Biol Blood Marrow Transplant xxx (2014) 1e8
1 2 3 American Society for Blood 4 and Marrow Transplantation 5 6 7 8 9 10 Q 8 Ling Ge 1, Fan Ye 1, Xinliang Mao 2, Jia Chen 1, Aining Sun 1, 11 Xiaming Zhu 1, Huiying Qiu 1, Zhengming Jin 1, Miao Miao 1, 12 Chengcheng Fu 1, Xiao Ma 1, Feng Chen 1, Shengli Xue 1, 13 Changgeng Ruan 1, Depei Wu 1, *, Xiaowen Tang 1, * 14 15 1 Department of Hematology, First Affiliated Hospital of Soochow University, Jiangsu Institute of 16 Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou, China 2 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow 17 18 Q 1 University, Soochow University, Suzhou, China 19 20 a b s t r a c t Article history: 21 Received 8 January 2014 Extramedullary relapse (EMR) of acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation 22 Accepted 25 March 2014 (allo-HSCT) is a contributor to post-transplantation mortality and remains poorly understood, especially the 23 different characteristics of EMR in patients with acute myelogenous leukemia (AML) and those with acute 24 Key Words: lymphoblastic leukemia (ALL). To investigate the incidence, risk factors, and clinical outcomes of EMR for AML 25 Acute leukemia and ALL, we performed a retrospective analysis of 362 patients with AL who underwent allo-HSCT at the First 26 Acute lymphoblastic leukemia affiliated Hospital of Soochow University between January 2001 and March 2012. Compared with patients Acute myelogenous leukemia 27 with AML, those with ALL had a higher incidence of EMR (12.9% versus 4.6%; P ¼ .009). The most common site Allogeneic hematopoietic stem 28 of EMR was the central nervous system, especially in the ALL group. Multivariate analyses identified the cell transplantation 29 leading risk factors for EMR in the patients with AML as advanced disease status at HSCT, hyperleukocytosis at Extramedullary relapse 30 diagnosis, history of extramedullary leukemia before HSCT, and a total body irradiationebased conditioning 31 regimen, and the top risk factors for EMR in the patients with ALL as hyperleukocytosis at diagnosis, adverse cytogenetics, and transfusion of peripheral blood stem cells. The prognosis for EMR of AL is poor, and 32 treatment options are very limited; however, the estimated 3-year overall survival (OS) was significantly 33 lower in patients with AML compared with those with ALL (0 versus 18.5%; P ¼ .000). The characteristics of 34 posteallo-HSCT EMR differed between the patients with AML and those with ALL, possibly suggesting 35 different pathogenetic mechanisms for EMR of AML and EMR of ALL after allo-HSCT; further investigation is 36 needed, however. 37 Ó 2014 American Society for Blood and Marrow Transplantation. 38 39 40 We studied the incidence, risk factors, treatments, outcomes, INTRODUCTION 41 and mechanisms of post-HSCT EMR in patients with ALL and Although allogeneic hematopoietic stem cell trans42 AML. plantation (allo-HSCT) is a potentially curative treatment for 43 patients with acute leukemia (AL), relapse remains the most 44 frequent cause of treatment failure and mortality. In particPATIENTS AND METHODS 45 Patients ular, a significant rate of extramedullary relapse (EMR) after 46 A total of 362 patients with AL who underwent allo-HSCT in our instiallo-HSCT has been reported [1-6], with a poor prognosis. 47 tution between January 2001 and March 2012 were enrolled in this retroAlthough risk factors for EMR have been described in paspective study, including 208 patients with AML, 147 with ALL, and 7 with 48 tients with acute myelogenous leukemia (AML), few studies acute mixed lineage leukemia (AMLL). These patients included 204 males 49 and 158 females, with a median age of 32 years (range, 3 to 63 years). The have compared the different characteristics of EMR in pa50 graft donor sources for allo-HSCT were unrelated in 27.1% of cases, sibling in tients with AML and patients with acute lymphoblastic leu51 58.3%, and haploidentical in 14.6%; 79.6% of the transplants were HLAkemia (ALL) in the post-HSCT setting. 52 matched. Stem cell sources included bone marrow (BM) in 45.6%, periphIn an effort to better understand post-HSCT EMR, we eral blood (PB) stem cells (PBSCs) in 36.5%, and BM plus PBSCs in 17.9%. In 53 performed a retrospective analysis on 362 patients with AL this study, 260 patients (71.8%) received a modified busulfan (Bu)/cyclo54 phosphamide (Cy) conditioning regimen, 89 (24.6%) received a total body who underwent allo-HSCT in the First affiliated Hospital of 55 irradiation (TBI)/Cy regimen, and 13 (3.6%) received a nonmyeloablative Soochow University between January 2001 and March 2012. 56 conditioning regimen. Patient characteristics are summarized in Table 1. Patients were treated according to clinical protocols approved by the Insti57 tutional Review Board and/or institutional care practice guidelines of Soo58 chow University. Financial disclosure: See Acknowledgments on page 7. 59 * Correspondence and reprint requests: Xiaowen Tang and Depei Wu, 60 Conditioning Regimen Department of Hematology, First Affiliated Hospital of Soochow University, 61 Of the 362 patients, 260 patients received a modified Bu/Cy regimen Jiangsu Institute of Hematology, 188 Shizi Rd, Suzhou 215006, PR China. 62 (Me-CCNU 250 mg/m2/day on day -10, Ara-C 4 g/m2/day on days 9 to 8, E-mail addresses: [email protected] (D. Wu), xwtang1020@ 63 163.com (X. Tang). Bu 0.8 to 1 mg/kg/6 hours on days 7 to 5, and Cy 1.8 g/m2/day on days 4
Extramedullary Relapse of Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Different Characteristics between Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia
1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.03.030
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ASBMT
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2
127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191
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administered to all patients with ALL and high-risk AML in the first year after allo-HSCT.
Table 1 Clinical Characteristics of 362 Patients with AL Post-HSCT Characteristic
AML (n ¼ 208)
ALL (n ¼ 147)
AMLL (n ¼ 7)
Age, yr, median (range) Sex, n Male Female Hyperleukocytosis at diagnosis, n EM leukemia before HSCT, n High cytogenetic risk, n Disease status at HSCT, n CR1 CR2 NR Conditioning regimen, n Bu/Cy TBI/Cy NST Stem cell source, n BM PB BM þ PB Donor type, n Sibling URD Haploidentical aGVHD grade, n I-II III-IV cGVHD, n
35 (3-63)
25 (4-57)
26 (20-54)
116 92 66 14 20
83 64 52 13 65
5 2 1 0 3
163 23 22
110 36 1
5 0 2
185 11 12
72 74 1
3 4 0
100 72 36
62 58 27
3 2 2
142 43 23
66 53 28
3 2 2
67 13 61
51 9 38
5 0 3
NR indicates no remission; NST, nonmyeloablative conditioning regimen; URD, unrelated donor.
to 3) as a preparative regimen, and 89 patients received a TBI/Cy regimen consisting of fractionated TBI 12 Gy on days 8 to 6, Ara-C 2 g/m2/day on day 5, and Cy 1.8 g/m2/day on days 4 to 3. Thirteen patients received nonmyeloablative Bu/fludarabine (Flu) conditioning regimen (Bu 0.8 mg/kg/ 6 hour on days 6 to 5, Flu 30 mg/m2/day on days 7 to 2, and Ara-C 0.5 g/m2/day on days 8 to 4).
Graft-Versus-Host Disease Prophylaxis Acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) were classified according to the criteria proposed by Przepiorka et al. [7] and Sullivan [8]. GVHD prophylaxis included cyclosporine A with short-term methotrexate for related identical transplantation and cyclosporine A, methotrexate, mycophenolate mofetil, and human antithymocyte globulin for unrelated and haploidentical transplantation. The haploidentical grafts were noneT cell depleted.
Central Nervous System Relapse Prophylaxis after Transplantation Prophylactic intrathecal chemotherapy (with methotrexate or cytosine arabinoside and dexamethasone) each month for 6 months was
Definitions and Statistical Analysis EMR included isolated EMR and EMR with concurrent bone marrow relapse (BMR); isolated EMR was defined as EMR without concurrent BMR. EMR was diagnosed in most cases by magnetic resonance imaging, computed tomography, or positron emission tomography. Histological confirmation was performed whenever possible. Central nervous system (CNS) relapse was diagnosed when leukemic cells were identified in the cerebrospinal fluid. Isolated CNS relapse was defined as CNS relapse without any other sites of leukemia relapse. Clinical remission (CR) was defined as 50 109/L at diagnosis of AML, B lymphoblastic leukemia as >30 109/L, and T lymphoblastic leukemia as >100 109/L. The cumulative incidence estimation for leukemia relapse was determined by treating death as a competing risk and was compared using the method of Gray [9]. Overall survival (OS) was calculated from the date of relapse post-transplantation to death or last follow-up for censored cases, and was estimated using the Kaplan-Meier method and compared with a log-rank test. Continuous variables were compared with the Mann-Whitney test, and categorical variables were compared with the chi-square test. A comprehensive multivariate analysis of risk factors for relapse was estimated using the Cox proportional hazards regression model. All statistical analyses were performed with SPSS version 16.0 (SPSS Inc, Chicago, IL) and R version 2.15.1 (R Project for Statistical Computing, Vienna, Austria).
