Allogeneic matched-sibling hematopoietic cell transplantation ... - Nature

Bone Marrow Transplantation (2013) 48, 1065–1069 & 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13 www.nature.com/bmt

ORIGINAL ARTICLE

Allogeneic matched-sibling hematopoietic cell transplantation for AML: comparable outcomes between Eastern Mediterranean (EMBMT) and European (EBMT) centers A Bazarbachi1, M Labopin2, A Ghavamzadeh3, S Giebel4, H Al-Zahrani5, S Ladeb6, G Leone7, F Abdel-Rahman8, V Liso9, AA Hamidieh3, W Rasheed5, A Ibrahim10, A Alabdulaaly11, S Kyrcz-Krzemien12, R Arnold13, MA Kharfan-Dabaja1, K Alimoghaddam3, M Aljurf5 and M Mohty14 Allogeneic hematopoietic cell transplantation (HCT) activity significantly increased in the Eastern Mediterranean area over the past decade. However, comparative outcomes with longer established centers, especially European Blood and Marrow Transplantation (EBMT) centers, have not been reported. We compared outcomes of matched-sibling allogeneic HCT between East Mediterranean Blood and Marrow Transplantation (EMBMT) and EBMT centers for adult patients with AML in first CR using myeloablative conditioning. We matched 431 patients from EMBMT with 431 patients from EBMT centers according to patient, disease and transplant characteristics. EMBMT recipients and donors were more likely to be CMV seropositive. There were no significant differences in the incidence of acute or chronic GVHD, or the 3-year cumulative incidence of non-relapse mortality (NRM) and relapse incidence (RI) between the two groups (NRM: EMBMT ¼ 16% vs EBMT ¼ 11), (RI: EMBMT ¼ 13% vs EBMT ¼ 19%). Notably, the 3-year leukemia-free survival (LFS) and OS were similar between the groups (LFS: EMBMT ¼ 70±2% vs EBMT ¼ 69±3%), (OS: EMBMT ¼ 74±2% vs EBMT ¼ 73±2%). Despite differences in socioeconomics, health resources and transplant experience, matched-sibling allogeneic HCT outcomes in emerging centers in the EMBMT region appear similar to EBMT centers. Bone Marrow Transplantation (2013) 48, 1065–1069; doi:10.1038/bmt.2013.1; published online 28 January 2013 Keywords: AML; allogeneic BMT; emerging centers; EMBMT; EBMT

INTRODUCTION The management of patients with AML is dictated by a number of factors including age, performance status and biologic, genetic and molecular characteristics inherent to the disease.1–2 Approximately 60% of cases of AML have an abnormal karyotype analysis.3 Patients with AML with intermediate and poor-risk cytogenetics are generally offered an allogeneic hematopoietic cell transplantation (HCT), preferably in the first chemosensitive response, provided a suitable HLA compatible donor, related or unrelated, is available.4,5 A recent meta-analysis for patients with intermediate-risk AML supports offering an allogeneic HCT in the first CR whenever possible.6 Gratwohl et al.7 recently reported a major variation in allogeneic HCT activity between different countries, likely dependent on socio-economic conditions such as the gross national income per capita. Importantly, the center experience is one of the major determinants of transplant outcomes, particularly non-relapse mortality (NRM).8 There has been a significant increase in allogeneic HCT activity in the WHO-designated Eastern Mediterranean area over the past decade alongside the establishment of the Eastern Mediterranean blood and marrow transplantation (EMBMT) group.9 Established in 2008, EMBMT is a cooperative platform for physicians, scientists and 1

healthcare workers from institutions in the WHO-designated Eastern Mediterranean area with the goal of sharing experience, initiating cooperative trials and establishing a common strategy to achieve optimization in the field of HCT. Currently, active HCT programs in 11 countries participate in EMBMT (Algeria, Egypt, Iran, Jordan, Lebanon, Morocco, Oman, Pakistan, Saudi Arabia, Syria and Tunisia). The increasing trends of HCT activity in the Eastern Mediterranean region have been reported recently.10 However, global outcome data in the EMBMT region, and particularly comparative outcome data with longer established centers have not been yet reported. The aim of this study was to compare post-transplant outcomes of matched-sibling allogeneic HCT between EMBMT and European countries within EBMT among adult AML patients in the first CR (CR1).

