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1 Originl Article Grnulocyte Colony stimulting Fctor primed Bone Mrrow: An Excellent Stem cell Source for Trnsplnttion in Acute Myelocytic Leukemi nd Chronic Myelocytic Leukemi Yuhng Li 1, Min Jing 1, Chen Xu 1, Jinlin Chen 1, Boto Li 1, Jun Wng 1, Jingwei Hu 1, Hongmei Ning 1, Hu Chen 1, Shuiping Chen 2, Lingding Hu 1 1 Center of Hemtopoietic Stem Cell Trnsplnttion, 307 Hospitl of People's Liertion Army, Beijing , Chin 2 Stte Key Lortory of Pthogen nd Biosecurity, Beijing Institute of Microiology nd Epidemiology, Beijing , Chin Astrct Bckground: Stedy stte one mrrow (SS BM) nd grnulocyte colony stimulting growth fctor primed BM/peripherl lood stem cell (G BM/G PBSC) re the min stem cell sources used in llogeneic hemtopoietic stem cell trnsplnttion. Here, we evluted the tretment effects of SS BM nd G BM/G PBSC in humn leucocyte ntigen (HLA) identicl siling trnsplnttion. Methods: A totl of 226 ptients (cute myelogenous leukemi complete remission 1, chronic myelogenous leukemi chronic phse 1) received SS BM, G BM, or G PBSC from n HLA identicl siling. Clinicl outcomes (grft versus host disese [GVHD], overll survivl, trnsplnt relted mortlity [TRM], nd leukemi free survivl [LFS]) were nlyzed. Results: When compred to SS BM, G BM gve fster recovery time to neutrophil or pltelet (P < 0.05). Incidence of grde III IV cute GVHD nd extensive chronic GVHD (cgvhd) ws lower thn seen with SS BM (P < 0.05) nd similr to G PBSC. Although the incidence of cgvhd in the G BM group ws similr to SS BM, oth were lower thn G PBSC (P < 0.05). G BM nd G PBSC exhiited similr survivl, LFS, nd TRM, ut were significntly different from SS BM (P < 0.05). There were no significnt differences in leukemi relpse rtes mong the groups (P > 0.05). Conclusions: G CSF primed one mrrow shred the dvntges of G PBSC nd SS BM. We conclude tht G BM is n excellent stem cell source tht my e preferle to G PBSC or SS BM in ptients receiving HLA identicl siling hemtopoietic stem cell trnsplnttion. Key words: Bone Mrrow; Grnulocyte Colony stimulting Growth Fctor; Humn Leucocyte Antigen identicl Siling Hemtopoietic Stem cell Trnsplnttion; Peripherl Blood Stem cells Introduction Hemtopoietic stem cell trnsplnttion (HSCT) is n importnt therpeutic option for mny mlignnt nd nonmlignnt disorders. Since the first report of one mrrow (BM) trnsplnttion, stedy stte BM (SS BM) hs een the only stem cell source for HSCT. In recent yers, grnulocyte colony stimulting fctor (G CSF) moilized peripherl lood stem cells (G PBSC) hve ecome n lterntive stem cell source. G PBSC is even preferred in dults receiving humn leucocyte ntigen (HLA) identicl siling trnsplnttion. Although G PBSC re enriched in progenitor cells s compred to SS BM, which llows fster engrftment, [1] the use of G PBSC will increse the incidence of chronic grft versus host disese (cgvhd). [2,3] To tke dvntge of G PBSC Access this rticle online Quick Response Code: Wesite: DOI: / while decrese the risk of cgvhd, G CSF primed BM (G BM) hs een explored. Recently, G BM hs een n ttrctive option for HLA hploidenticl/mismtched donor trnsplnttion. [4 6] However, G BM does not seem to e considered n lterntive to SS BM in HLA identicl HSCT due to nonsignificnt improvement in survivls, [7 9] lthough its fesileness, sfety, well engrftment nd limited incidence of GVHD hve een demonstrted. [7 16] The conclusions from previous studies on HLA identicl trnsplnttion with G BM might e limited due to the numer of ptients, underlying diseses, disese sttus t the time of trnsplnttion, G CSF schedules, conditioning regimens, nd GVHD prophylxis. In this study, we conducted retrospective nonrndomized controlled study to evlute the clinicl outcomes of G BM, SS BM, nd G PBSC in HLA identicl siling HSCT in our center. The results suggested tht G BM ws n excellent stem cell source in HLA identicl siling HSCT. Address for correspondence: Lingding Hu, Center of Hemtopoietic Stem Cell Trnsplnttion, 307 Hospitl of People's Liertion Army, Beijing , Chin E-Mil: hulingding@sin.com 20 Chinese Medicl Journl Jnury 5, 2015 Volume 128 Issue 1