RESULTS Patient Characteristics We retrospectively analyzed a consecutive series of 362 patients with AL who underwent allo-HSCT in our single institution. Of these 362 patients, 163 of 208 with AML, 110 of 147 with ALL, and 5 of 7 with AMLL were in first CR status (CR1) at the time of allo-HSCT. After transplantation, 40.1% patients experienced aGVHD, including 34.0% with mild (grade I-II) and 6.1% with severe (grade III-IV) aGVHD, and 28.2% patients developed cGVHD. After a follow-up ranging from 1 month to 139 months (median, 17 months), 90 patients (24.9%) developed either EMR or BMR; 64 of these relapsed patients had isolated BMR only, 11 had isolated EMR, and 15 had EMR with concurrent BMR. Incidence and Characteristics of EMR in AL The estimated 10-year cumulative incidence of overall relapse posteallo-HSCT was 27%. That of EMR was 7.9%, with 3.1% of patients experiencing isolated EMR. Compared with patients with AML, those with ALL had a higher estimated 10-year cumulative incidence of EMR (12.9% versus 4.6%; P ¼ .009) (Figure 1).
Figure 1. (A) Cumulative incidence of EMR after allo-HSCT for AL. EMR with or without BMR (dotted line), 7.9% (n ¼ 26); isolated EMR (solid line), 3.1% (n ¼ 11); EMR with concurrent BMR (dashed line), 4.7% (n ¼ 15). (B) Cumulative incidence of EMR after HSCT for AML versus ALL (4.6% versus 12.9%; P ¼ .009).
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192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256
L. Ge et al. / Biol Blood Marrow Transplant xxx (2014) 1e8
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 Q 2 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321
3
To identify differences in pathogenesis between BMR and EMR, we performed further analyses with separate consideration of isolated BMR. Patients with advanced disease status had a higher frequency of BMR, and also were more likely to develop EMR. Multivariate analyses also revealed that the patients without cGVHD were more likely to experience BMR (RR ¼ 5.907; P ¼ .00); however, there was no significant difference in the incidence of EMR between patients with cGVHD and those without cGVHD. In addition, the incidence of BMR was higher in patients who received a TBI-based conditioning regimen or nonmyeloablative conditioning regimen compared with patients who received a Bu-containing regimen (RR ¼ 2.100; P ¼ .012 versus RR ¼ 3.159; P ¼ .031) (Table 5).
Twenty-six of the 362 patients experienced EMR after allo-HSCT, including 11 with isolated EMR and 15 with EMR and concurrent BMR. Of these latter 15 patients, 6 who initially had EMR later developed BMR, 4 with BMR later developed EMR, and the remaining 5 developed EMR and BMR almost simultaneously. In our center, the median time to BMR post-HSCT was 5 months (range, 1 to 60 months), and the median time to EMR was 4 months (range, 1 to 38 months; P ¼ .879). Involved extramedullary (EM) sites involved included the CNS, testis, skin, soft tissue, bone, lymph nodes, nasopharynx, and peritoneum. Multifocal involvement at EMR was observed in 5 of 26 patients (19.2%). CNS relapse (n ¼ 18) was the most common type of EMR, with a cumulative incidence of 5.4%, whereas the cumulative incidence of isolated CNS relapse was 2.5%. Among the 26 patients who developed EMR, 5 had a history of EM leukemia before undergoing allo-HSCT, all of whom relapsed at the same site as in the previous leukemia. Ten patients had mild aGVHD (grade I-II), 3 had severe aGVHD (grade III-IV), and 3 developed cGVHD before the onset of EMR. Characteristics of the 11 patients who had isolated EMR and the 15 patients who had EMR with concurrent BMR are presented in Tables 2 and 3.
Differences in Risk Factors for EMR in AML and ALL To identify differences in the pathogenesis of EMR between patients with AML and those with ALL, we performed further multivariate analyses with these 2 groups of patients separately. We found that in the patients with AML, advanced disease status, a history of EM leukemia before HSCT, use of a TBI-based conditioning regimen, and hyperleukocytosis at diagnosis were associated with a higher frequency of EMR (RR ¼ 16.264, P ¼ .001; RR ¼ 10.416, P ¼ .011; RR ¼ 10.455, P ¼ .035; and RR ¼ 4.699, P ¼ .041, respectively), whereas in the patients with ALL, the top risk factors for EMR were receipt of PBSC grafts, hyperleukocytosis at diagnosis, and high-risk cytogenetics (RR ¼ 6.015, P ¼ .007; RR ¼ 2.996, P ¼ .032; and RR ¼ 2.889, P ¼ .042, respectively) (Table 6).
Risk Factors for Overall Relapse and EMR in AL We analyzed the variables of interest by Cox proportional hazard modeling to identify risk factors for AL relapse, including age, sex, disease type, donor type, stem cell source, hyperleukocytosis at diagnosis, cytogenetic risk, disease status at HSCT, HLA mismatch, conditioning regimen, EM leukemia before HSCT, aGVHD, and cGVHD. The results of our univariate and multivariate analyses are summarized in Tables 4 and 5. In terms of overall relapse, our multivariate analyses showed that patients with high-risk cytogenetics, advanced disease status, TBI-based conditioning regimen, without cGVHD, and male sex were more likely to relapse (Table 4). The multivariate analyses also revealed a higher rate of EMR in patients with high-risk cytogenetics, advanced disease status, and male sex (relative risk [RR] ¼ 3.860, P ¼ .002; RR ¼ 6.663, P ¼ .003; and RR ¼ 2.844, P ¼ .038, respectively). A history of EM leukemia before undergoing HSCT and hyperleukocytosis at diagnosis also correlated with an increased risk of EMR (RR ¼ 3.011; P ¼ .038 and RR ¼ 3.382; P ¼ .004, respectively). Meanwhile, patients who received PBSC grafts were more likely to develop EMR (RR ¼ 5.495; P ¼ .002) (Table 5).
Postrelapse Treatment and Clinical Outcomes in AL Four patients refused any treatment and died of relapse. The remaining 22 patients who experienced EMR with or without BMR received various treatment modalities. Nine patients developed isolated CNS relapse and were treated with intrathecal chemotherapy and/or cranial irradiation. One patient who experienced EMR in both the CNS and peritoneum received local chemotherapy, and another patient who developed EMR in lymph nodes was treated with chemotherapy and donor lymphocyte infusion (DLI); however, both patients died of progressive disease. Eight patients received chemotherapy, followed by local irradiation and DLI; 7 of these patients achieved CR, and 2 were still surviving as of the date of this report. The other 5 patients died of GVHD, leukemia recurrence, or CNS relapse. Two patients received chemotherapy and local irradiation, and both died
Table 2 Characteristics of Patients with AL Who Developed Isolated EMR after HSCT Patient
Sex
Age, yr
Disease
Disease Status at HSCT
EM Leukemia before HSCT
Donor Type
Stem Cell Source
HLA Match
Relapse Site
GVHD before Relapse
1 2 3 4 5
F M M F M
31 22 36 22 48
ALL ALL ALL ALL ALL
CR1 CR1 CR1 CR2 CR2
No No No No No
URD URD URD Haploidentical Sibling
PB PB PB PB PB
Yes Yes Yes No Yes
CNS CNS CNS CNS CNS
6 7 8 9
M M F M
10 44 35 18
ALL ALL ALL ALL
CR3 CR4 CR1 CR2
Haploidentical Sibling Sibling URD
BM þ PB PB BM þ PB PB
No Yes Yes Yes
CNS CNS CNS, peritoneum Lymph nodes
10 11
M M
44 29
AML AML
CR1 CR2
CNS No No Lymph nodes No CNS
cGVHD aGVHD grade No aGVHD grade aGVHD grade and cGVHD aGVHD grade No aGVHD grade No
Sibling Haploidentical
BM PB
Yes No
CNS CNS
No No
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Results
I I III IV I
Alive Dead Alive Dead Alive
Direct Cause of Death Infection Relapse
Alive Dead Dead Dead
Infection Relapse Relapse
Dead Dead
Relapse Relapse
322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386
Relapse Relapse Relapse Relapse Relapse Relapse GVHD Relapse I
I
I
Dead Dead Dead Dead Dead Dead Dead Dead
12 3 0
8 3 4 1 0 0 0 0
y y z
* * y y z z z z
No Yes Yes Yes
I
No aGVHD grade No aGVHD grade No aGVHD grade No aGVHD grade and cGVHD
Relapse Alive Dead Alive aGVHD grade I No No
31 8 3 2
Yes Yes
Dead Dead Dead Dead No aGVHD grade I aGVHD grade I aGVHD grade I
GVHD Relapse Relapse Relapse
from leukemia recurrence. The remaining patient was treated with supportive care and died of progressive disease. In general, the estimated 3-year OS postrelapse was better in patients with isolated EMR than in patients with BMR only and those with EMR with concurrent BMR, but the difference was not statistically significant (18.2% versus 12.0% versus 8.0%; P ¼ .206) (Figure 2). Although the median OS postrelapse was 9 months versus 4 months versus 4 months, these differences were not significance either (P ¼ .099). However, the estimated 3-year OS in these patients with EMR was significantly lower in those with AML compared with those with ALL (0 versus 18.5%; P ¼ .00).
