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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2021, Vol. 15 Issue (1) : 108-115    https://doi.org/10.1007/s11684-019-0730-8
RESEARCH ARTICLE
Fludarabine and intravenous busulfan conditioning with post-transplantation cyclophosphamide for allogeneic peripheral stem cell transplantation for adult patients with lymphoid malignancies: a prospective single-arm phase II study
Ling Wang, Lining Wang, Xing Fan, Wei Tang, Jiong Hu()
Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Abstract

Post-transplantation cyclophosphamide (PT-Cy) alone or in combination with other immunosuppressive drugs has emerged as a promising strategy in the setting of allogeneic hematopoietic stem cell transplantation. Improved survival rate was reported in lymphoid malignancies following PT-Cy strategy compared with myeloid disease in non-myeloablative bone marrow transplant setting. Thus, we aimed to evaluate the safety and efficacy of PT-Cy combined with cyclosporine as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and T cell-replete peripheral stem cell transplantation in lymphoid malignancies. This single-arm phase II clinical trial (NCT01435447) involving 31 adult patients was conducted from January 2013 to June 2018. The donor-type neutrophil engraftment rate was 100%, and the overall incidence of grade II to IV and grade III to IV acute GVHD was 39% and 24%, respectively. The cumulative incidence rates of chronic GVHD (35%), including moderate to severe forms (10%), were reduced compared with those of the historical group (P=0.03 and P=0.04, respectively). With a median follow-up of 18 months, the estimated 2-year overall and event-free survival was 64.8% (95% confidence interval: 47.8%–86.7%) and 58.4% (95% CI: 41.9%–81.7%), respectively. The 2-year cumulative incidence rate of relapse was 19.5% (95% CI: 9.0%–35.8%), whereas the non-relapse mortality rate was 21.8% (95% CI: 11.3%–38.1%). These results demonstrated the feasibility of PT-Cy as GVHD prophylaxis in this clinical setting. This strategy could significantly reduce the incidence of chronic GVHD and its moderate to severe forms but not of acute GVHD and results in similar survival outcomes compared with the historical group. A prospective study with additional patients is warranted to confirm the role of PT-Cy in lymphoid malignancy.
Keywords post-transplantation cyclophosphamide      allogeneic hematopoietic stem cell transplantation      lymphoid malignancies     
Corresponding Author(s): Jiong Hu   
Just Accepted Date: 09 April 2020   Online First Date: 12 June 2020    Issue Date: 11 February 2021
 Cite this article:   
Ling Wang,Lining Wang,Xing Fan, et al. Fludarabine and intravenous busulfan conditioning with post-transplantation cyclophosphamide for allogeneic peripheral stem cell transplantation for adult patients with lymphoid malignancies: a prospective single-arm phase II study[J]. Front. Med., 2021, 15(1): 108-115.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0730-8
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I1/108
PT-Cy Historical group P value
No. of patients 31 48
Median follow-up (month) 18 (3.5−60) 39 (3.0–108) <0.001
Age (year, median, range)) 30 (18–57) 23 (16–49) 0.38
Sex 0.63
Male 21 (67.7%) 30 (62.5%)
Female 10 (32.3%) 18 (37.5%)
Diagnosis 0.96
ALL 25 (80.6%) 43 (89.6%)
Ph− ALL 17 33
Ph+ ALL 8 10
Lymphoid malignancies 6 (19.4%) 5 (10.4%)