2 Methods Ptients A totl of 226 erly stge myeloid leukemi ptients, including de novo cute myelogenous leukemi (AML) (complete remission 1 [CR1]) nd chronic myelogenous leukemi (CML) (chronic phse 1 [CP1]), with HLA identicl siling donor, were enrolled in this study (Mrch 2004 Mrch 2009). Ptients who hve received second trnsplnts/ reduced intensity preprtive regiments were excluded. The min clinicl chrcteristics of ptients t the time of HSCT were listed in Tle 1. 43, 60, nd 123 ptients were enrolled in the G BM, SS BM, nd G PBSC groups, respectively. This study ws pproved y the Ethics Committee of the ffilited hospitl of Acdemy of Militry Medicl Sciences. Informed consents were otined from ll ptients, donors, or their legl gurdins. Tretment In the G PBSC group, donors received G CSF t 8.0 mg kg -1 d -1 divided in two sucutneous injections for 5 consecutive dys (dy 3 to dy +1), nd PBSC ws hrvested on dy 0 nd dy +1. In the G BM group, donors received G CSF t 5.0 mg kg -1 d -1 y single sucutneous injection for 3 consecutive dys (dy 3 to dy 1), nd G BM ws hrvested on dy 0. In the SS BM group, BM ws hrvested t dy 0. BMs ws hrvested from donors sed on trget volume of 20 ml/kg.the stem cells were infused on the sme dy they were collected. The medin totl nucleted cells infused into recipients were /kg (G BM, rnge: /kg), /kg (G PBSC, rnge: /kg), nd /kg (SS BM, rnge: /kg) of recipient weight, respectively. Plsm or red cell depletion of the grfts ws performed if ny ABO incomptiility ws presented efore infusions. Tle 1: Ptient chrcteristics Items G BM SS BM G PBSC P Numer of ptients Sex (mle/femle) Recipients (mle/femle) 29/14 35/25 80/ Donors (mle/femle) 21/22 29/31 61/ Age (yers) Recipients 36 (12-52) 28 (15-45) 35 (14-56) Donors 35 (14-60) 28 (12 v 42) 35 (12-67) Femle donor/mle recipient (%) Dignosis AML CML Conditioning regimen Cy/frctionted TBI (%) SS BM: Stedy stte one mrrow; G PBSC: G peripherl lood stem cell; G BM: G CSF primed one mrrow; AML: Acute myelocytic leukemi; CML: Chronic myelocytic leukemi; TBI: Totl ody irrdition. All recipients received the stndrd preprtive regimen involving cyclophosphmide (60 mg kg -1 d -1 2, dy 4, dy 3) nd totl ody irrdition (TBI) (5 Gy/dy 2, dy 2, dy 1). The GVHD prophylxis included cyclosporin A (CSA) nd the short term methotrexte (MTX). Evlutions nd definitions Neutrophil recovery ws defined s hving occurred fter the first of 3 dys with n solute neutrophil count >500/ml fter the post trnsplnt ndir. Pltelet recovery ws defined s the first of 7 consecutive dys with pltelet count >50,000/ml without pltelet trnsfusions. Acute nd cgvhd (GVHD) were grded y the Settle criteri. [17,18] Trnsplnt relted mortlity (TRM) ws defined s deth from ny cuse except relpse. Leukemi free survivl (LFS) ws defined s the time intervl from trnsplnttion to the first event (either relpse or deth). Overll survivl (OS) ws clculted from the time of trnsplnttion to deth. Sttistic nlysis The cumultive incidence curves of GVHD, TRM, LFS, nd OS were plotted using the Kpln Meier method, nd the long rnk test ws used for independence comprison etween vriles. For ll nlysis, P < 0.05 ws considered s sttisticlly significnt. All sttisticl nlysis ws performed with the SPSS sttistics 20.0 (SPSS Inc., Chicgo, IL, USA). Results Hemtopoietic reconstitution The medin time to neutrophil recovery ws 15 dys (rnge, 11 26), 17 dys (rnge, 13 31), nd 25 dys (rnge, 15 63) in the G PBSC group, the G BM group, nd the SS BM group, respectively [Figure 1]. The medin time to pltelet recovery were 22 dys (rnge, ), 32 dys (rnge, ), nd 47 dys (rnge, ) in the G PBSC group, the G BM group, nd the SS BM group, respectively [Figure 1]. The time to neutrophils nd pltelet engrftment ws significntly different mong ll groups (G PBSC vs. G BM, G PBSC vs. SS BM, G BM vs. SS BM) (P < 0.05). G CSF primed one mrrow reduced the risk of grft versus host disese The cumultive incidences of grde II IV GVHD were (30.4 ± 7.0)%, (26.7 ± 5.9)%, nd (36.2 ± 4.4)% in the Figure 1: Engrftment. () Time to solute neutrophil count recovery ove /L. () Time to pltelets recovery ove /L. Chinese Medicl Journl Jnury 5, 2015 Volume 128 Issue 1 21