Yes Yes No Yes Yes No No No PB PB PB PB BM BM þ PB BM þ PB BM þ PB URD Sibling URD URD Sibling Haploidentical Haploidentical Haploidentical EMR followed by BMR. BMR followed by EMR. BMR and EMR occurred at the same time. z
* y
CR1 CR1 CR3 NR CR1 NR NR NR M M M F M M M M 8 9 10 11 12 13 14 15
18 42 18 34 41 35 25 11
ALL AML AML AML AML AML AML AML
No No CNS No No No Skin, testis No
Yes Yes Yes BM BM BM Sibling Sibling Sibling No No No CR1 CR1 CR1 ALL ALL ALL M M M 5 6 7
42 17 8
CR1 CR1 CR1 CR1 F M M M 1 2 3 4
38 18 21 25
ALL ALL ALL ALL
No No No No
URD Sibling URD URD
PB BM þ PB PB PB
Yes Yes Yes Yes
BM, CNS BM, CNS BM, CNS BM, CNS, nasopharynx BM, CNS, testis BM, testis BM, testis, soft tissue BM, bone BM, CNS BM, CNS BM, CNS BM, skin BM, skin BM, testis BM, testis, soft tissue, sacrum
* * * *
Yes Yes Yes Yes
Results GVHD before Relapse First Relapse Remission Months between Relapses Order of Relapse Relapse Site HLA Match Stem Cell Source Donor Type EM Leukemia before HSCT Disease Status at HSCT Disease Age, yr Sex Patient
Table 3 Characteristics of Patients with AL Who Developed EMR with Concurrent BMR after HSCT
387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451
L. Ge et al. / Biol Blood Marrow Transplant xxx (2014) 1e8
Direct Cause of Death
4
DISCUSSION EMR after allo-HSCT is relatively rare and not well studied. Although most previous studies reported on patients with AML, there are too little data comparing characteristics of EMR between patients with AML and patients with ALL. To our knowledge, this is the first report to examine the differences in EMR occurring after allo-HSCT in patients with AML and those with ALL. We found that significant differences between the 2 groups of patients. The incidence of EMR after allo-HSCT varies among transplantation centers, ranging from 6% to 20% in singleinstitution reports [5,6,10-12]; however, in a retrospective European Group for Blood and Marrow Transplantation (EBMT) survey, the incidence of post-HSCT EMR was only 0.65% in patients with AML [1]. The lower incidence of EMR found in that multicenter study may be related to underreporting in retrospective registry data, as well as to the greater number of patients reported in recent series owing to longer follow-up, longer survival, and generally improved outcomes of HSCT [4]. In general, the incidence of EMR is higher in patients with ALL compared with those with AML [4-6]. In our center, the estimated 10-year cumulative incidence of overall post-HSCT relapse in patients with AL was 27%; that of EMR was 7.9%, with 3.1% of patients experiencing Q 3 isolated EMR. The incidence of EMR was 12.9% in patients with ALL and 4.6% in those with AML (P ¼ .009). Historical risk factors for EMR after HSCT include Philadelphia chromosomeepositive AL, AML subtype M4/M5, age 18 yr Disease AML ALL AMLL Donor type Sibling URD Haploidentical HLA mismatch/match Stem cell source BM PB BM þ PB Hyperleukocytosis at diagnosis, yes/no Cytogenetic risk, high/intermediate-low Disease status at HSCT CR1 CR2 NR EM leukemia before HSCT, yes/no Conditioning regimen Bu/Cy TBI/Cy NST aGVHD, no/yes cGVHD, no/yes
1.826 (1.168-2.853) 1.565 (0.960-2.551)
.008 .072
1.696 (1.082-2.657)
.021
1.000 1.756 (1.154-2.672) 1.598 (0.386-6.613)
.009 .518
1.000 1.522 (0.942-2.459) 2.361 (1.375-4.052) 1.732 (1.084-2.767)
.086 .002 .022
1.000 1.302 1.376 1.223 2.190
(0.817-2.077) (0.791-2.393) (0.799-1.873) (1.428-3.357)
.267 .258 .354 .000
1.704 (1.054-2.755)
.030
1.000 2.621 (1.605-4.282) 5.140 (2.844-9.289) 1.617 (0.812-3.220)
.000 .000 .172
1.000 1.838 (1.087-3.110) 7.123 (3.855-13.163)
.023 .000
1.000 2.147 1.686 0.857 4.547
.001 .314 .471 .000
1.000 1.846 (1.112-3.064) 2.262 (0.806-6.349)
.018 .121
5.127 (2.551-10.304)
.000
(1.384-3.329) (0.610-4.658) (0.564-1.303) (2.282-9.059)
compared with TBI-containing regimens [14]. This result may be related to the low plasma levels of Bu achieved in some patients [16]; however, other, more controversial results failed to show such a difference
3. There are paradoxical results from previous studies regarding pretransplantation conditioning regimens. One retrospective study found a higher incidence of isolated EMR associated with Bu/Cy regimens
Table 5 Univariate and Multivariate Analyses of Risk Factors for EMR (n ¼ 26) and BMR (n ¼ 64) in Patients with AL Factor
Sex, male/female Age, 18/>18 yr Disease AML ALL AMLL Donor type Sibling URD Haploidentical HLA mismatch/match) Stem cell source BM PB BM þ PB Hyperleukocytosis at diagnosis, yes/no Cytogenetic risk, high/ intermediate-low Disease status at HSCT CR1 CR2 NR EM leukemia before HSCT, yes/no Conditioning regimen Bu TBI NST aGVHD, no/yes cGVHD, no/yes
EMR
BMR
Univariate RR (95% CI) P Value Multivariate RR (95% CI)
P Value Univariate RR (95% CI)
P Value Multivariate RR (95% CI)
3.486 (1.314-9.250) 2.224 (0.967-5.117)
.012 .060
.038
1.543 (0.926-2.572) 1.434 (0.780-2.636)
.096 .247
1.000 2.911 (1.296-6.539) 0.000 (0.000-)
.010 .977
1.000 1.509 (0.916-2.484) 2.005 (0.480-8.376)
.106 .340
1.000 2.464 (1.025-5.926) 3.236 (1.170-8.950) 1.735 (0.727-4.140)
.044 .024 .214
1.000 1.249 (0.697-2.236) 2.098 (1.105-3.983) 1.737 (0.996-3.029)
.455 .024 .052
1.000 4.425 (1.605-12.199) 3.271 (0.998-10.719) 2.394 (1.107-5.176)
.004 .050 .027
5.495 (1.880-16.062) .002 2.583 (0.752-8.870) .132 3.382 (1.484-7.707) .004
1.000 0.855 (0.484-1.510) 1.120 (0.588-2.135) 0.961 (0.566-1.630)
.589 .730 .881
2.999 (1.385-6.495)
.005
3.860 (1.647-9.045)
2.013 (1.201-3.375)
.008
1.000 2.770 (1.126-6.813) 4.451 (1.467-13.505) 3.427 (1.291-9.093)
.026 .008 .013
1.154 (0.431-3.087) .775 6.663 (1.923-23.085) .003 3.011 (1.064-8.521) .038
1.000 2.645 0.000 0.635 3.694
.015 .979 .248 .033
(1.210-5.780) (0.000) (0.294-1.371) (1.108-12.320)
2.844 (1.060-7.631)
.002
P Value
1.000 2.598 (1.447-4.664) .001 5.488 (2.728-11.043) .000 1.029 (0.374-2.833) .955
1.000 2.052 (1.098-3.835) .024 7.387 (3.593-15.189) .000
1.000 1.959 2.247 0.958 5.085
1.000 2.100 (1.179-3.739) 3.159 (1.114-8.956)
(1.151-3.334) (0.802-6.292) (0.580-1.584) (2.193-11.791)
.013 .123 .868 .000
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.012 .031
5.907 (2.531-13.784) .000
582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646
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
L. Ge et al. / Biol Blood Marrow Transplant xxx (2014) 1e8
Table 6 Characteristics of Patients with AML and Patients with ALL Characteristics
EMR in AML (n ¼ 9)
EMR in ALL (n ¼ 17)
Cumulative incidence, % EMR site, n* CNS Testis Skin/soft tissue Bone Lymph nodes Nasopharynx Peritoneum EM leukemia before HSCT, n Risk factorsy
4.60
12.90
5 2 3 1 0 0 0 2
13 3 1 1 1 1 1 3
Hyperleukocytosis at diagnosis (RR ¼ 4.699; P ¼ .041)
Hyperleukocytosis at diagnosis (RR ¼ 2.996; P ¼ .032) High-risk cytogenetics (RR ¼ 2.889; P ¼ .042) PB stem cell source (RR ¼ 6.015; P ¼ .007)
Advanced disease status (RR ¼ 16.264; P ¼ .001) EM leukemia before HSCT (RR ¼ 10.416; P ¼ .011) TBI-based conditioning regimen (RR ¼ 10.455; P ¼ .035) Type of therapy, n Local Systemic None Estimated 3-yr OS, %
2 4 3 0
8 7 2 18.50
P Value .009 .382 1.000 .104 1.000 1.000 1.000 1.000 1.000
.399 1.000 .302 .000
Five of 26 patients (19%) presented with extramedullary disease in multiple sites. The variables were analyzed by Cox proportional hazard modeling to identify the risk factors for relapse, including age, sex, donor type, stem cell source, hyperleukocytosis at diagnosis, cytogenetic risk, disease status at HSCT, HLA mismatch, conditioning regimen, EM leukemia before HSCT, aGVHD and cGVHD, ALL with or without the Philadelphia chromosome, and AML subtype M4/M5. * y
[10,17]. Oshima et al. [18] reported a higher incidence of CNS relapse in patients who received TBI-containing preconditioning, possibly because a significantly higher proportion of patients with CNS leukemia received such a regimen compared with those without CNS leukemia (81.5% versus 57.9%; P < .001). The role of conditioning regimen in preventing EMR has not been evaluated precisely. In our study, use of a TBIcontaining regimen was associated with a higher incidence of EMR compared with use of a Bu/Cy regimen in the patients with AML, but not in those with ALL. This difference may be related to the fact that all 11 patients with AML who received a TBI-containing regimen were high-risk patients; 5 had a history of EM leukemia before HSCT, 3 patients were not in remission
Figure 2. Estimated 3-year OS for patients with AL relapse post-HSCT. Isolated EMR (solid line), 18.2%; isolated BMR (dashed line), 12.0%; EMR with concurrent BMR (dotted line), 8.0%; P ¼ .206.
