title: Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.
abstract: BACKGROUND
  Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant disorders. In the past two decades, peripheral blood stem cells replaced bone marrow as stem cell source due to faster engraftment and practicability. Previous meta-analyses analysed patients treated from 1990 to 2002 and demonstrated no impact of the stem cell source on overall survival, but a greater risk for graft-versus-host disease (GvHD) in peripheral blood transplants. As transplant indications and conditioning regimens continue to change, whether the choice of the stem cell source has an impact on transplant outcomes remains to be determined.
  
  
  OBJECTIVE
  To assess the effect of bone marrow versus peripheral blood stem cell transplantation in adult patients with haematological malignancies with regard to overall survival, incidence of relapse and non-relapse mortality, disease-free survival, transplant-related mortality, incidence of GvHD and time to engraftment.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (from 1948 to February 2014), trial registries and conference proceedings. The search was conducted in October 2011 and was last updated in February 2014. We did not apply any language restrictions.
  
  
  METHODS
  We included randomised controlled trials (RCTs) comparing bone marrow and peripheral blood allogeneic stem cell transplantation in adults with haematological malignancies.
  
  
  METHODS
  Two review authors screened abstracts and extracted and analysed data independently. We contacted study authors for additional information. We used the standard methodological procedures expected by The Cochrane Collaboration.
  
  
  RESULTS
  We included nine RCTs that met the pre-defined selection criteria, involving a total of 1521 participants. Quality of data reporting was heterogeneous among the studies. Overall, the risk of bias in the included studies was low.For the primary outcome overall survival, our analysis demonstrated comparable results between bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) (six studies, 1330 participants; hazard ratio (HR) 1.07; 95% CI 0.91 to 1.25; P value = 0.43; high-quality evidence).Disease-free survival (six studies, 1225 participants; HR 1.04; 95% CI 0.89 to 1.21; P value = 0.6; moderate-quality of evidence) and non-relapse or transplant-related mortality (three studies, 758 participants; HR 0.98; 95% CI 0.76 to 1.28; P = 0.91; high-quality evidence) were also comparable between transplantation arms.In the related-donor setting, data from two of eight studies with 211 participants (21%) indicated a higher relapse incidence in participants transplanted with bone marrow stem cells rather than peripheral blood stem cells (HR 2.73; 95% CI 1.47 to 5.08; P value = 0.001). There was no clear evidence of a difference in relapse incidence between transplantation groups in unrelated donors (HR 1.07; 95% CI 0.78 to 1.47; P value = 0.66). The difference between the donor-related and -unrelated subgroups (P-value = 0.008) was considered to be statistically significant.BMT was associated with lower rates of overall and extensive chronic GvHD than PBSCT (overall chronic GvHD: four studies, 1121 participants; HR 0.72; 95% CI 0.61 to 0.85; P value = 0.0001, extensive chronic GvHD: four studies, 765 participants; HR 0.69; 95% CI 0.54 to 0.9; P value = 0.006; moderate-quality evidence for both outcomes). The incidence of acute GvHD grades II to IV was not lower (six studies, 1330 participants; HR 1.03; 95% CI 0.89 to 1.21; P value = 0.67; moderate-quality evidence), but there was a trend for a lower incidence of grades III and IV acute GvHD with BMT than with PBSCT (three studies, 925 participants; HR 0.75; 95% CI 0.55 to 1.02; P value = 0.07; moderate-quality evidence).Times to neutrophil and platelet engraftment were longer with BMT than with PBSCT (neutrophil: five studies, 662 participants; HR 1.96; 95% CI 1.64 to 2.35; P value < 0.00001; platelet: four studies, 333 participants; HR 2.17; 95% CI 1.69 to 2.78; P value < 0.00001).
  
