Improvements in Unrelated Donor Transplantation

Unrelated donor transplant outcomes have improved in the last decade and recent studies have shown similar outcomes for unrelated donor and sibling donor transplantation in certain diseases and patient populations. For a description of some of these studies, see Comparing Unrelated Donor to Sibling Donor Transplant. Key factors in improved unrelated donor transplant outcomes are discussed below.

More precise HLA matching

The outcomes of unrelated donor or cord blood transplants are strongly affected by the degree of HLA matching between the donor and transplant recipient. HLA matching plays an important role in engraftment, incidence of graft-versus-host disease (GVHD) and overall survival. More precise matching is now possible because:

DNA-based tissue typing enables typing at a higher resolution.
The understanding of matching criteria, including which HLA loci are most significant to outcomes, has improved and continues to be refined.

For details, see Advances in HLA Typing.

Improving the donor search process

Searching the Be The Match Registry^®, operated by the National Marrow Donor Program^® (NMDP), for a matched unrelated donor is faster, more efficient and more likely to yield a suitably matched donor or cord blood unit than ever before. The increased likelihood of finding a match is due in large part to the growth of the Be The Match Registry, which currently has more than 10 million potential donors and nearly 165,000 cord blood units. Every search through the NMDP provides patients with access to more than 19 million potential donors and more than 590,000 cord blood units on U.S. and global registries.

Increased speed and the improved efficiency of searches are the result of the NMDP’s new enhanced matching algorithm that identifies the donors or cord blood units (CBU) with the highest potential to match the patient. This allows transplant physicians searching the Be The Match Registry to more quickly and efficiently identify the best immunogenetically matched donor or CBU for their patients.

The NMDP’s advanced matching algorithm, named HapLogic^SM, is based on the mathematical analyses of the haplotypes of millions of donors on the Be The Match Registry. HapLogic uses advanced logic to predict the likelihood that a donor or CBU will be a high-resolution 10/10 match to a searching patient. [1]

The improved search algorithm is one of several advances in the search process for transplants facilitated through the NMDP. Searching for an unrelated donor through the NMDP also means that physicians have a single point of access for all three sources of hematopoietic cells.

Expanded sources of cells for transplant

Today physicians working with the NMDP can select from three potential hematopoietic cell options for patients in need of an unrelated donor — marrow, cells from peripheral blood and umbilical cord blood.

A phase III randomized multicenter trial is underway to determine whether hematopoietic cells from the marrow or peripheral blood offer advantages to patients. The study protocol is available from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) website. [2]
Cord blood transplants with up to 2 HLA antigen mismatches between the cord blood unit and the recipient have shown survival outcomes similar to those for 6 of 6 HLA-matched unrelated donor marrow transplants. [3,4]

For further information on using an NMDP cord blood unit, see Likelihood of Finding an Unrelated Donor or Cord Blood Unit.

Impact of transplant timing on outcomes

Appropriate timing of the transplant is a critical factor in improved patient outcomes. For most diseases, transplants performed early in the disease process are associated with lower TRM and disease recurrence. For example, in a 2007 study of 3,857 unrelated donor transplants, patients with intermediate-stage disease had a 38% greater risk of mortality than patients with early-stage disease. Patients with advanced disease had approximately twice the mortality risk as patients with early-stage disease. [5]

In an analysis of 1,180 patients transplanted for leukemia or other hematological malignancies from before 1990 to 2002, Bacigalupo et al. found that with the changes in transplant over time, for patients transplanted in first remission, TRM has been significantly reduced and 2-year survival significantly improved. However, for patients transplanted in second remission or relapse there has been little to no reduction in TRM or improvement in survival. [6]

Several studies, for example two studies of transplant for CML and one of transplant for acute leukemias, have shown more significant differences in survival based on the timing of transplant than on whether the donor was a sibling or an unrelated volunteer. [4,6,7]

For further discussion of the impact of timing on outcomes, see Transplant Outcomes by Disease and Disease Stage.