at transplantation, 2 patients were in CR2 or greater (CR2) at transplantation, and 1 patient had adverse cytogenetics. 4. Transplantation of PBSCs was identified as a risk factor for EMR. A possible explanation for this may be the higher rate of CR2/refractory disease status at the time of transplantation in the patients who received PBSC grafts compared with those who received BM grafts (28.8% versus 15.1%; P ¼ .004). Another possible explanation is that transfusion of PBSCs may be related to the presence of a graft-versus-leukemia (GVL) effect that did not protect EM sites after allo-HSCT. The increased incidence of GVHD in patients with EMR implies that GVL surveillance preferentially maintains remission in the BM while allowing leukemic cells in peripheral tissues to evade immune surveillance [13]. Furthermore, we identified transfusion of PBSCs as a independent risk factor for EMR in patients with ALL, but not in those with AML, suggesting that the GVL effect may be less effective at EM sites in ALL. This may be related to the induction of T cell anergy by ALL cells [19], inadequate expression of important costimulatory molecules or adhesion molecules [20,21], or ALL resistance to killing by natural killer cells [22]. Previous research also has shown that the GVL effect may be less effective at EM sites in patients with AML. Patients with EMR are more likely than those with BMR to have preceding aGVHD or cGVHD [10], a high incidence of EMR after immunomodulation (eg, DLI) or Q 4 a second HSCT [23,24]. The patient heterogeneity and small sample size in a single transplantation center preclude drawing conclusions regarding the association of EMR and these risk factors; multicenter studies with larger numbers of patients are needed. In the present study, the development of cGVHD was protective against relapse in the BM, but this protective effect did not extend to EM sites. Multivariate analyses showed that the patients without cGVHD were more likely to experience
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BMR. This finding suggests that the pathogenesis of EMR differs from that of BMR and identifies the EM sites as potential sanctuary sites for leukemia cells, possibly because of decreased expression of HLA minor histocompatibility antigens and adhesion molecules [25]. To date, there are no standardized therapeutic strategies for EMR. Generally, some combination of systemic and local therapy should be considered, given that local therapy alone often results in subsequent systemic relapse. Local therapy includes surgical excision, intrathecal injection, and/or radiation, and systemic therapy involves immunotherapy with chemotherapy, DLI, and second allo-HSCT. The optimal therapeutic strategy remains controversial, however. Recent studies have reported good treatment response with some immune-targeting drugs, including gemtuzumab ozogamicin [26], a recombinant humanized monoclonal antibody that targets the CD33 antigen, which is expressed in >90% of leukemic cells. Sorafenib, a multikinase inhibitor, has significant activity against FLT3-ITDþ blasts in vitro and demonstrated encouraging clinical results as a single agent [27] and in combination with chemotherapy [28] for patients with AML and the FLT3-ITD mutation. Either agent may be an effective therapeutic choice for EMR after allo-HSCT [29,30]. Recently, hypomethylating agents, such as 5-azacitidine and decitabine, were successfully used in the salvage treatment of patients with AML who relapsed or experienced EMR after allo-HSCT [31-33]. It was hypothesized that hypomethylating agents are directly cytotoxic and also might increase the GVL effect by inducing leukemic cell differentiation and expression of HLA-DR to enhance the effects of DLI given concomitantly [33,34]. Owing to a lack of effective treatments, the prognosis for EMR after allo-HSCT is poor. Generally, patients with isolated EMR have a better prognosis than those with BMR [10]. In the UK Medical Research Council’s UKALL12/ECOG 2993 study [35], analysis of outcomes in 609 adults with recurring ALL revealed a better 5-year OS in patients with EMR compared with patients with BMR and those with BMR and CNS relapse (14% versus 6% versus 0; P ¼ .004). The Children’s Oncology Group CCG-1961 study [36] reported obvious differences in the 3-year OS of childhood ALL in patients with BMR (with or without EMR), those with isolated CNS EMR, and those with other isolated EMR (29.7% versus 52.2% versus 68.2%; P < .0001, log-rank test). In the ALL-REZ BFM 90 trial [37], multivariate Cox regression analysis identified the site of relapse as an independent predictor for event-free survival (RR for subsequent event at an isolated EM site versus combined and isolated BM sites of relapse of 1, 1.7, and 2.3, respectively; P < .001). In the present study, in the post-HSCT setting, we also found a trend toward better prognosis in patients with isolated EMR compared with patients with BMR or systemic relapse (18.2% versus 12.0% versus 8.0%; P ¼ .206). In addition, our patients with ALL had a significantly higher estimated 3-year OS compared with those with AML, possibly related to the higher proportion of isolated EMR in the patients with ALL. Thus, treatment should focus on preventing systemic relapse [13]. In conclusion, our results reported here demonstrate that EMR after allo-HSCT poses a significant challenge for transplantation physicians. Our patients with ALL had a higher cumulative incidence of EMR compared with those with AML. CNS relapse is the most common subtype of EMR. Patients with high-risk cytogenetics, advanced disease status, history of EM leukemia before allo-HSCT, hyperleukocytosis at diagnosis, receipt of PBSCs blood stem cell, and male are at
7
increased risk for EMR. These patients should be closely evaluated for early evidence of EMR. 18F-FDG-PET/CT may be Q 6 a useful tool for this purpose [38]. Prophylactic intrathecal chemotherapy [39] and low-dose azacitidine or decitabine administered after allo-HSCT [33,40] may reduce the rate of recurrence. The prognosis for EMR after allo-HSCT is poor, and efficacious treatment strategies are lacking. In addition to an early diagnosis with new modalities, clinical studies using new agents that may offer systemic activity while preserving the GVL effect are warranted in an effort to improve clinical outcomes. Considering the limitations of this study and previous related studies, including single institution experience, small sample size of patients with EMR, and patient heterogeneity, future studies with larger numbers of patients are warranted to further define the incidence, risk factors, and appropriate therapeutic strategies for EMR after allo-HSCT.
ACKNOWLEDGMENTS Financial disclosure: This work was supported by National Natural Science Foundation of China (Grant 81270645), the Natural Science Foundation of Jiangsu Province (Grant BK2012627), the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (Grant 11KJB320015), the Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Provincial Health Office (Grant H201125), the Jiangsu Province Key Medical Center (Grant ZX201102), and the National Public Health Research Foundation (Grant 201202017). Q7 Conflict of interest statement: There are no conflicts of interest to report.