PATIENTS AND METHODS Study design, inclusion criteria and study end points This was a retrospective multicenter analysis. Data were provided by the acute leukemia working party of the EBMT group and by centers contributing to EMBMT. EBMT registry is a voluntary working group of more than 500 transplant centers, participants of which are required once

Department of Internal Medicine, American University Beirut Medical Center, Beirut, Lebanon; 2AP-HP, Hoˆpital Saint Antoine, service d’he´matologie et the´rapie cellulaire, Paris, France; Tehran University of Medical Sciences, Hematology, Oncology and Stem Cell Transplantation research center, Tehran, Iran; 4Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; 5King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 6Center National de Greffe de Moelle Osseuse de Tunis, Tunis, Tunisia; 7Department of Hematology, Universita` Cattolica del Sacro Cuore, Rome, Italy; 8King Hussein Cancer Center, Amman, Jordan; 9Department of Hematology, Universita` di Bari, Bari, Italy; 10Makassed General Hospital, Beirut, Lebanon; 11Riyadh Military Hospital, Riyadh, Saudi Arabia; 12Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland; 13Department of Hematology, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany and 14Department of Hematology, Universite´ de Nantes, Nantes, France. Correspondence: Professor A Bazarbachi, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 113-6044, Beirut 1107 2020, Lebanon. E-mail: [email protected] Received 14 June 2012; revised 29 November 2012; accepted 22 December 2012; published online 28 January 2013 3

Similar BMT outcomes for AML in EMBMT and EBMT A Bazarbachi et al

1066 a year to report all consecutive SCT and follow-up. The acute leukemia working party of the EBMT group approved this study that was conducted according to the principles of the declaration of Helsinki. The primary aim was to compare the outcomes of matched-sibling allogeneic HCT between EMBMT and European countries within EBMT from 2003–2010 among the adult (X18 years age) AML patients in CR1. Unrelated donor HCT’s were excluded because of the very limited number of unrelated donor allogeneic HCT performed at EMBMT participating centers, which would not allow a meaningful comparative analysis for unrelated donor transplantation. Cell source comprised BM or G-CSF-mobilized PBSC’s.

Data collection Data were collected using two different strategies. Indeed, six EMBMT centers also report their data to the EBMT central registry. Therefore, we thought first to perform a search on the EBMT registry for patients satisfying the pre-established inclusion criteria in EBMT centers or in EMBMT centers who also report to the EBMT registry. Then, an invitation to participate was also sent to six EMBMT centers that had not reported transplant activity to EBMT and two additional centers responded. Finally, missing data were collected through electronic communications through the EBMT acute leukemia working party office to individual centers. The collected variables comprised recipient specific (age, gender, CMV serologic status and disease status), donor specific (age, gender and CMV serologic status) and transplant specific variables (stem cell source (BM, PBSC), donor source (minimal residual disease (MRD) only), conditioning regimens (myeloablative only), GVHD prophylaxis regimens, and year of allogeneic HCT). We also collected post-transplant outcome variables (such as grades of acute GVHD, relapse, date of relapse, survival status at last follow-up, date of last follow-up or death).