PTCL 1 1
ALCL 1 1
NK/T cell lymphoma 2 0
DLBCL 2 2
HD 0 1
Disease status 0.58
CR1 27 (87.1%) 41 (85.4%)
PR/CR2 or beyond 4a (12.9%) 7b (14.6%)
Donor type
MSD 18 (58.1%) 20 (41.7%) <0.001
MUD 10 (32.3%) 28 (58.3%)
Haplo 3 (9.6%) 0
Graft source
PBSC 31 (100%) 45 (93.7%) 0.16
Bone marrow 0 3 (6.3%)
Conditioning
Flu-Bu4 31 (100%) 0 <0.001
Bu4-Cy 0 48 (100%)
GVHD prophylaxis
PT-Cy+ CsA 31 (100%) 0 <0.001
CsA+ MTX+ MMF±ATG 0 48 (100%)
Tab.1  Patient characteristics of the study group and compared with those of the historical group
PT-Cy Historical group P value
2-year OS 64.8%±9.7% 59.0%±7.3% 0.93
2-year EFS 58.4%±6.7% 57.8%±7.2% 0.96
2-year NRM 21.8%±6.7% 12.9%±5.8% 0.34
2-year CIR 19.5%±6.7% 33.0%±3.4% 0.27
aGVHD
II–IV aGVHD 39.0%±8.8% 40.4%±7.2% 0.88
III–IV aGVHD 23.6%±7.6% 10.6%±4.6% 0.14
cGVHD
cGVHD 35.4%±9.5% 65.1%±8.0% 0.03
moderate/severe cGVHD 10.1%±6.8% 33.6%±9.1% 0.04
2-year GRFS 42.0%±9.7% 33.1%±6.8% 0.78
Tab.2  Transplantation outcomes of patients in the study group and compared with those in the historical group
Fig.1  (A) Kaplan–Meier curves with 95% confidence bounds for overall survival. (B) Kaplan–Meier curves with 95% confidence bounds for event-free survival. (C) Cumulative incidence of relapse and non-relapse mortality.
MSD (n = 18) Non-MSD group* (n = 13) P value
2-year OS 61.6%±12.6% 70.1%±14.7% 0.94
2-year EFS 57.8%±12.4% 60.6%±15.7% 0.98
2-year NRM 12.9%±8.9% 28.9%±14.7% 0.57
2-year CIR 26.1%±13.3% 13.0%±9.5% 0.45
aGVHD
II–IV aGVHD 25.6%±9.9% 63.6%±14.5% 0.02
III–IV aGVHD 11.2%±7.4% 23.8%±14.8% 0.79
cGVHD
cGVHD 25.8%±11.2% 50.0%±15.8% 0.28
moderate/severe cGVHD 0 35.2%±16.5% 0.029
2-year GRFS 50.0%±15.8% 38.9%±11.8% 0.81
Tab.3  Effect of donor type on treatment outcome
1 L Hill, A Alousi, P Kebriaei, R Mehta, K Rezvani, E Shpall. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol 2018; 9(1): 21–46
https://doi.org/10.1177/2040620717741860 pmid: 29317998
2 C Garnett, JF Apperley, J Pavlů. Treatment and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol 2013; 4(6): 366–378
https://doi.org/10.1177/2040620713489842 pmid: 24319572
3 L Luznik, EJ Fuchs. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 2010; 47(1-3): 65–77
https://doi.org/10.1007/s12026-009-8139-0 pmid: 20066512
4 TM Robinson, PV O’Donnell, EJ Fuchs, L Luznik. Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide. Semin Hematol 2016; 53(2): 90–97
https://doi.org/10.1053/j.seminhematol.2016.01.005 pmid: 27000732
5 SR McCurdy, YL Kasamon, CG Kanakry, J Bolaños-Meade, HL Tsai, MM Showel, JA Kanakry, HJ Symons, I Gojo, BD Smith, MP Bettinotti, WH Matsui, AE Dezern, CA Huff, I Borrello, KW Pratz, DE Gladstone, LJ Swinnen, RA Brodsky, MJ Levis, RF Ambinder, EJ Fuchs, GL Rosner, RJ Jones, L Luznik. Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. Haematologica 2017; 102(2): 391–400
https://doi.org/10.3324/haematol.2016.144139 pmid: 27846611
6 L Luznik, PV O’Donnell, HJ Symons, AR Chen, MS Leffell, M Zahurak, TA Gooley, S Piantadosi, M Kaup, RF Ambinder, CA Huff, W Matsui, J Bolaños-Meade, I Borrello, JD Powell, E Harrington, S Warnock, M Flowers, RA Brodsky, BM Sandmaier, RF Storb, RJ Jones, EJ Fuchs. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14(6): 641–650
https://doi.org/10.1016/j.bbmt.2008.03.005 pmid: 18489989
7 RH Collins Jr, S Goldstein, S Giralt, J Levine, D Porter, W Drobyski, J Barrett, M Johnson, A Kirk, M Horowitz, P Parker. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant 2000; 26(5): 511–516