Improvement in survival over time

The following curves showing 2-year overall survival of NMDP transplant recipients show significant improvements since the NMDP facilitated its first transplant in 1987. Improvements are most evident during the two most recent time periods (2004-2007 and 2008-2010) and are especially striking in severe aplastic anemia (SAA) and acute myelogenous leukemia (AML).

Figure 1.
Survival of adult (age ≥18) patients with acute myelogenous leukemia (AML) receiving NMDP transplants during four time periods. (NMDP data)

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Survival is significantly better at two years post-transplant for AML patients transplanted during 2004-2007 and 2008-2010 compared to 1999-2003 and also compared to 1987-1998 (log-rank p-value <0.001).

Figure 2.
Survival of adult (age ≥18) patients with acute lymphoblastic leukemia (ALL) receiving NMDP transplants during four time periods. (NMDP data)

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Survival is significantly better at two years post-transplant for patients transplanted during 2008-2010 and 2004-2007 compared to patients transplanted during the previous periods (log-rank p-value <0.001).

Figure 3.
Survival of pediatric (age <18 years) patients with AML in first complete remission (CR1) receiving NMDP transplants during four time periods. (NMDP data)

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Survival is significantly better at two years post-transplant for pediatric ALL patients in CR1 transplanted during 2004-2007 and 2008-2010 compared to 1999-2003 and also compared to 1987-1998 (log-rank p-value <0.001).

Figure 4.
Survival of pediatric (age <18 years) patients with ALL in CR1 receiving NMDP transplants during four time periods. (NMDP data)

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Survival is significantly better at two years post-transplant for pediatric ALL patients in CR1 transplanted during 2004-2007 and 2008-2010 compared to patients transplanted during the two previous time periods (log-rank p-value = 0.008).

Figure 5.
Survival of adult (age ≥18) patients with chronic myelogenous leukemia (CML) receiving NMDP transplants during four time periods. (NMDP data)

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Survival is significantly better at two years post-transplant for patients transplanted during 2008-2010 compared to patients transplanted during 1987-1998 and 1999-2003 (log-rank p-value <0.001), but was not significantly different compared to patients transplanted during 2004-2007.

Figure 6.
Survival of adult (age ≥18) patients with myleodysplastic syndromes (MDS) receiving NMDP transplants during four time periods. (NMDP data)

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Survival is significantly better at two years post-transplant for patients transplanted during 2004-2007 and 2008-2010 compared to patients transplanted during the two previous time periods (log-rank p-value <0.001).

Figure 7.
Survival of adult (age ≥18) patients with severe aplastic anemia (SAA) receiving NMDP transplants during four time periods. (NMDP data)

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Figure 8.
Survival of pediatric (age <18 years) patients with SAA receiving NMDP transplants during four time periods. (NMDP data)

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References

Hurley CK, Wagner JE, Setterholm MI, Confer DL. Advances in HLA: Practical implications for selecting adult donors and cord blood units. Biol Blood Marrow Transplant. 2006; 12(1) Suppl. 1:28-33.
http://www.bbmt.org/article/S1083-8791(05)00689-0/
fulltext
BMT CTN Protocol 0201 - A Phase III randomized multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors.
https://web.emmes.com/study/bmt2/protocol/
0201_protocol/0201__protocol.html
Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003; 101(11):4233-4244.
http://www.bloodjournal.org/cgi/content/full/101/11/4233
Wagner JE, Barker JN, DeFor T, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002; 100(5):1611-1618.
http://www.bloodjournal.org/cgi/content/full/100/5/1611
Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007; 110(13):4576-4583.
http://bloodjournal.hematologylibrary.org/cgi/content/full/110/13/4576
Bacigalupo A, Sormani MP, Lamparelli T, et al. Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation. Haematologica, 2004; 89(10):1238-1247.
http://www.haematologica.org/cgi/content/abstract/89/10/1238
Eapen M, Rubinstein P, Zhang MJ, et al. Comparable long-term survival after unrelated and HLA-matched sibling donor hematopoietic stem cell transplantations for acute leukemia in children younger than 18 months. J Clin Oncol. 2006; 24(1):145-151.
http://www.jco.org/cgi/content/full/24/1/145