  
  CONCLUSIONS
  This systematic review  found high-quality evidence that overall survival following allo-HSCT using the current clinical standard stem cell source - peripheral blood stem cells - was similar to that following allo-HSCT using bone marrow stem cells in adults with haematological malignancies. We found moderate-quality evidence that PBSCT was associated with faster engraftment of neutrophils and platelets, but a higher risk of GvHD (in terms of more overall and extensive chronic GvHD). There was an imprecise effect on relapse and on severe (grades III to IV) acute GvHD. Quality of life, which is severely affected by GvHD, was not evaluated.Against the background of transplantation practices that have clearly changed over the past 10 to 15 years, our aim was to provide current data on the best stem cell source for allo-HSCT, by including the results of recently conducted trials. Our review includes participants recruited up to 2009, a proportion of whom were older, had received reduced-intensity conditioning regimens or had been transplanted with stem cells from unrelated donors. However, only one, large, study included relatively recently treated participants. Nevertheless, our findings are comparable to those of previous meta-analyses suggesting that our results hold true for today's practice.
authors.affiliation: Department I of Internal Medicine, Stem Cell Transplantation Program, University Hospital of Cologne, Cologne, Germany, 50924.
authors.forename: Udo
authors.initials: U
authors.lastname: Holtick
authors.forename: Melanie
authors.initials: M
authors.lastname: Albrecht
authors.forename: Jens M
authors.initials: JM
authors.lastname: Chemnitz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
authors.forename: Christof
authors.initials: C
authors.lastname: Scheid
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
mesh_terms: D000328:Adult; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000401:mortality; D006086:Graft vs Host Disease / Q000209:etiology*; D019337:Hematologic Neoplasms / Q000401:mortality / Q000601:surgery*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000401:mortality; D006801:Humans; D009928:Organ Specificity; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence
references.citation: Biol Blood Marrow Transplant. 2005 Feb;11(2):85-92
references.pmid: 15682068
references.citation: Biol Blood Marrow Transplant. 2009 Nov;15(11):1415-21
references.pmid: 19822301
references.citation: Transpl Infect Dis. 2003 Dec;5(4):167-73
references.pmid: 14987200
references.citation: Bone Marrow Transplant. 2003 Aug;32(3):257-64
references.pmid: 12858196
references.citation: Bone Marrow Transplant. 2003 Nov;32(9):873-80
references.pmid: 14561987
references.citation: Bone Marrow Transplant. 1999 Aug;24(4):355-8
references.pmid: 10467322
references.citation: Bone Marrow Transplant. 2006 Oct;38(8):539-46
references.pmid: 16953207
references.citation: Bone Marrow Transplant. 2007 Jan;39(2):71-87
references.pmid: 17213849
references.citation: N Engl J Med. 2001 Dec 20;345(25):1794-800
references.pmid: 11752355
references.citation: J Clin Epidemiol. 2009 Oct;62(10):1006-12
references.pmid: 19631508
references.citation: Biol Blood Marrow Transplant. 2013 Sep;19(9):1374-80
references.pmid: 23791626
references.citation: Curr Opin Oncol. 2012 Mar;24(2):191-6
references.pmid: 22185938
references.citation: J Clin Oncol. 2000 Feb;18(3):537-46
references.pmid: 10653869
references.citation: Bone Marrow Transplant. 1998 Dec;22(12):1145-51
references.pmid: 9894716
references.citation: J Clin Oncol. 2005 Aug 1;23(22):5074-87
references.pmid: 16051954
references.citation: Lancet. 2009 May 2;373(9674):1550-61
references.pmid: 19282026
references.citation: Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56
references.pmid: 16338616
references.citation: Bone Marrow Transplant. 2009 Feb;43(4):275-91