Statistical analysis In the first part of the analysis, we compared the patient- and diseaserelated characteristics of the two groups (EMBMT or EBMT) using the w2 statistic for categorical and the Mann–Whitney test for continuous variables. Variables considered were, patient age at transplantation, patient and donor sex matching, French American British classification (FAB) classification, cytogenetic-risk groups according to the South West Oncology Group (SWOG) classification, status at transplantation, interval from diagnosis to transplant, year of transplant, patient and donor CMV serology and conditioning regimen. In a second step, we performed a matched-pair analysis on the population of patients transplanted in CR1 from an HLA identical sibling using a myeloablative conditioning. Each patient from EMBMT was matched with one patient from EBMT on the following criteria: age at transplantation (five classes according to quintiles), FAB classification, cell source and interval from diagnosis to allogeneic HCT (five classes according to quintiles). The two matched groups were then compared with respect to other factors: cytogenetics, recipient and donor gender, CMV serology positivity and conditioning regimen (including or not TBI). Finally, multivariate analysis was performed in order to adjust the comparison on nonmatching factors differing between the two groups. All factors differing between the two groups or associated with the outcome with a P-value less than 0.15 in univariate analysis were included in the final model. Leukemia-free survival (LFS) was defined as survival without evidence of relapse or progression. NRM was defined as death while in CR. Probabilities of OS and LFS were calculated using the Kaplan–Meier estimate; the logrank test was used for univariate comparisons. Cumulative incidence curves were used for relapse incidence (RI) and NRM in a competing risk setting, as death and relapse are competing together; the Gray test was used for univariate comparisons. Multivariate analysis was performed using cox proportional hazards for OS and LFS, and Fine-Gray model for RI and NRM. All tests were two-sided with type I error rate fixed at 0.05. Statistical analyses were performed with SPSS 19 (SPSS Inc., Chicago, IL, USA) and R 2.13.2 software packages (R Development Core Team, Vienna, Austria). Matched pair was performed in R using the library Matching. For each EMBMT case, we selected one EBMT patient from the EBMT subgroup fitting the matching factors by random with replacement.

RESULTS Allogeneic HCT activity for acute leukemia within EMBMT centers In total, from 1984–2010, 2016 patients with various types of acute leukemia (1360 AML (68%), 580 ALL (29%), 53 biphenotypic Bone Marrow Transplantation (2013) 1065 – 1069

leukemia and 23 unknown subtype), who received allogeneic HCT at EMBMT centers were identified. These represented more than 90% of patients transplanted in EMBMT centers, as only four centers with modest transplant activity are neither reporting to EBMT nor participated in this study. However, only 1349 (67%) patients were adults (defined as 18 years or older).

Comparison between EMBMT and EBMT centers A total of 537 EMBMT and 4009 EBMT patients met the selection criteria of adult AML (age X18 years) transplanted between 2003 and 2009 using HLA identical sibling and myeloablative conditioning. The two populations were different regarding patient, disease and transplant characteristics (Table 1). Age at transplantation was significantly younger at EMBMT centers (median 30.6 years; range 18–55) vs EBMT centers (median 42.9 years; range 18–74) (Po0.001; Table 1). Patients’ gender was similar between the two groups. However, significantly fewer female donors were used in EMBMT centers (40%) compared with EBMT centers (47%) (Po0.003), and accordingly female to male transplants were less frequent in EMBMT centers (18%) as compared with EBMT centers (23%) (P ¼ 0.02) (Table 1). The FAB distribution was also significantly different between EMBMT centers (M0-M6-M7: 6% vs EBMT centers M0-M6-M7: 10%, (P ¼ 0.008; Table 1). Similarly, the cytogenetic-risk group distribution was significantly different between EMBMT centers (good: 14%; intermediate: 72%; poor: 14% vs EBMT centers good: 10%; intermediate: 77%; poor: 13%, P ¼ 0.001; Table 1). The disease status at transplant was notably more favorable in EMBMT centers (CR1: 90%; CR2: 7%; advanced disease: 3%) as compared with EBMT centers (CR1: 73%; CR2–CR3: 11%; advanced disease: 16%) (Po0.0001) (Table 1). Importantly, for CR1 patients, interval from diagnosis to transplant was significantly longer in EMBMT centers (median 172 days; range 41–650) than in EBMT centers (median 136 days; range 23–601) (Po0.0001) (Table 1). Allograft recipients at EMBMT centers were more likely to be CMV seropositive (90% vs 64%; Po0.0001) and to receive an allograft from a CMV seropositive donor as well (89% vs 57%; Po0.0001) (Table 1). Conversely, EMBMT patients were less likely to receive TBI-based conditioning (4% vs 45%; Po0.0001), in vivo T-cell depletion (0% vs 8%; Po0.0001) or BM-derived stem cells (17% vs 23%; P ¼ 0.001) (Table 1).