3 G BM, SS BM, nd G PBSC group, respectively [Figure 2]. There ws no significnt difference on incidence of GVHD mong these groups (P > 0.05). The cumultive incidence of grde III IV GVHD in the G BM group ([4.7 ± 3.2]%) ws significntly lower thn tht in the SS BM group ([17.5 ± 5.0]%, P < 0.05). There ws tendency of lower frequency of grde III IV GVHD in the G PBSC group compred to SS BM, lthough it ws not sttisticlly significnt ([16.4 ± 3.4]% vs. [17.5 ± 5.0]%, P = 0.058) [Figure 2]. For cgvhd, the cumultive incidence in the G BM group ws similr to tht in the SS BM group ([28.4 ± 7.8]% vs. [34.0 ± 6.9]%, P > 0.01), while there ws significnt differences etween the G BM nd G PBSC group ([28.4 ± 7.80]% vs. [64.4 ± 5.1]%, P < 0.05), nd etween the SS BM nd G PBSC group ([34.0 ± 6.9]% vs. [64.4 ± 5.1]%, P < 0.05) [Figure 2c]. Similr ptterns were oserved when the cumultive incidences of extensive cgvhd were nlyzed (G BM vs. G PBSC: [11.8 ± 5.6]% vs. [42.7 ± 5.1]%, P < 0.05; G BM vs. SS BM: [11.8 ± 5.6]% vs. [21.7 ± 6.1]%, P < 0.05) [Figure 2d]. G CSF primed one mrrow incresed the survivl rtes The OS rte in the G BM group nd the G PBSC group were (76.3 ± 6.6)% nd (70.3 ± 4.6)%, respectively. Both were significntly higher thn the SS BM group ([45.1 ± 6.6]%, P < 0.05) [Figure 3]. The incidences of LFS in the G BM nd G PBSC were (68.7 ± 7.2)% nd (68.9 ± 4.7)%, oth were significntly higher thn tht in the SS BM group ([45.3 ± 6.6]%, P < 0.05) [Figure 3]. The cumultive incidence of TRM in the SS BM group ws (41.2 ± 6.7)%, which ws significntly higher thn tht in the G PBSC nd the G BM groups ([19.0 ± 3.9]%, P < 0.05; [12.0 ± 5.0]%, P < 0.05) [Figure 3c]. However, there were no significnt differences in leukemi relpse rtes etween ny two groups (G BM, [23.9 ± 7.0]%; G PBSC, [20.3 ± 4.4]%; SS BM, [24.0 ± 7.0]%) (P > 0.1) [Figure 3d]. Tle 2 shows the cuses of deth in ech group. A totl of 33 of 60 ptients (55%) died due to vriety of fctors (leukemi relpse, GVHD, infections, interstitil pneumoni/idiopthic pneumoni syndrome, grft rejection, etc.) in the SS BM group. In contrst, only 25.6% (11/43) of the G BM group nd 26.0% (32/123) of the G PBSC group died due to the sme resons. Menwhile, there ws no significnt difference etween AML nd CML on OS ([59.8 ± 5.0]% versus [67.7 ± 4.7]%, P > 0.05), LFS ([57.3 ± 5.1]% vs. [66.0 ± 4.8]%, P > 0.05), nd TRM ([23.7 ± 4.4]% versus [24.1 ± 4.4]%, P > 0.05). However, AML is ssocited with more leukemi relpse compred to CML ([27.7 ± 5.1]% versus [16.4 ± 4.2]%, P < 0.05). Discussion Stedy stte one mrrow, G PBSC, nd G BM re the min stem cell sources in llogeneic HSCT. A numer of groups hve reported on the clinicl outcomes of ptients who received G BM, G PBSC, or SS BM during HLA identicl siling HSCT. [7 16] These studies show tht G BM nd G PBSC resulted in significntly fster neutrophil nd pltelet recovery thn SS BM, which is consistent with the results presented here. However, previous studies indicted tht G BM ppered to hve no dvntge in survivls when compred to SS BM. [7 9] In this study, compred with ptients treted with SS BM, those ptients who were treted with G BM nd G PBSC c d Figure 2: Cumultive incidence of grft-versus-host disese (GVHD). () Grdes II IV cute GVHD. () Grdes III IV cute GVHD. (c) Chronic GVHD. (d) Extensive chronic GVHD. 22 c d Figure 3: Survivl of the entire cohort y therpy. () Overll survivl. () Leukemi-free survivl. (c) Trnsplnt-relted mortlity. (d) Leukemi relpse. Chinese Medicl Journl Jnury 5, 2015 Volume 128 Issue 1