references.pmid: 19169283
references.citation: Biol Blood Marrow Transplant. 2007 Dec;13(12):1461-8
references.pmid: 18022576
references.citation: Haematologica. 2005 Jan;90(1):86-93
references.pmid: 15642674
references.citation: Cochrane Database Syst Rev. 2009 Jan 21;(1):CD006406
references.pmid: 19160282
references.citation: Bone Marrow Transplant. 2010 Jan;45(1):1-11
references.pmid: 19946340
references.citation: Nat Rev Cancer. 2010 Mar;10(3):213-21
references.pmid: 20168320
references.citation: Ann Hematol. 2012 Mar;91(3):427-37
references.pmid: 21789620
references.citation: Trials. 2007 Jun 07;8:16
references.pmid: 17555582
references.citation: Haematologica. 2013 Aug;98(8):1282-90
references.pmid: 23508009
references.citation: Semin Hematol. 2012 Jan;49(1):104-9
references.pmid: 22221790
references.citation: Br J Haematol. 2007 Apr;137(1):77-8; author reply 79-80
references.pmid: 17359373
references.citation: Br J Haematol. 2009 Dec;147(5):614-33
references.pmid: 19735262
references.citation: J Intern Med. 2012 Nov;272(5):472-83
references.pmid: 22519980
references.citation: Blood. 2002 Nov 1;100(9):3128-34
references.pmid: 12384409
references.citation: Blood. 2002 Jul 15;100(2):415-9
references.pmid: 12091330
references.citation: Biol Blood Marrow Transplant. 2012 Nov;18(11):1727-33
references.pmid: 22766220
references.citation: Haematologica. 2001 Jun;86(6):665-6
references.pmid: 11418381
references.citation: Blood. 2001 Dec 1;98(12):3186-91
references.pmid: 11719353
references.citation: Transfus Apher Sci. 2003 Aug;29(1):53-9
references.pmid: 12877895
references.citation: Haematologica. 2012 Aug;97(8):1142-8
references.pmid: 22315497
references.citation: JAMA. 2011 Nov 2;306(17):1874-83
references.pmid: 22045765
references.citation: Am J Clin Oncol. 2009 Dec;32(6):618-28
references.pmid: 19593085
references.citation: Lancet Oncol. 2010 Apr;11(4):331-8
references.pmid: 20117965
references.citation: N Engl J Med. 2012 Oct 18;367(16):1487-96
references.pmid: 23075175
references.citation: Transplantation. 1974 Oct;18(4):295-304
references.pmid: 4153799
references.citation: Blood. 2001 Jun 1;97(11):3380-9
references.pmid: 11369627
references.citation: Blood. 2012 Mar 15;119(11):2675-8
references.pmid: 22308289
references.citation: Blood. 2009 Jul 2;114(1):7-19
references.pmid: 19336756
references.citation: Biol Blood Marrow Transplant. 2012 Sep;18(9):1422-9
references.pmid: 22446014
references.citation: Blood. 2002 Sep 1;100(5):1525-31
references.pmid: 12176866
references.citation: Lancet. 2000 Apr 8;355(9211):1231-7
references.pmid: 10770306
references.citation: Blood Rev. 2006 Jan;20(1):15-27
references.pmid: 16426941
references.citation: Bone Marrow Transplant. 2011 Apr;46(4):485-501
references.pmid: 21358689
references.citation: N Engl J Med. 2001 Jan 18;344(3):175-81
references.pmid: 11172139
references.citation: Leukemia. 2012 Apr;26(4):746-56
references.pmid: 21926960
references.citation: Transfusion. 2001 Feb;41(2):190-5
references.pmid: 11239221
references.citation: Expert Rev Hematol. 2013 Feb;6(1):103-7
references.pmid: 23373785
references.citation: Blood. 2000 Jun 15;95(12):3702-9
references.pmid: 10845900
references.citation: Haematologica. 2002 Dec;87(12):1281-5
references.pmid: 12495902
references.citation: N Engl J Med. 2007 Oct 11;357(15):1472-5
references.pmid: 17928594
references.citation: Stat Med. 1998 Dec 30;17(24):2815-34
references.pmid: 9921604
references.citation: Exp Hematol. 2003 Oct;31(10):855-64
references.pmid: 14550800
references.citation: Curr Opin Immunol. 2006 Oct;18(5):565-70
references.pmid: 16893632
references.citation: Blood. 2002 Aug 1;100(3):761-7
references.pmid: 12130483
references.citation: Bone Marrow Transplant. 2013 Nov;48(11):1429-36
references.pmid: 23665819
references.citation: Haematologica. 2005 May;90(5):643-8
references.pmid: 15921379