Matched-pair analysis between EMBMT and EBMT centers When disease status was restricted to adult patients in CR1, a total of 440 EMBMT and 1984 EBMT subjects met this criterion (when limited to allogeneic HCT performed between 2003 and 2009) using HLA identical sibling and myeloablative conditioning regimens. Among these patients, we were able to match 431 patients from 8 EMBMT centers with 431 patients from 27 EBMT centers. Characteristics of the selected patients are shown in Table 2. For the matching factors, age at transplantation (five classes) was therefore similar in the two groups. FAB distribution and stem cell source were exactly identical for both groups. Finally, the interval from diagnosis to HCT (five classes) was similar between the groups. Other unmatched characteristics are detailed in Table 2. There was no difference in cytogenetic-risk groups between EMBMT centers (good: 9%; intermediate: 86%; poor: 5%) compared with EBMT centers (good: 6%; intermediate: 91%; poor: 3%) (P ¼ 0.46) and no difference in recipient gender. However, as previously noted in the unmatched sample, male recipients transplanted at EMBMT centers were also less likely to receive allografts from female donors (18% vs 25% P ¼ 0.03) and EMBMT patients were less likely to receive TBI-based conditioning (3% vs 46%; Po0.001). Similarly, EMBMT recipients as well as donors were more likely to be CMV seropositive (89% vs 62%; Po0.001 and 89% vs 52%; Po0.001, respectively. & 2013 Macmillan Publishers Limited


1067 Table 1.

Unmatched comparison between EMBMT and EBMT centers: patients, disease and transplant characteristics

Median (range) follow-up, months Age at HCT (years) Year of allograft

EMBMT (n ¼ 537)

EBMT (n ¼ 4009)

P-value

35 (2.5–100.5) 30.6 (18–55) 2007 (03–09)

30 (1–105) 42.9 (18–74) 2006 (03–09)

o0.0001 o0.0001

N

%

N

%

Patient gender

Male Female Missing

279 253 5

52 48

2023 1980 6

51 49

0.41

Donor gender

Male Female Missing

323 214

60 40

2118 1855 36

53. 47

0.003

Donor-recipient (female to male)

No Yes Missing

437 95 5

82 18

3073 894 42

77 23

0.02

Recipient CMV seropositivity

Negative Positive Missing

47 422 68

10 90

973 1757 1279

36. 64

o0.0001

Donor CMV seropositivity

Negative Positive Missing

50 414 73

11 89

1157 1551 1301

43 57

o0.0001

TBI-based regimens

No Yes Missing

518 19

96 4

2181 1771 57

55 45

o0.0001

In vitro T-cell depletion

No Yes Missing

534 2 1

100 0

3637 312 60

92 8

o0.0001

BM PB

90 447

17 83

926 3083

23 77

0.001

M1-M4 M0-M5-M6-M7 Missing

473 33 31

94 6

3112 387 510

90 10

0.008

Good Intermediate Poor NA/missing

37 185 35 280

14 72 14

133 971 159 2746

10 77 13

0.001

CR1 CR2 þ Advanced Missing

475 39 16 7

90 7 3

2799 444 612 154

73 11 16

o0.0001

Cell source FAB classification

Cytogenetics

Remission status at HCT

CR1 patients: interval from diagnosis to HCT (days)

172 (41–650)

136 (23–601)

o0.0001

Abbreviations: EBMT ¼ European Blood and Marrow Transplantation; EMBMT ¼ East Mediterranean Blood and Marrow Transplantation; HCT ¼ hematopoietic cell transplantation; MMF ¼ mycophenolate mofetil; PB ¼ mobilized PBSC’s.