4 Tle 2: Cuses of deth Items G BM (n = 43) SS BM (n = 60) G PBSC (n = 123) Leukemi relpse GVHD (or with infections) cgvhd Infections Interstitil pneumoni/ idiopthic pneumoni syndrome Grft rejection HVOD Cererl hemorrhge Orgn dysfunction Gstric cncer Hemocytolysis Asthm Heptitis B Totl (n (%)) 11 (25.6) 33 (55.0) 32 (26.0) GVHD: Acute grft versus host disese; cgvhd: Chronic grft versus host disese; HVOD: Heptic veno occlusive disese; G PBSC: G peripherl lood stem cell; G BM: G CSF primed one mrrow. hd significntly higher OS [Figure 3] nd LFS [Figure 3]. As to TRM nd III IV grde GVHD, the incidences of ptients treted with G BM were significntly lower chnce to develop GVHD nd greter chnce of survivl thn those treted with SS BM [Figure 2 nd ]. Interestingly, G BM could significntly decrese the incidences of cgvhd nd extensive cgvhd, compred with G PBSC [Figures 2c nd d], which ws consistent with previous study. [13] However, G BM did not increse the incidences of leukemi relpse [Figure 2d]. These results clerly indicted tht G BM shred the dvntges of oth G PBSC nd SS BM, which ws chrcterized y fst engrftment, low incidences of very severe GVHD/cGVHD/TRM, nd high incidences of LFS/OS. This report ws the first study tht included ll three min stem cell sources (G BM, G PBSC, SS BM), nd we concluded tht G BM ws n excellent stem cell source for HLA identicl siling HSCT. Mny groups hve compred the different clinicl outcomes of G BM with SS BM or G PBSC in HLA identicl siling HSCT, [7 13,15,19] however, the results hve een very controversil, especilly regrding the OS. Our study indicted tht G BM ws superior to SS BM nd G PBSC, nd tht significnt improvement in OS ws oserved in the G BM group. The vrinces might e cused y severl fctors. First ws the numer of the enrolled ptient nd the follow up durtions. Previous reports studied fewer ptients (22, 48, nd 50 ptients) with shorter follow up durtion (the medin time <12 months). [7 9] We hve conducted the current study with more ptients (226) nd longer follow up time (medin time, G BM: 60 months; G PBSC: 30 months; SS BM: 40 months), which could rech sufficient sttisticl power. The second ws the G CSF priming schedules. Previous studies hve shown tht G CSF stimultion cused fold increse in CD34 + cell count, 3 fold increse in colony forming cells, nd fold increse in short term repopulting cells in G BM, when compred to SS BM. [20] However, different priming schedules (doses nd durtion of G CSF dministrtion) might cuse controversil results regrding the engrftment cpility of G BM, [21,22] which would in turn cuse different tretment outcomes. The priming schedules in previous studies were very diverse. [10 13,15,19] The dose of G CSF for BM priming rnged from 5 µg kg -1 d -1 to 12.1 µg kg -1 d -1 nd the length of G CSF tretment rnged from 2 to 5 dys. In the present study, ll donors received uniformed G CSF priming schedule, which ws 5.0 µg kg -1 d -1 for 3 consecutive dys. In ddition, the disese sttus efore the trnsplnttion would hve n impct on the outcome. To rule out the interference of disese sttus, we only included ptients with de novo AML (CR1) nd CML (CP1). We found tht AML ptients hd higher leukemi relpse rtes thn CML, which suggested tht different underlying disese efore trnsplnttion might ply role in the tretment effect of HSCT. Finlly, the preprtive regimens, the GVHD prophylxis, nd the supportive cre might ply role in the outcome. We used the clssic Cy routine comined with frctionted TBI s preprtive regimens nd stndrd CSA plus short term MTX s prophylctic mesures to prevent GVHD in ll ptients. The uniform mngement could reduce the interferences of these fctors nd give more credile results. Further investigtion is needed to ddress how these fctors influenced the tretment effects in HSCT. Despite the vilility of mny new immune suppressive drugs nd