https://doi.org/10.1038/sj.bmt.1702555 pmid: 11019840
8 F Dazzi, C Fozza. Disease relapse after haematopoietic stem cell transplantation: risk factors and treatment. Best Pract Res Clin Haematol 2007; 20(2): 311–327
https://doi.org/10.1016/j.beha.2006.10.002 pmid: 17448964
9 W Tang, L Wang, WL Zhao, YB Chen, ZX Shen, J Hu. Intravenous busulfan-cyclophosphamide as a preparative regimen before allogeneic hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2011; 17(10): 1555–1561
https://doi.org/10.1016/j.bbmt.2011.04.003 pmid: 21549217
10 H Glucksberg, R Storb, A Fefer, CD Buckner, PE Neiman, RA Clift, KG Lerner, ED Thomas. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18(4): 295–304
https://doi.org/10.1097/00007890-197410000-00001 pmid: 4153799
11 MH Jagasia, HT Greinix, M Arora, KM Williams, D Wolff, EW Cowen, J Palmer, D Weisdorf, NS Treister, GS Cheng, H Kerr, P Stratton, RF Duarte, GB McDonald, Y Inamoto, A Vigorito, S Arai, MB Datiles, D Jacobsohn, T Heller, CL Kitko, SA Mitchell, PJ Martin, H Shulman, RS Wu, CS Cutler, GB Vogelsang, SJ Lee, SZ Pavletic, ME Flowers. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant 2015; 21(3): 389–401.e1
https://doi.org/10.1016/j.bbmt.2014.12.001 pmid: 25529383
12 National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0; NIH publication #09–7473. Published May 29, 2009; Revised Version 4.03 June 14, 2010
13 EL Kaplan, P Meier. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53(282): 457–481
https://doi.org/10.1080/01621459.1958.10501452
14 TA Gooley, W Leisenring, J Crowley, BE Storer. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18(6): 695–706
https://doi.org/10.1002/(SICI)1097-0258(19990330)18:6<695::AID-SIM60>3.0.CO;2-O pmid: 10204198
15 A Ruggeri, M Labopin, A Bacigalupo, B Afanasyev, JJ Cornelissen, A Elmaagacli, M Itälä-Remes, D Blaise, E Meijer, Y Koc, N Milpied, HC Schouten, N Kroeger, M Mohty, A Nagler. Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. J Hematol Oncol 2018; 11(1): 40
https://doi.org/10.1186/s13045-018-0586-4 pmid: 29544522
16 GR Hill, JLM Ferrara. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000; 95(9): 2754–2759
https://doi.org/10.1182/blood.V95.9.2754.009k25_2754_2759 pmid: 10779417
17 ME Horwitz. Reduced intensity versus myeloablative allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, myelodysplastic syndrome and acute lymphoid leukemia. Curr Opin Oncol 2011; 23(2): 197–202
https://doi.org/10.1097/CCO.0b013e328342b82a pmid: 21252669
18 SF Abdul Wahid, NA Ismail, MR Mohd-Idris, FW Jamaluddin, N Tumian, EY Sze-Wei, N Muhammad, ML Nai. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev 2014; 23(21): 2535–2552
https://doi.org/10.1089/scd.2014.0123 pmid: 25072307
19 T Pagliardini, S Harbi, S Fürst, L Castagna, F Legrand, C Faucher, A Granata, PJ Weiller, B Calmels, C Lemarie, C Chabannon, R Bouabdallah, D Mokart, N Vey, D Blaise, R Devillier. Post-transplantation cyclophosphamide-based haploidentical versus ATG-based unrelated donor allogeneic stem cell transplantation for patients younger than 60 years with hematological malignancies: a single-center experience of 209 patients. Bone Marrow Transplant 2019; 54(7): 1067–1076
https://doi.org/10.1038/s41409-018-0387-y pmid: 30401970
20 R Devillier, A Granata, S Fürst, S Harbi, C Faucher, PJ Weiller, C Chabannon, L Castagna, D Blaise. Low incidence of chronic GVHD after HLA-haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in older patients. Br J Haematol 2017; 176(1): 132–135