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1 2 3 American Society for Blood 4 and Marrow Transplantation 5 6 7 8 9 10 Q 8 Ling Ge 1, Fan Ye 1, Xinliang Mao 2, Jia Chen 1, Aining Sun 1, 11 Xiaming Zhu 1, Huiying Qiu 1, Zhengming Jin 1, Miao Miao 1, 12 Chengcheng Fu 1, Xiao Ma 1, Feng Chen 1, Shengli Xue 1, 13 Changgeng Ruan 1, Depei Wu 1, *, Xiaowen Tang 1, * 14 15 1 Department of Hematology, First Affiliated Hospital of Soochow University, Jiangsu Institute of 16 Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou, China 2 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow 17 18 Q 1 University, Soochow University, Suzhou, China 19 20 a b s t r a c t Article history: 21 Received 8 January 2014 Extramedullary relapse (EMR) of acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation 22 Accepted 25 March 2014 (allo-HSCT) is a contributor to post-transplantation mortality and remains poorly understood, especially the 23 different characteristics of EMR in patients with acute myelogenous leukemia (AML) and those with acute 24 Key Words: lymphoblastic leukemia (ALL). To investigate the incidence, risk factors, and clinical outcomes of EMR for AML 25 Acute leukemia and ALL, we performed a retrospective analysis of 362 patients with AL who underwent allo-HSCT at the First 26 Acute lymphoblastic leukemia affiliated Hospital of Soochow University between January 2001 and March 2012. Compared with patients Acute myelogenous leukemia 27 with AML, those with ALL had a higher incidence of EMR (12.9% versus 4.6%; P ¼ .009). The most common site Allogeneic hematopoietic stem 28 of EMR was the central nervous system, especially in the ALL group. Multivariate analyses identified the cell transplantation 29 leading risk factors for EMR in the patients with AML as advanced disease status at HSCT, hyperleukocytosis at Extramedullary relapse 30 diagnosis, history of extramedullary leukemia before HSCT, and a total body irradiationebased conditioning 31 regimen, and the top risk factors for EMR in the patients with ALL as hyperleukocytosis at diagnosis, adverse cytogenetics, and transfusion of peripheral blood stem cells. The prognosis for EMR of AL is poor, and 32 treatment options are very limited; however, the estimated 3-year overall survival (OS) was significantly 33 lower in patients with AML compared with those with ALL (0 versus 18.5%; P ¼ .000). The characteristics of 34 posteallo-HSCT EMR differed between the patients with AML and those with ALL, possibly suggesting 35 different pathogenetic mechanisms for EMR of AML and EMR of ALL after allo-HSCT; further investigation is 36 needed, however. 37 Ó 2014 American Society for Blood and Marrow Transplantation. 38 39 40 We studied the incidence, risk factors, treatments, outcomes, INTRODUCTION 41 and mechanisms of post-HSCT EMR in patients with ALL and Although allogeneic hematopoietic stem cell trans42 AML. plantation (allo-HSCT) is a potentially curative treatment for 43 patients with acute leukemia (AL), relapse remains the most 44 frequent cause of treatment failure and mortality. In particPATIENTS AND METHODS 45 Patients ular, a significant rate of extramedullary relapse (EMR) after 46 A total of 362 patients with AL who underwent allo-HSCT in our instiallo-HSCT has been reported [1-6], with a poor prognosis. 47 tution between January 2001 and March 2012 were enrolled in this retroAlthough risk factors for EMR have been described in paspective study, including 208 patients with AML, 147 with ALL, and 7 with 48 tients with acute myelogenous leukemia (AML), few studies acute mixed lineage leukemia (AMLL). These patients included 204 males 49 and 158 females, with a median age of 32 years (range, 3 to 63 years). The have compared the different characteristics of EMR in pa50 graft donor sources for allo-HSCT were unrelated in 27.1% of cases, sibling in tients with AML and patients with acute lymphoblastic leu51 58.3%, and haploidentical in 14.6%; 79.6% of the transplants were HLAkemia (ALL) in the post-HSCT setting. 52 matched. Stem cell sources included bone marrow (BM) in 45.6%, periphIn an effort to better understand post-HSCT EMR, we eral blood (PB) stem cells (PBSCs) in 36.5%, and BM plus PBSCs in 17.9%. In 53 performed a retrospective analysis on 362 patients with AL this study, 260 patients (71.8%) received a modified busulfan (Bu)/cyclo54 phosphamide (Cy) conditioning regimen, 89 (24.6%) received a total body who underwent allo-HSCT in the First affiliated Hospital of 55 irradiation (TBI)/Cy regimen, and 13 (3.6%) received a nonmyeloablative Soochow University between January 2001 and March 2012. 56 conditioning regimen. Patient characteristics are summarized in Table 1. Patients were treated according to clinical protocols approved by the Insti57 tutional Review Board and/or institutional care practice guidelines of Soo58 chow University. Financial disclosure: See Acknowledgments on page 7. 59 * Correspondence and reprint requests: Xiaowen Tang and Depei Wu, 60 Conditioning Regimen Department of Hematology, First Affiliated Hospital of Soochow University, 61 Of the 362 patients, 260 patients received a modified Bu/Cy regimen Jiangsu Institute of Hematology, 188 Shizi Rd, Suzhou 215006, PR China. 62 (Me-CCNU 250 mg/m2/day on day -10, Ara-C 4 g/m2/day on days 9 to 8, E-mail addresses: [email protected] (D. Wu), xwtang1020@ 63 163.com (X. Tang). Bu 0.8 to 1 mg/kg/6 hours on days 7 to 5, and Cy 1.8 g/m2/day on days 4
Extramedullary Relapse of Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Different Characteristics between Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia
1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.03.030
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ASBMT
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
2
127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191
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administered to all patients with ALL and high-risk AML in the first year after allo-HSCT.
Table 1 Clinical Characteristics of 362 Patients with AL Post-HSCT Characteristic
AML (n ¼ 208)
ALL (n ¼ 147)
AMLL (n ¼ 7)
Age, yr, median (range) Sex, n Male Female Hyperleukocytosis at diagnosis, n EM leukemia before HSCT, n High cytogenetic risk, n Disease status at HSCT, n CR1 CR2 NR Conditioning regimen, n Bu/Cy TBI/Cy NST Stem cell source, n BM PB BM þ PB Donor type, n Sibling URD Haploidentical aGVHD grade, n I-II III-IV cGVHD, n
35 (3-63)
25 (4-57)
26 (20-54)
116 92 66 14 20
83 64 52 13 65
5 2 1 0 3
163 23 22
110 36 1
5 0 2
185 11 12
72 74 1
3 4 0
100 72 36
62 58 27
3 2 2
142 43 23
66 53 28
3 2 2
67 13 61
51 9 38
5 0 3
NR indicates no remission; NST, nonmyeloablative conditioning regimen; URD, unrelated donor.
to 3) as a preparative regimen, and 89 patients received a TBI/Cy regimen consisting of fractionated TBI 12 Gy on days 8 to 6, Ara-C 2 g/m2/day on day 5, and Cy 1.8 g/m2/day on days 4 to 3. Thirteen patients received nonmyeloablative Bu/fludarabine (Flu) conditioning regimen (Bu 0.8 mg/kg/ 6 hour on days 6 to 5, Flu 30 mg/m2/day on days 7 to 2, and Ara-C 0.5 g/m2/day on days 8 to 4).
Graft-Versus-Host Disease Prophylaxis Acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) were classified according to the criteria proposed by Przepiorka et al. [7] and Sullivan [8]. GVHD prophylaxis included cyclosporine A with short-term methotrexate for related identical transplantation and cyclosporine A, methotrexate, mycophenolate mofetil, and human antithymocyte globulin for unrelated and haploidentical transplantation. The haploidentical grafts were noneT cell depleted.
Central Nervous System Relapse Prophylaxis after Transplantation Prophylactic intrathecal chemotherapy (with methotrexate or cytosine arabinoside and dexamethasone) each month for 6 months was
Definitions and Statistical Analysis EMR included isolated EMR and EMR with concurrent bone marrow relapse (BMR); isolated EMR was defined as EMR without concurrent BMR. EMR was diagnosed in most cases by magnetic resonance imaging, computed tomography, or positron emission tomography. Histological confirmation was performed whenever possible. Central nervous system (CNS) relapse was diagnosed when leukemic cells were identified in the cerebrospinal fluid. Isolated CNS relapse was defined as CNS relapse without any other sites of leukemia relapse. Clinical remission (CR) was defined as 50 109/L at diagnosis of AML, B lymphoblastic leukemia as >30 109/L, and T lymphoblastic leukemia as >100 109/L. The cumulative incidence estimation for leukemia relapse was determined by treating death as a competing risk and was compared using the method of Gray [9]. Overall survival (OS) was calculated from the date of relapse post-transplantation to death or last follow-up for censored cases, and was estimated using the Kaplan-Meier method and compared with a log-rank test. Continuous variables were compared with the Mann-Whitney test, and categorical variables were compared with the chi-square test. A comprehensive multivariate analysis of risk factors for relapse was estimated using the Cox proportional hazards regression model. All statistical analyses were performed with SPSS version 16.0 (SPSS Inc, Chicago, IL) and R version 2.15.1 (R Project for Statistical Computing, Vienna, Austria).
