Section Head, Hematologic Malignancies and Stem Cell Transplantation

Department of Medicine, Division of Hematology/Oncology

Hematopoietic cell transplant (HCT) is potentially curative for a wide variety of malignant diseases, including acute and chronic leukemias, lymphoma, and myelodysplasia. Historically, preferred donors for HCT have been human leukocyte antigen (HLA)-matched sibling donors (MSDs). Each full biologic sibling has a 25% chance of being HLA identical to the patient.

Given the average family size in the United States, only about 30% of US patients will have an MSD available. Most patients referred for HCT will require an alternative donor graft. These graft sources may include a matched unrelated donor via the Be The Match program, umbilical cord blood (UCB), or a partially matched family donor (haploidentical) transplant.

This review summarizes the chance of finding a donor and the pros and cons of each of these graft sources. The fantastic news is that due to great progress in alternative donor transplants, almost all transplant-eligible patients (up to age 75 years) in 2017 will be able to find a suitable donor and proceed to transplant, a major advance over the past 10 years.

The National Marrow Donor Program (NMDP), located in Minneapolis, Minnesota, was founded in 1986 and has grown to more than 25 million volunteer donors worldwide.

 Now known as Be The Match, this organization is supported by government funds and philanthropy.

The chance of finding an adult volunteer matched unrelated donor (MUD) via the NMDP depends on the ethnicity of the recipient. White Caucasians of Northern European descent have the greatest chance of finding an MUD. Chances of finding an MUD are significantly less for African American or Hispanic recipients due to HLA polymorphisms and the composition of the registry.

Overall survival and disease-free survival (DFS) are now similar in MSD and MUD recipients.

 More recently, the use of mismatched unrelated transplant, defined as high-resolution DNA matching at 7/8 of the HLA loci, has increased the availability of unrelated donors for minority patients. African- American patients have a 23% chance of finding an MUD in the registry but a 70% chance of finding an HLA-mismatched unrelated donor (MMUD), and better HLA matching has improved outcomes over the last 10 years.

 Novel techniques, such as the use of bortezomib, have decreased graft-versus- host disease (GVHD) after MMUD transplants.

UCB can be harvested from the umbilical cord after the delivery of the baby or from the placenta after the delivery of the placenta. There is no known risk to the mother or the baby. UCB contains blood that forms progenitor cells similar to bone marrow or peripheral blood stem cells.

Currently, UCB transplants (UCBTs) in adult recipients account for approximately 10% of the alternative donor transplants performed in the United States.

 UCB units are readily available, have decreased rates of chronic GVHD compared with other graft sources, and require less strict HLA matching than units from MUD 

 UCBT has been associated with a decreased rate of relapse, especially in patients with minimal residual disease.

GVHD indicates graft-versus-host disease; HCT, hematopoietic cell transplant; UCBT, umbilical cord blood transplant. Ballen KK, Koreth J, Chen YB, Dey BR, Spitzer TR. 

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Disadvantages of UCBT include an increased risk of infections, particularly viral infections, which can lead to early transplant-related mortality.

 The cost of each UCB unit is approximately $40,000; many UCBTs in the United States are performed with double UCBTs, at a cost of $80,000 for graft acquisition alone. Several studies have demonstrated comparable survival among UCBT and other graft sources.

 UCBT is a reasonable transplant alternative and should be considered when an MSD or MUD donor is not available.

Haploidentical (haplo) donors are half-matched donors. A parent or a child and 50% of siblings will be a half match to the patient. Advantages of haplo donors are their ready availability, less strict HLA matching, and decreased cost of graft acquisition

Traditional methods to reduce GVHD have included intensive T-cell depletion techniques that were difficult to accomplish in smaller centers.

Posttransplant cyclophosphamide, pioneered by investigators at Johns Hopkins University, produces immunologic tolerance in recipients after receiving unmanipulated haplo bone marrow transplants; this relatively simple technique has decreased the risks of GVHD and graft rejection. The use of posttransplant cyclophosphamide, which can be performed in almost any transplant center, has led to a marked increase in the number of haplo transplants performed in the United States and Europe.

Controversial issues in haplo HCT include whether bone marrow or peripheral blood stem cells produce equivalent outcomes, selection of the optimal haplo donor, and long-term outcomes including risks of second malignancy.

Several retrospective studies have compared outcomes among MUD, UCBT, and haplo HCT. In general, survival is similar regardless of graft source. UCBT has been associated with a higher risk of infection, MUD with higher risk of GVHD, and haplo HCT with a higher risk of relapse.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) performed 2 parallel prospective independent studies of 50 patients each: 1 study with haplo transplants and 1 with UCB transplants.

 One-year DFS was similar between the 2 groups: 46% UCB versus 48% haplo. Haplo and UCBT are currently being compared in a randomized, prospective study (BMT CTN 1101; NCT01597778). Future directions include strategies to prevent relapse, regardless of graft source, by using posttransplant maintenance therapy.

Allogeneic stem cell transplantation is a curative procedure for patients with hematologic malignancies. Due to the increasing and successful use of UCB, MMUD, and haplo, almost every patient can find a suitable donor.

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Due to great progress in alternative donor transplants, almost all transplant-eligible patients, up to age 75 years, in 2017 will be able to find a suitable donor and proceed to transplant, a major advance over the past 10 years.

Karen K. Ballen, MD

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