Comparable outcomes between matched EMBMT and EBMT patients When unadjusted outcomes were compared for the 862 matched patients, the 3-year cumulative incidence of NRM was not significantly different, although a trend towards a higher NRM in EMBMT centers (16%) as compared with EBMT centers (11%) (P ¼ 0.07) was noted (Figure 1a). However, there was a favorable trend towards a lower RI (Figure 1b) in EMBMT (13%) as compared with EBMT patients (19%) (P ¼ 0.053). Interestingly, the incidence of acute GVHD grade II IV was similar between both data sets (Table 2). However, the percentage of acute GVHD grade III IV was higher 16.5% (n ¼ 58) in the EMBMT group vs 8.9% (n ¼ 29) in the EBMT group; P ¼ 0.003. Likewise, no difference in the 2-year & 2013 Macmillan Publishers Limited

incidence of chronic GVHD was observed (Table 2). Finally, the 3-year LFS and OS were similar between the two groups (LFS: EMBMT ¼ 70±2% vs EBMT ¼ 69±3%; P ¼ 0.97) (Figure 2a), (OS: EMBMT ¼ 74±2% vs EBMT ¼ 73±2%; P ¼ 0.81) (Figure 2b). A multivariate analysis adjusted for age, gender matching, cell source, interval from diagnosis to HCT, FAB subtype, patient and donor CMV serology and TBI-based conditioning was subsequently performed. There was no difference in terms of NRM in EMBMT vs EBMT centers (hazard ratio (HR) 1.26; 95% confidence interval (CI): 0.68–2.35; P ¼ 0.46). However, RI was significantly lower at EMBMT centers (HR: 0.56; confidence interval: 0.35–0.9; P ¼ 0.02). Finally, the 3-year LFS and OS were not statistically different between EMBMT vs EBMT centers (LFS HR: 0.75; Bone Marrow Transplantation (2013) 1065 – 1069


1068 Table 2.

Matched pair comparative analysis between EMBMT and European EBMT centers EMBMT Matching factors Age (five classes) FAB (M0/M1/ y/M7) Cell source (BM/PB) Interval from diagnosis to HCT (five classes) (days) Non-matching factors Cytogenetics Good Intermediate Poor Missing Recipient gender Male Female Missing Donorrecipient (female to male) No Yes Missing Recipient CMV seropositivity Negative Positive Missing Donor CMV seropositivity Negative Positive Missing TBI-based regimens No yes Acute GVHD Xgrade II No Yes Missing Two-year chronic GVHD

EBMT

P-value

31.4 (18–55)

31.8 (18–56)

0.99

11/65/182/1/94/ 63/13/2 71/360

11/65/182/1/94/ 63/13/2 71/360

1

172 days (41–650)

168 days (26–598)

0.71

1.0

0.8

0.6

1

0.4

P =0.07

0.2

0.0 0 15 (9%) 138 (86%) 8 (5%) 270

6 (6%) 90 (91%) 3 (3%) 332

223 (52%) 203 (48%) 5

200 (47%) 230 (53%) 1

1

16 ± 2%

EMBMT

11 ± 2%

EBMT

2 3 4 Years after transplantation

5

0.46

1.0 0.8 0.09

0.6 P =0.053 0.4

348 (82%) 78 (18%) 5

322 (75%) 105 (25%) 4

41 (11%) 339 (89%) 51

101 (38%) 162 (62%) 168

40 (11%) 336 (89%) 55

127 (48%) 136 (52%) 168

420 11 294 (70%) 128 (30%) 9 40±3

235 196 298 (75%) 100 (25%) 33 46±3

0.03

EBMT

13 ± 2%

EMBMT

0.0 o0.001

o0.001

o0.001

0.1 0.14

Abbreviations: EBMT ¼ European Blood and Marrow Transplantation; EMBMT ¼ East Mediterranean Blood and Marrow Transplantation; HCT ¼ hematopoietic cell transplantation; PB ¼ mobilized PBSC’s.

confidence interval: 0.52–1.1; P ¼ 0.14), (OS HR: 0.76; confidence interval: 0.5–1.1; P ¼ 0.19) (Table 3).