RESULTS Patient Characteristics We retrospectively analyzed a consecutive series of 362 patients with AL who underwent allo-HSCT in our single institution. Of these 362 patients, 163 of 208 with AML, 110 of 147 with ALL, and 5 of 7 with AMLL were in first CR status (CR1) at the time of allo-HSCT. After transplantation, 40.1% patients experienced aGVHD, including 34.0% with mild (grade I-II) and 6.1% with severe (grade III-IV) aGVHD, and 28.2% patients developed cGVHD. After a follow-up ranging from 1 month to 139 months (median, 17 months), 90 patients (24.9%) developed either EMR or BMR; 64 of these relapsed patients had isolated BMR only, 11 had isolated EMR, and 15 had EMR with concurrent BMR. Incidence and Characteristics of EMR in AL The estimated 10-year cumulative incidence of overall relapse posteallo-HSCT was 27%. That of EMR was 7.9%, with 3.1% of patients experiencing isolated EMR. Compared with patients with AML, those with ALL had a higher estimated 10-year cumulative incidence of EMR (12.9% versus 4.6%; P ¼ .009) (Figure 1).
Figure 1. (A) Cumulative incidence of EMR after allo-HSCT for AL. EMR with or without BMR (dotted line), 7.9% (n ¼ 26); isolated EMR (solid line), 3.1% (n ¼ 11); EMR with concurrent BMR (dashed line), 4.7% (n ¼ 15). (B) Cumulative incidence of EMR after HSCT for AML versus ALL (4.6% versus 12.9%; P ¼ .009).
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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 Q 2 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321
3
To identify differences in pathogenesis between BMR and EMR, we performed further analyses with separate consideration of isolated BMR. Patients with advanced disease status had a higher frequency of BMR, and also were more likely to develop EMR. Multivariate analyses also revealed that the patients without cGVHD were more likely to experience BMR (RR ¼ 5.907; P ¼ .00); however, there was no significant difference in the incidence of EMR between patients with cGVHD and those without cGVHD. In addition, the incidence of BMR was higher in patients who received a TBI-based conditioning regimen or nonmyeloablative conditioning regimen compared with patients who received a Bu-containing regimen (RR ¼ 2.100; P ¼ .012 versus RR ¼ 3.159; P ¼ .031) (Table 5).
Twenty-six of the 362 patients experienced EMR after allo-HSCT, including 11 with isolated EMR and 15 with EMR and concurrent BMR. Of these latter 15 patients, 6 who initially had EMR later developed BMR, 4 with BMR later developed EMR, and the remaining 5 developed EMR and BMR almost simultaneously. In our center, the median time to BMR post-HSCT was 5 months (range, 1 to 60 months), and the median time to EMR was 4 months (range, 1 to 38 months; P ¼ .879). Involved extramedullary (EM) sites involved included the CNS, testis, skin, soft tissue, bone, lymph nodes, nasopharynx, and peritoneum. Multifocal involvement at EMR was observed in 5 of 26 patients (19.2%). CNS relapse (n ¼ 18) was the most common type of EMR, with a cumulative incidence of 5.4%, whereas the cumulative incidence of isolated CNS relapse was 2.5%. Among the 26 patients who developed EMR, 5 had a history of EM leukemia before undergoing allo-HSCT, all of whom relapsed at the same site as in the previous leukemia. Ten patients had mild aGVHD (grade I-II), 3 had severe aGVHD (grade III-IV), and 3 developed cGVHD before the onset of EMR. Characteristics of the 11 patients who had isolated EMR and the 15 patients who had EMR with concurrent BMR are presented in Tables 2 and 3.
Differences in Risk Factors for EMR in AML and ALL To identify differences in the pathogenesis of EMR between patients with AML and those with ALL, we performed further multivariate analyses with these 2 groups of patients separately. We found that in the patients with AML, advanced disease status, a history of EM leukemia before HSCT, use of a TBI-based conditioning regimen, and hyperleukocytosis at diagnosis were associated with a higher frequency of EMR (RR ¼ 16.264, P ¼ .001; RR ¼ 10.416, P ¼ .011; RR ¼ 10.455, P ¼ .035; and RR ¼ 4.699, P ¼ .041, respectively), whereas in the patients with ALL, the top risk factors for EMR were receipt of PBSC grafts, hyperleukocytosis at diagnosis, and high-risk cytogenetics (RR ¼ 6.015, P ¼ .007; RR ¼ 2.996, P ¼ .032; and RR ¼ 2.889, P ¼ .042, respectively) (Table 6).
Risk Factors for Overall Relapse and EMR in AL We analyzed the variables of interest by Cox proportional hazard modeling to identify risk factors for AL relapse, including age, sex, disease type, donor type, stem cell source, hyperleukocytosis at diagnosis, cytogenetic risk, disease status at HSCT, HLA mismatch, conditioning regimen, EM leukemia before HSCT, aGVHD, and cGVHD. The results of our univariate and multivariate analyses are summarized in Tables 4 and 5. In terms of overall relapse, our multivariate analyses showed that patients with high-risk cytogenetics, advanced disease status, TBI-based conditioning regimen, without cGVHD, and male sex were more likely to relapse (Table 4). The multivariate analyses also revealed a higher rate of EMR in patients with high-risk cytogenetics, advanced disease status, and male sex (relative risk [RR] ¼ 3.860, P ¼ .002; RR ¼ 6.663, P ¼ .003; and RR ¼ 2.844, P ¼ .038, respectively). A history of EM leukemia before undergoing HSCT and hyperleukocytosis at diagnosis also correlated with an increased risk of EMR (RR ¼ 3.011; P ¼ .038 and RR ¼ 3.382; P ¼ .004, respectively). Meanwhile, patients who received PBSC grafts were more likely to develop EMR (RR ¼ 5.495; P ¼ .002) (Table 5).
Postrelapse Treatment and Clinical Outcomes in AL Four patients refused any treatment and died of relapse. The remaining 22 patients who experienced EMR with or without BMR received various treatment modalities. Nine patients developed isolated CNS relapse and were treated with intrathecal chemotherapy and/or cranial irradiation. One patient who experienced EMR in both the CNS and peritoneum received local chemotherapy, and another patient who developed EMR in lymph nodes was treated with chemotherapy and donor lymphocyte infusion (DLI); however, both patients died of progressive disease. Eight patients received chemotherapy, followed by local irradiation and DLI; 7 of these patients achieved CR, and 2 were still surviving as of the date of this report. The other 5 patients died of GVHD, leukemia recurrence, or CNS relapse. Two patients received chemotherapy and local irradiation, and both died
Table 2 Characteristics of Patients with AL Who Developed Isolated EMR after HSCT Patient
Sex
Age, yr
Disease
Disease Status at HSCT
EM Leukemia before HSCT
Donor Type
Stem Cell Source
HLA Match
Relapse Site
GVHD before Relapse
1 2 3 4 5
F M M F M
31 22 36 22 48
ALL ALL ALL ALL ALL
CR1 CR1 CR1 CR2 CR2
No No No No No
URD URD URD Haploidentical Sibling
PB PB PB PB PB
Yes Yes Yes No Yes
CNS CNS CNS CNS CNS
6 7 8 9
M M F M
10 44 35 18
ALL ALL ALL ALL
CR3 CR4 CR1 CR2
Haploidentical Sibling Sibling URD
BM þ PB PB BM þ PB PB
No Yes Yes Yes
CNS CNS CNS, peritoneum Lymph nodes
10 11
M M
44 29
AML AML
CR1 CR2
CNS No No Lymph nodes No CNS
cGVHD aGVHD grade No aGVHD grade aGVHD grade and cGVHD aGVHD grade No aGVHD grade No
Sibling Haploidentical
BM PB
Yes No
CNS CNS
No No
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Results
I I III IV I
Alive Dead Alive Dead Alive
Direct Cause of Death Infection Relapse
Alive Dead Dead Dead
Infection Relapse Relapse
Dead Dead
Relapse Relapse
322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386
Relapse Relapse Relapse Relapse Relapse Relapse GVHD Relapse I
I
I
Dead Dead Dead Dead Dead Dead Dead Dead
12 3 0
8 3 4 1 0 0 0 0
y y z
* * y y z z z z
No Yes Yes Yes
I
No aGVHD grade No aGVHD grade No aGVHD grade No aGVHD grade and cGVHD
Relapse Alive Dead Alive aGVHD grade I No No
31 8 3 2
Yes Yes
Dead Dead Dead Dead No aGVHD grade I aGVHD grade I aGVHD grade I
GVHD Relapse Relapse Relapse
from leukemia recurrence. The remaining patient was treated with supportive care and died of progressive disease. In general, the estimated 3-year OS postrelapse was better in patients with isolated EMR than in patients with BMR only and those with EMR with concurrent BMR, but the difference was not statistically significant (18.2% versus 12.0% versus 8.0%; P ¼ .206) (Figure 2). Although the median OS postrelapse was 9 months versus 4 months versus 4 months, these differences were not significance either (P ¼ .099). However, the estimated 3-year OS in these patients with EMR was significantly lower in those with AML compared with those with ALL (0 versus 18.5%; P ¼ .00).