ntiodies, GVHD still remined the most serious complictions in HSCT. To otin the optiml results, we need to decrese the GVHD while enhnce the grft versus leukemi (GVL) effect. To effect, lot of pproches hve een developed to minimize the GVHD, such s the depletion of T cells in vitro nd in vivo, nd the introduction of suicide gene into T cells. [23,24] These pproches could decrese the incidence of GVHD, ut the lower GVHD rtes might e due to using of nti thymocyte gloulin, depletion of T cells, or other fctors. In this study, we found tht the GVL effect in G BM ws superior to G PBSC nd SS BM. As presented in this study, G BM could remrkly lower the risk of GVHD (III IV grde GVHD, cgvhd, extensive cgvhd), nd ccordingly improve the survivl. However, the incidence of leukemi relpse did not increse, suggesting tht G BM might e n lterntive wy to enhnce GVL effect nd lower the risk of GVHD. Menwhile, the use of G BM in HSCT might e simple nd low prices pproch to seprte GVHD nd GVL effects which did not require dditionl immunosuppression drugs or specil mesurements. This ws the first retrospective report on HLA identicl siling HSCT tht ws conducted in single center with ll three min grfts (G BM, G PBSC, SS BM). Compred with previous studies, the overll clinicl outcomes of G BM, G PBSC, nd SS BM in this study might e more credile ecuse the numer of ptients ws higher nd the tretments (preprtive Chinese Medicl Journl Jnury 5, 2015 Volume 128 Issue 1 23

5 regimens, GVHD prophylxis, nd supportive cre) were uniform. Recently, phse 3, rndomized tril compring G BM nd SS BM is ongoing, [15] nd nother rndomized multicenter study compring G PBSC nd G BM in ptients receiving HLA identicl siling HSCT is lso eing conducted in Cnd. [25] Although the corresponding results re not relesed yet, we elieve tht these studies will further illuminte the dvntges of G BM in HSCT. This study hs severl limittions including the retrospective nture, the heterogeneous ptient cohorts, nd lcking of moleculr typing. However, the results re remrkle ecuse of comprtively lrge numer of ptients with long follow up s well s uniform dt collection. In summry, our study hs provided sufficient dt to conclude tht G BM is n excellent stem cell source in HLA identicl siling HSCT. G BM trnsplnt is chrcterized y fst engrftment, low incidence of severe GVHD/cGVHD, nd improved survivl. We recommend G BM rther thn G PBSC or SS BM for ptients receiving HLA identicl siling HSCT. Menwhile, G BM is potentilly good stem cell source in unrelted nd hploidenticl HSCT, which need to e further investigted in the future. References 1. Arcese W, Avers F, Bndini G, De Vincentiis A, Fld M, Lnt L, et l. Clinicl use of llogeneic hemtopoietic stem cells from sources other thn one mrrow. Hemtologic 1998;83: Schmitz N, Beksc M, Hsenclever D, Bciglupo A, Ruutu T, Ngler A, et l. Trnsplnttion of moilized peripherl lood cells to HLA identicl silings with stndrd risk leukemi. Blood 2002;100: Storek J, Gooley T, Sidk M, Bensinger WI, Mloney DG, Chuncey TR, et l. Allogeneic peripherl lood stem cell trnsplnttion my e ssocited with high risk of chronic grft versus host disese. Blood 1997;90: Wller EK, Logn BR, Hrris WA, Devine SM, Porter DL, Mineishi S, et l. Improved survivl fter trnsplnttion of more donor plsmcytoid dendritic or nïve T cells from unrelted donor mrrow grfts: Results from BMTCTN J Clin Oncol 2014;32: Mo XD, Xu LP, Zhng XH, Liu DH, Wng Y, Chen H, et l. 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Clin Trnsplnt 2011;25: Received: Edited y: Limin Chen How to cite this rticle: Li Y, Jing M, Xu C, Chen J, Li B, Wng J, et l. Grnulocyte Colony-stimulting Fctor-primed Bone Mrrow: An Excellent Stem-cell Source for Trnsplnttion in Acute Myelocytic Leukemi nd Chronic Myelocytic Leukemi. Chin Med J 2015;128:20-4. Source of Support: Nil. Conflict of Interest: None declred. Chinese Medicl Journl Jnury 5, 2015 Volume 128 Issue 1