https://doi.org/10.1111/bjh.13923 pmid: 27073182
21 L Luznik, J Bolaños-Meade, M Zahurak, AR Chen, BD Smith, R Brodsky, CA Huff, I Borrello, W Matsui, JD Powell, Y Kasamon, SN Goodman, A Hess, HI Levitsky, RF Ambinder, RJ Jones, EJ Fuchs. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood 2010; 115(16): 3224–3230
https://doi.org/10.1182/blood-2009-11-251595 pmid: 20124511
22 CG Kanakry, PV O’Donnell, T Furlong, MJ de Lima, W Wei, M Medeot, M Mielcarek, RE Champlin, RJ Jones, PF Thall, BS Andersson, L Luznik. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 2014; 32(31): 3497–3505
https://doi.org/10.1200/JCO.2013.54.0625 pmid: 25267759
23 M Mielcarek, T Furlong, PV O’Donnell, BE Storer, JS McCune, R Storb, PA Carpenter, ME Flowers, FR Appelbaum, PJ Martin. Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood 2016; 127(11): 1502–1508
https://doi.org/10.1182/blood-2015-10-672071 pmid: 26764356
24 AD Law, MQ Salas, W Lam, FV Michelis, S Thyagu, DDH Kim, JH Lipton, R Kumar, H Messner, A Viswabandya. Reduced-intensity conditioning and dual T lymphocyte suppression with antithymocyte globulin and post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical hematopoietic stem cell transplants for hematological malignancies. Biol Blood Marrow Transplant 2018; 24(11): 2259–2264
https://doi.org/10.1016/j.bbmt.2018.07.008 pmid: 30009980
25 IS Moiseev, OV Pirogova, AL Alyanski, EV Babenko, TL Gindina, EI Darskaya, OA Slesarchuk, SN Bondarenko, BV Afanasyev. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transplant 2016; 22(6): 1037–1042
https://doi.org/10.1016/j.bbmt.2016.03.004 pmid: 26970381
26 F Carnevale-Schianca, D Caravelli, S Gallo, V Coha, L D’Ambrosio, E Vassallo, M Fizzotti, F Nesi, L Gioeni, M Berger, A Polo, L Gammaitoni, P Becco, L Giraudo, M Mangioni, D Sangiolo, G Grignani, D Rota-Scalabrini, A Sottile, F Fagioli, M Aglietta. Post-transplant cyclophosphamide and tacrolimus–mycophenolate mofetil combination prevents graft-versus-host disease in allogeneic peripheral blood hematopoietic cell transplantation from HLA-matched donors. Biol Blood Marrow Transplant 2017; 23(3): 459–466
https://doi.org/10.1016/j.bbmt.2016.12.636 pmid: 28039079
27 X He, Y Ye, X Xu, J Wang, Y Huang, G Weng, M Zhang, K Guo. Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide is associated with lower aGVHD and higher survival but more extensive and long standing bone marrow damage. BioMed Res Int 2016; 2016: 3071214
https://doi.org/10.1155/2016/3071214 pmid: 27843940
28 T Czerw, M Labopin, S Giebel, G Socié, L Volin, N Fegueux, T Masszi, D Blaise, S Chaganti, JJ Cornelissen, J Passweg, J Maertens, M Itälä-Remes, D Wu, M Mohty, A Nagler. Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT. Cancer 2018; 124(12): 2523–2533
https://doi.org/10.1002/cncr.31354 pmid: 29603136
29 N Kekre, JH Antin. ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint. Blood Adv 2017; 1(9): 573–576
https://doi.org/10.1182/bloodadvances.2016001552 pmid: 29296977
30 K Sayehmiri, KV Carson, S Bakhtiyari, S Shokouhi, K Alimoghadam. Effects of aGVHD and cGVHD according to relapse status on survival rate in patients with acute lymphocytic leukemia. Hematology 2014; 19(8): 441–447
https://doi.org/10.1179/1607845414Y.0000000151 pmid: 24620946
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