Yes Yes No Yes Yes No No No PB PB PB PB BM BM þ PB BM þ PB BM þ PB URD Sibling URD URD Sibling Haploidentical Haploidentical Haploidentical EMR followed by BMR. BMR followed by EMR. BMR and EMR occurred at the same time. z
* y
CR1 CR1 CR3 NR CR1 NR NR NR M M M F M M M M 8 9 10 11 12 13 14 15
18 42 18 34 41 35 25 11
ALL AML AML AML AML AML AML AML
No No CNS No No No Skin, testis No
Yes Yes Yes BM BM BM Sibling Sibling Sibling No No No CR1 CR1 CR1 ALL ALL ALL M M M 5 6 7
42 17 8
CR1 CR1 CR1 CR1 F M M M 1 2 3 4
38 18 21 25
ALL ALL ALL ALL
No No No No
URD Sibling URD URD
PB BM þ PB PB PB
Yes Yes Yes Yes
BM, CNS BM, CNS BM, CNS BM, CNS, nasopharynx BM, CNS, testis BM, testis BM, testis, soft tissue BM, bone BM, CNS BM, CNS BM, CNS BM, skin BM, skin BM, testis BM, testis, soft tissue, sacrum
* * * *
Yes Yes Yes Yes
Results GVHD before Relapse First Relapse Remission Months between Relapses Order of Relapse Relapse Site HLA Match Stem Cell Source Donor Type EM Leukemia before HSCT Disease Status at HSCT Disease Age, yr Sex Patient
Table 3 Characteristics of Patients with AL Who Developed EMR with Concurrent BMR after HSCT
387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451
L. Ge et al. / Biol Blood Marrow Transplant xxx (2014) 1e8
Direct Cause of Death
4
DISCUSSION EMR after allo-HSCT is relatively rare and not well studied. Although most previous studies reported on patients with AML, there are too little data comparing characteristics of EMR between patients with AML and patients with ALL. To our knowledge, this is the first report to examine the differences in EMR occurring after allo-HSCT in patients with AML and those with ALL. We found that significant differences between the 2 groups of patients. The incidence of EMR after allo-HSCT varies among transplantation centers, ranging from 6% to 20% in singleinstitution reports [5,6,10-12]; however, in a retrospective European Group for Blood and Marrow Transplantation (EBMT) survey, the incidence of post-HSCT EMR was only 0.65% in patients with AML [1]. The lower incidence of EMR found in that multicenter study may be related to underreporting in retrospective registry data, as well as to the greater number of patients reported in recent series owing to longer follow-up, longer survival, and generally improved outcomes of HSCT [4]. In general, the incidence of EMR is higher in patients with ALL compared with those with AML [4-6]. In our center, the estimated 10-year cumulative incidence of overall post-HSCT relapse in patients with AL was 27%; that of EMR was 7.9%, with 3.1% of patients experiencing Q 3 isolated EMR. The incidence of EMR was 12.9% in patients with ALL and 4.6% in those with AML (P ¼ .009). Historical risk factors for EMR after HSCT include Philadelphia chromosomeepositive AL, AML subtype M4/M5, age 18 yr Disease AML ALL AMLL Donor type Sibling URD Haploidentical HLA mismatch/match Stem cell source BM PB BM þ PB Hyperleukocytosis at diagnosis, yes/no Cytogenetic risk, high/intermediate-low Disease status at HSCT CR1 CR2 NR EM leukemia before HSCT, yes/no Conditioning regimen Bu/Cy TBI/Cy NST aGVHD, no/yes cGVHD, no/yes
1.826 (1.168-2.853) 1.565 (0.960-2.551)
.008 .072
1.696 (1.082-2.657)
.021
1.000 1.756 (1.154-2.672) 1.598 (0.386-6.613)
.009 .518
1.000 1.522 (0.942-2.459) 2.361 (1.375-4.052) 1.732 (1.084-2.767)
.086 .002 .022
1.000 1.302 1.376 1.223 2.190
(0.817-2.077) (0.791-2.393) (0.799-1.873) (1.428-3.357)
.267 .258 .354 .000
1.704 (1.054-2.755)
.030
1.000 2.621 (1.605-4.282) 5.140 (2.844-9.289) 1.617 (0.812-3.220)
.000 .000 .172
1.000 1.838 (1.087-3.110) 7.123 (3.855-13.163)
.023 .000
1.000 2.147 1.686 0.857 4.547
.001 .314 .471 .000
1.000 1.846 (1.112-3.064) 2.262 (0.806-6.349)
.018 .121
5.127 (2.551-10.304)
.000
(1.384-3.329) (0.610-4.658) (0.564-1.303) (2.282-9.059)
compared with TBI-containing regimens [14]. This result may be related to the low plasma levels of Bu achieved in some patients [16]; however, other, more controversial results failed to show such a difference
3. There are paradoxical results from previous studies regarding pretransplantation conditioning regimens. One retrospective study found a higher incidence of isolated EMR associated with Bu/Cy regimens
Table 5 Univariate and Multivariate Analyses of Risk Factors for EMR (n ¼ 26) and BMR (n ¼ 64) in Patients with AL Factor
Sex, male/female Age, 18/>18 yr Disease AML ALL AMLL Donor type Sibling URD Haploidentical HLA mismatch/match) Stem cell source BM PB BM þ PB Hyperleukocytosis at diagnosis, yes/no Cytogenetic risk, high/ intermediate-low Disease status at HSCT CR1 CR2 NR EM leukemia before HSCT, yes/no Conditioning regimen Bu TBI NST aGVHD, no/yes cGVHD, no/yes
EMR
BMR
Univariate RR (95% CI) P Value Multivariate RR (95% CI)
P Value Univariate RR (95% CI)
P Value Multivariate RR (95% CI)
3.486 (1.314-9.250) 2.224 (0.967-5.117)
.012 .060
.038
1.543 (0.926-2.572) 1.434 (0.780-2.636)
.096 .247
1.000 2.911 (1.296-6.539) 0.000 (0.000-)
.010 .977
1.000 1.509 (0.916-2.484) 2.005 (0.480-8.376)
.106 .340
1.000 2.464 (1.025-5.926) 3.236 (1.170-8.950) 1.735 (0.727-4.140)
.044 .024 .214
1.000 1.249 (0.697-2.236) 2.098 (1.105-3.983) 1.737 (0.996-3.029)
.455 .024 .052
1.000 4.425 (1.605-12.199) 3.271 (0.998-10.719) 2.394 (1.107-5.176)
.004 .050 .027
5.495 (1.880-16.062) .002 2.583 (0.752-8.870) .132 3.382 (1.484-7.707) .004
1.000 0.855 (0.484-1.510) 1.120 (0.588-2.135) 0.961 (0.566-1.630)
.589 .730 .881
2.999 (1.385-6.495)
.005
3.860 (1.647-9.045)
2.013 (1.201-3.375)
.008
1.000 2.770 (1.126-6.813) 4.451 (1.467-13.505) 3.427 (1.291-9.093)
.026 .008 .013
1.154 (0.431-3.087) .775 6.663 (1.923-23.085) .003 3.011 (1.064-8.521) .038
1.000 2.645 0.000 0.635 3.694
.015 .979 .248 .033
(1.210-5.780) (0.000) (0.294-1.371) (1.108-12.320)
2.844 (1.060-7.631)
.002
P Value
1.000 2.598 (1.447-4.664) .001 5.488 (2.728-11.043) .000 1.029 (0.374-2.833) .955
1.000 2.052 (1.098-3.835) .024 7.387 (3.593-15.189) .000
1.000 1.959 2.247 0.958 5.085
1.000 2.100 (1.179-3.739) 3.159 (1.114-8.956)
(1.151-3.334) (0.802-6.292) (0.580-1.584) (2.193-11.791)
.013 .123 .868 .000
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.012 .031
5.907 (2.531-13.784) .000
582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646
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
L. Ge et al. / Biol Blood Marrow Transplant xxx (2014) 1e8
Table 6 Characteristics of Patients with AML and Patients with ALL Characteristics
EMR in AML (n ¼ 9)
EMR in ALL (n ¼ 17)
Cumulative incidence, % EMR site, n* CNS Testis Skin/soft tissue Bone Lymph nodes Nasopharynx Peritoneum EM leukemia before HSCT, n Risk factorsy
4.60
12.90
5 2 3 1 0 0 0 2
13 3 1 1 1 1 1 3
Hyperleukocytosis at diagnosis (RR ¼ 4.699; P ¼ .041)
Hyperleukocytosis at diagnosis (RR ¼ 2.996; P ¼ .032) High-risk cytogenetics (RR ¼ 2.889; P ¼ .042) PB stem cell source (RR ¼ 6.015; P ¼ .007)
Advanced disease status (RR ¼ 16.264; P ¼ .001) EM leukemia before HSCT (RR ¼ 10.416; P ¼ .011) TBI-based conditioning regimen (RR ¼ 10.455; P ¼ .035) Type of therapy, n Local Systemic None Estimated 3-yr OS, %
2 4 3 0
8 7 2 18.50
P Value .009 .382 1.000 .104 1.000 1.000 1.000 1.000 1.000
.399 1.000 .302 .000
Five of 26 patients (19%) presented with extramedullary disease in multiple sites. The variables were analyzed by Cox proportional hazard modeling to identify the risk factors for relapse, including age, sex, donor type, stem cell source, hyperleukocytosis at diagnosis, cytogenetic risk, disease status at HSCT, HLA mismatch, conditioning regimen, EM leukemia before HSCT, aGVHD and cGVHD, ALL with or without the Philadelphia chromosome, and AML subtype M4/M5. * y
[10,17]. Oshima et al. [18] reported a higher incidence of CNS relapse in patients who received TBI-containing preconditioning, possibly because a significantly higher proportion of patients with CNS leukemia received such a regimen compared with those without CNS leukemia (81.5% versus 57.9%; P < .001). The role of conditioning regimen in preventing EMR has not been evaluated precisely. In our study, use of a TBIcontaining regimen was associated with a higher incidence of EMR compared with use of a Bu/Cy regimen in the patients with AML, but not in those with ALL. This difference may be related to the fact that all 11 patients with AML who received a TBI-containing regimen were high-risk patients; 5 had a history of EM leukemia before HSCT, 3 patients were not in remission
Figure 2. Estimated 3-year OS for patients with AL relapse post-HSCT. Isolated EMR (solid line), 18.2%; isolated BMR (dashed line), 12.0%; EMR with concurrent BMR (dotted line), 8.0%; P ¼ .206.