DISCUSSION In this report, we compared post-transplant outcomes of allogeneic HCT between EMBMT and European countries within EBMT, from 2003–2010, among adults with AML. Comparison was restricted to patients who underwent matched-sibling allogeneic HCT using myeloablative conditioning. Unmatched comparison between EMBMT and EBMT centers revealed major differences regarding patient, disease and transplant characteristics, and these differences are well known to affect transplant outcomes both in term of NRM and RI.11 Age at transplant was notably younger in EMBMT centers likely reflecting the significantly younger population in this region as Bone Marrow Transplantation (2013) 1065 – 1069

19 ± 2% 0.2

0

1


5

Figure 1. Cumulative incidence of (a) NRM and (b) RI in EMBMT and EBMT centers.

compared with European EBMT countries. The lower rate of female donors in EMBMT centers and the resulting lower percentage of female to male allografts is not clearly understood in this study. This however may affect transplant outcome as previously reported.12 Other differences in disease characteristics were also noted with notably more EMBMT patients transplanted in CR1. Hence, comparison of outcomes was later restricted to patients with AML in CR1 only. Interestingly, there was no significant difference for the matched patient cohorts between EMBMT and EBMT centers in term of NRM or RI, albeit a trend towards a lower RI in EMBMT patients was observed. Furthermore, despite a higher putative consanguinity rate in EMBMT centers13–15 the incidence of acute grade II IV GVHD and the 2-year incidence of chronic GVHD were similar between both groups, with a higher rate of grade III IV acute GVHD in the EMBMT group. Finally, the 3-year LFS and OS were remarkably extremely similar between the two groups. However, this study still has some limitations. Cytogenetic data were missing in 68 and 63% of the EBMT and EMBMT group, respectively. Selection effects cannot be totally excluded particularly that cytogenetic methods and classification were not standardized in the different centers. Moreover, comorbidities were not assessed in the matched-pair analysis. Overall, despite differences in socioeconomics, health resources and more recent transplant experience, matched-sibling allogeneic HCT outcomes in emerging centers in the Eastern Mediterranean region appear similar to EBMT centers. In a recent study, Giebel et al.16 demonstrated that transplantations performed in countries belonging to the upper human development index category were associated with higher LFS compared with the remaining ones (HR ¼ 1.36, P ¼ 0.008). Moreover, a recent survey & 2013 Macmillan Publishers Limited


1069 1.0 0.8

70 ± 2% 69 ± 3%

0.6

EMBMT EBMT

between the two regions. These encouraging results might be attributed to the fact that EMBMT activity is concentrated in few experienced referral centers. In conclusion, allogeneic matchedsibling HCT in EMBMT centers results in comparable outcomes to those in longer established EBMT centers. Recent developments in HCT activity in EMBMT centers include transplanting patients with older age, using reduced intensity conditioning regimens.

0.4

CONFLICT OF INTEREST The authors declare no conflict of interest.

0.2 P =0.97

REFERENCES

0.0 0

1


5

1.0

0.8

0.6

74 ± 2%

EMBMT

73 ± 2%

EBMT

0.4

0.2 P =0.81 0.0 0

Figure 2.

Table 3.

1


5

(a) LFS and (b) OS in EMBMT and EBMT centers.

Comparative outcomes between matched EMBMT and EBMT

patients Outcomes Leukemia-free survival OS Relapse incidence Non-relapse mortality

HR

95% CI

P-value

0.75 0.76 0.56 1.26

0.52–1.1 0.5–1.15 0.35–0.9 0.68–2.35

0.14 0.19 0.02 0.46

Abbreviations: EBMT ¼ European Blood and Marrow Transplantation; EMBMT ¼ East Mediterranean Blood and Marrow Transplantation; CI ¼ confidence interval; HR ¼ hazard ratio. Multivariate analysis (EMBMT vs EBMT) adjusted for age, gender matching, cell source, interval from diagnosis to hematopoietic cell transplantation, FAB subtype, patient and donor CMV serology and TBI.

revealed that HCT is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health-care expenditures, and higher team densities.7 Finally, introduction of a quality management system has been recently shown to affect outcome, as patient outcome was systematically better when the transplantation center was at a more advanced phase of Joint Agency Commercial Imagery Evaluation accreditation, independent of year of transplantation and other risk factors.17 The lower RI in EMBMT centers may be attributed to center effect with a lower number of centers in EMBMT as compared with EBMT. Importantly, NRM, LFS and OS were not statistically different

& 2013 Macmillan Publishers Limited

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Bone Marrow Transplantation (2013) 1065 – 1069