Which is the most suitable source of donor blood-forming (stem) cells for transplanting into adults with blood cancers?

Stem cell transplantation

Stem cell transplantation is an important treatment option for individuals with blood cancers (haematological malignancies). During the procedure, blood-forming (stem) cells, derived from the bone marrow, peripheral blood or umbilical cord blood of a healthy donor, are transplanted into a person with a blood cancer. The aim is to replenish the recipient's body with healthy cells after treatment with conditioning regimens such as chemotherapy or radiation (or both). Peripheral blood stem cells and bone marrow stem cells are the standard stem cell sources used in adults. The most successful transplantations occur when stem cells are transplanted from a healthy donor whose tissue is genetically compatible with that of the recipient (matched related donor). If no matched donor can be identified, it is possible to transplant cells from a matched unrelated donor or from donors carrying certain mismatches. In principle, the higher the degree of genetic mismatch, the higher the risk of severe transplant-related complications, especially graft-versus-host disease (GvHD), in which a donor's white blood cells (T cells) attack the recipient's healthy tissues.

Peripheral blood versus bone marrow stem cells

Peripheral blood stem cells are collected after the donor has received a drug that acts to mobilise stem cells from the bone marrow to the peripheral blood. Bone marrow stem cell donation involves the removal of stem cells from the pelvic bone of the donor under general anaesthesia. Donor convenience as well as logistic reasons favour peripheral blood stem cell donation.

This review addresses the question of which stem cell source - bone marrow or peripheral blood - is the most suitable for individuals undergoing stem cell transplantation.

Clinical results from several studies have been published comparing the use of bone marrow stem cells and peripheral blood stem cells in individuals with haematological malignancies. In most of these studies, the rates at which stem cells received during transplantation start to grow and make new blood cells (known as engraftment) have been shown to be faster following the transplantation of peripheral blood stem cells (PBSCT) than following transplantation of bone marrow stem cells (BMT) platelets. Some studies have reported PBSCT to be associated with a higher risk of developing GvHD than BMT. GvHD is associated with a lower risk of relapse, reflecting the capability of the immune response to simultaneously attack the malignant cells (Graft versus Malignacy effect). On the other hand, GvHD can be an important driver of transplant-related mortality and morbidity. Disease-free and overall survival have usually been reported not to differ between PBSCT and BMT. A systematic review from 2005, based on data from individual recipients, could not identify a preferred stem cell source and was largely based on data from the late 1990s. Since then, transplant indications and strategies, as well as supportive care measures, have changed substantially.

Results of this meta-analysis

In this systemic review we included nine randomised controlled trials involving 1521 participants. Key inclusion criteria were adults undergoing stem cell transplantation for a blood cancer using either bone marrow stem cells or peripheral stem cells as a stem cell source. Participants were treated between 1994 and 2009. The evidence is current to February 2014.

In summary, we found overall and disease-free survival to be comparable for both PBSCT and BMT. Recipients of bone marrow stem cells from related donors were more likely to relapse than recipients of peripheral blood stem cells from related donors, but this difference was not seen in the recipients of bone marrow stem cells from unrelated donors. The incidence of acute GvHD following PBSCT and BMT was comparable; however, there was a tendency to more severe GvHD with PBSCT. PBSCT was associated with higher rates of chronic GvHD. The time to engraftment was significantly shorter with PBSCT than with BMT. The quality of the evidence was considered moderate to high.

Conclusion

Against the background of altering clinical strategies these results confirm that the current practice of using peripheral blood rather than bone marrow as a source of stem cells for stem cell transplantation in adults with haematological malignancies is not deleterious with respect to overall survival.

Authors' 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.

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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.

Objectives: 

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.

Search strategy: 

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.

Selection criteria: 

We included randomised controlled trials (RCTs) comparing bone marrow and peripheral blood allogeneic stem cell transplantation in adults with haematological malignancies.

Data collection and analysis: 

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.

Main 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).

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