at transplantation, 2 patients were in CR2 or greater (CR2) at transplantation, and 1 patient had adverse cytogenetics. 4. Transplantation of PBSCs was identified as a risk factor for EMR. A possible explanation for this may be the higher rate of CR2/refractory disease status at the time of transplantation in the patients who received PBSC grafts compared with those who received BM grafts (28.8% versus 15.1%; P ¼ .004). Another possible explanation is that transfusion of PBSCs may be related to the presence of a graft-versus-leukemia (GVL) effect that did not protect EM sites after allo-HSCT. The increased incidence of GVHD in patients with EMR implies that GVL surveillance preferentially maintains remission in the BM while allowing leukemic cells in peripheral tissues to evade immune surveillance [13]. Furthermore, we identified transfusion of PBSCs as a independent risk factor for EMR in patients with ALL, but not in those with AML, suggesting that the GVL effect may be less effective at EM sites in ALL. This may be related to the induction of T cell anergy by ALL cells [19], inadequate expression of important costimulatory molecules or adhesion molecules [20,21], or ALL resistance to killing by natural killer cells [22]. Previous research also has shown that the GVL effect may be less effective at EM sites in patients with AML. Patients with EMR are more likely than those with BMR to have preceding aGVHD or cGVHD [10], a high incidence of EMR after immunomodulation (eg, DLI) or Q 4 a second HSCT [23,24]. The patient heterogeneity and small sample size in a single transplantation center preclude drawing conclusions regarding the association of EMR and these risk factors; multicenter studies with larger numbers of patients are needed. In the present study, the development of cGVHD was protective against relapse in the BM, but this protective effect did not extend to EM sites. Multivariate analyses showed that the patients without cGVHD were more likely to experience
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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
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BMR. This finding suggests that the pathogenesis of EMR differs from that of BMR and identifies the EM sites as potential sanctuary sites for leukemia cells, possibly because of decreased expression of HLA minor histocompatibility antigens and adhesion molecules [25]. To date, there are no standardized therapeutic strategies for EMR. Generally, some combination of systemic and local therapy should be considered, given that local therapy alone often results in subsequent systemic relapse. Local therapy includes surgical excision, intrathecal injection, and/or radiation, and systemic therapy involves immunotherapy with chemotherapy, DLI, and second allo-HSCT. The optimal therapeutic strategy remains controversial, however. Recent studies have reported good treatment response with some immune-targeting drugs, including gemtuzumab ozogamicin [26], a recombinant humanized monoclonal antibody that targets the CD33 antigen, which is expressed in >90% of leukemic cells. Sorafenib, a multikinase inhibitor, has significant activity against FLT3-ITDþ blasts in vitro and demonstrated encouraging clinical results as a single agent [27] and in combination with chemotherapy [28] for patients with AML and the FLT3-ITD mutation. Either agent may be an effective therapeutic choice for EMR after allo-HSCT [29,30]. Recently, hypomethylating agents, such as 5-azacitidine and decitabine, were successfully used in the salvage treatment of patients with AML who relapsed or experienced EMR after allo-HSCT [31-33]. It was hypothesized that hypomethylating agents are directly cytotoxic and also might increase the GVL effect by inducing leukemic cell differentiation and expression of HLA-DR to enhance the effects of DLI given concomitantly [33,34]. Owing to a lack of effective treatments, the prognosis for EMR after allo-HSCT is poor. Generally, patients with isolated EMR have a better prognosis than those with BMR [10]. In the UK Medical Research Council’s UKALL12/ECOG 2993 study [35], analysis of outcomes in 609 adults with recurring ALL revealed a better 5-year OS in patients with EMR compared with patients with BMR and those with BMR and CNS relapse (14% versus 6% versus 0; P ¼ .004). The Children’s Oncology Group CCG-1961 study [36] reported obvious differences in the 3-year OS of childhood ALL in patients with BMR (with or without EMR), those with isolated CNS EMR, and those with other isolated EMR (29.7% versus 52.2% versus 68.2%; P < .0001, log-rank test). In the ALL-REZ BFM 90 trial [37], multivariate Cox regression analysis identified the site of relapse as an independent predictor for event-free survival (RR for subsequent event at an isolated EM site versus combined and isolated BM sites of relapse of 1, 1.7, and 2.3, respectively; P < .001). In the present study, in the post-HSCT setting, we also found a trend toward better prognosis in patients with isolated EMR compared with patients with BMR or systemic relapse (18.2% versus 12.0% versus 8.0%; P ¼ .206). In addition, our patients with ALL had a significantly higher estimated 3-year OS compared with those with AML, possibly related to the higher proportion of isolated EMR in the patients with ALL. Thus, treatment should focus on preventing systemic relapse [13]. In conclusion, our results reported here demonstrate that EMR after allo-HSCT poses a significant challenge for transplantation physicians. Our patients with ALL had a higher cumulative incidence of EMR compared with those with AML. CNS relapse is the most common subtype of EMR. Patients with high-risk cytogenetics, advanced disease status, history of EM leukemia before allo-HSCT, hyperleukocytosis at diagnosis, receipt of PBSCs blood stem cell, and male are at
7
increased risk for EMR. These patients should be closely evaluated for early evidence of EMR. 18F-FDG-PET/CT may be Q 6 a useful tool for this purpose [38]. Prophylactic intrathecal chemotherapy [39] and low-dose azacitidine or decitabine administered after allo-HSCT [33,40] may reduce the rate of recurrence. The prognosis for EMR after allo-HSCT is poor, and efficacious treatment strategies are lacking. In addition to an early diagnosis with new modalities, clinical studies using new agents that may offer systemic activity while preserving the GVL effect are warranted in an effort to improve clinical outcomes. Considering the limitations of this study and previous related studies, including single institution experience, small sample size of patients with EMR, and patient heterogeneity, future studies with larger numbers of patients are warranted to further define the incidence, risk factors, and appropriate therapeutic strategies for EMR after allo-HSCT.
ACKNOWLEDGMENTS Financial disclosure: This work was supported by National Natural Science Foundation of China (Grant 81270645), the Natural Science Foundation of Jiangsu Province (Grant BK2012627), the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (Grant 11KJB320015), the Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Provincial Health Office (Grant H201125), the Jiangsu Province Key Medical Center (Grant ZX201102), and the National Public Health Research Foundation (Grant 201202017). Q7 Conflict of interest statement: There are no conflicts of interest to report.
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