P < .001)
L I H VH
9% 36% 50% 61%
11% (3%-25%) 38% (31%-46%) 57% (41%-71%) NA
14% 31% 47% 69%
19% 36% 55% 63%
(3%-20%) (30%-43%) (37%-60%) (28%-82%)
(4%-50%) (19%-44%) (31%-61%) (26%-90%)
(13%-24%) (33%-40%) (50%-60%) (44%-81%)
Transplantation-related Mortality (95% CI) OR
Study Cohort All Patients (P ¼ .59)
Study Cohort T Celledepleted Patients (P ¼ .34)
Study Cohort NoneT Celledepleted Patients (P ¼ .85)
Armand et al. (P ¼ .11)
L I H VH
18% 19% 27% 18%
14% (4%-30%) 20% (15%-27%) 17% (7%-30%) NA
44% 17% 32% 10%
26% 24% 27% 31%
(8%-30%) (14%-25%) (18%-36%) (19%-48%)
(12%-73%) (9%-28%) (20%-44%) (3%-41%)
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(19%-32%) (21%-27%) (22%-32%) (18%-45%)
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CEBPA [23] in AML are of good prognosis, whereas mutations of FLT3-ITD [24,25] and hyperexpression of EVI1 [26] are of poor prognosis. Thus, the DRI may have to be adapted by adding molecular markers to the current cytogenetic ones. Similarly, additional cytogenetic markers could be added for patients with myeloma where t(4;14) and del(17p) are associated with a worse prognosis [27]. The present study has some limitations. It was retrospective and covered a long period (14 years), during which supportive care and the efficacy of antifungal prophylaxis have evolved and improved over time. Despite these limitations, however, the data reported herein are informative. Our data confirm that patients undergoing HSCT can be stratified into 4 DRI groups with statistically significant different outcomes. In addition, this new scoring scheme can be applied also to TDEP HSCT patients with a lower incidence of acute GVHD and could serve as an additional tool to help physicians determine individual risks and benefits of HSCT. In conclusion, our data illustrate the prognostic value of the DRI in a cohort with a majority of TDEP patients. ACKNOWLEDGMENTS We acknowledge the valuable contribution of the medical and nursing staff of the 5FL ward of the Division of Hematology and the medical day care unit of the Division of Oncology of Geneva’s University Hospitals. We thank also Corinne Charrin and Colette Grand for their excellent technical assistance in the stem cell laboratory. Financial disclosure statement: The authors have no financial conflicts of interest to disclose. Conflict of interest statement: ---. Authorship statement: Y.B. and Y.C. designed the study. E.R., Y.T., M.N.H., M.B., O.T., M.A., C.D., A.C., A.P.G., E.C., and S.M.L. contributed data and reviewed the manuscript. Y.B., E.R., and Y.C. analyzed the data and wrote the manuscript. All authors read and approved the final manuscript. REFERENCES 1. Armitage JO. Bone marrow transplantation. New Engl J Med. 1994;330: 827-838. 2. Passweg JR, Halter J, Bucher C, et al. Hematopoietic stem cell transplantation: a review and recommendations for follow-up care for the general practitioner. Swiss Med Wkly. 2012;142:w13696. 3. Gratwohl A, Brand R, Frassoni F, et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005;36:757-769. 4. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912-2919. 5. Gratwohl A, Stern M, Brand R, et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115:4715-4726. 6. Hamilton BK, Copelan EA. Concise review: the role of hematopoietic stem cell transplantation in the treatment of acute myeloid leukemia. Stem Cells. 2012;30:1581-1586. 7. Parmar S, de Lima M, Deeg HJ, Champlin R. Hematopoietic stem cell transplantation for myelodysplastic syndrome: a review. Semin Oncol. 2011;38:693-704. 8. Kim SW, Yoon SS, Suzuki R, et al. Comparison of outcomes between autologous and allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphomas with central review of pathology. Leukemia. 2013;27:1394-1397.
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