Haploidentical Transplants Offer Hope for Some

What do you do when a loved one needs a transplant, but there is no perfectly matched donor in the family or national registry of donors? Some patients are turning to their parents or children for help.
A “haploidentical” transplant is a transplant that uses marrow or stem cells from a relative who is only a partial match. Children inherit protein markers from their parents called Human Leukocyte Antigens (HLA). Half are inherited from their mother, the other half are inherited from their father. These antigens are important in transplantation and, in the best of all worlds, should be the same for the donor and patient.

Haploidentical donors share one haplotype (an identical set of HLA antigens from a family member) and are mismatched for at least one antigen on the other haplotype. Thus, haploidentical transplants have traditionally been considered very risky.

Most often haploidentical donors come from the immediate family—a parent or child or mismatched sibling. Because the donor and patient are not a perfect match, haploidentical transplants are often complicated by severe graft-versus-host disease (GVHD), rejection of the transplant, or poor recovery of the immune system. Yet haploidentical transplants remain an option for some patients who have no other possible donor.1

When several registry matches fell through for Elizabeth Pelkey in 2000, she was transplanted using the mismatched marrow from her younger brother, Jacob. Her mother, Holly, remembers her 12-year old daughter saying “If I try the transplant, at least I’ll have some chance to live.” The transplant was a success and today Elizabeth is an active college freshman.

“The transplant offered great hope for us and ultimately it saved Elizabeth’s life,” says Holly. “Those times were stressful and what a balancing act—one child a patient and another child a donor—but it was worth it.”

“Approximately 70 percent of patients do not have a suitably matched family donor,” says Eva Guinan MD, Dana Farber Cancer Institute, where Elizabeth was transplanted. “Despite the existence of unrelated donor programs and cord blood banks, many patients are still unable to find a suitable donor for transplant.”

The European Experience

In 2002 researchers in Perugia, Italy reported success with haploidentical transplants, particularly with patients who had leukemia in remission.2 Doctors gave patients mega-doses of the donor’s stem cells that had been manipulated prior to transplant to remove the T cells believed to cause GVHD. This approach is now used at some centers in Europe, Asia and the US.

The downside, however, is patients usually take longer to recover a well-functioning immune system. This increases the risk of infection, and interferes with the immune system’s ability to destroy cancer cells that may remain after transplant.

New US Studies

Three hospitals—Dana Farber Cancer Institute/Children’s Hospital of Boston, MD Anderson Cancer Center and Children’s Hospital of Los Angeles—are testing a new approach to haploidentical transplantation that may minimize these risks. The approach was prompted by promising results from two earlier clinical trials3 in which patients experienced a lower than expected rate of GVHD and other complications. The new trial is open to patients with ALL,  AML or myelodysplasia who do not have a matched related or unrelated donor.

Patients on the trial will receive an extra infusion of donor cells approximately one month after transplant. The donor cells will be manipulated prior to the infusion, so that they can recognize and fight infection and tumor cells without triggering GVHD. The objective is to jump-start the immune system so that the patient is not at risk of infection for a long period of time.

“It’s not simple speculation that this approach can work,” says Guinan. “The technique has been used successfully in the laboratory and, if it is successful in humans, might make transplantation an option for more patients.”

Other promising haploidentical transplant approaches have used lower dosages of chemotherapy and/or radiation prior to transplant (“mini”-transplantation or reduced intensity transplantation) in an effort to reduce the incidence of GVHD and other transplant-related complications. Preliminary studies from several institutions, including Massachusetts General Hospital, Duke University and Johns Hopkins, have demonstrated that these approaches are feasible and may be associated with potent anti-tumor responses in some patients with advanced leukemia or lymphoma.4,5

This year, six years after her transplant, Elizabeth moved away from home to attend college. Holly is delighted. “Elizabeth now gets the chance to pursue a pre-health major.” Her younger brother, Jacob often reminds Elizabeth, “Anywhere you go, I go with you!”

To learn more about the haploidentical study described above contact Eva C. Guinan, MD, by phone at 617-632-4932, or email at eva_guinan@dfci.harvard.edu

1 Spitzer TR. Haploidentical stem cell transplantation: The always present but overlooked donor. Hematology Am Soc Hematol Educ Program 2005; 390-395.
2 Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A., Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y & Martelli MF. (2005) Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol, 23, 3447-3454.
3 Guinan EC, Boussiotis VA, Neuberg D, Brennan LL, Hirano N, Nadler LM. & Gribben JG (1999) Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med, 340, 1704-1714.
4 O’Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2002; 295:2097-2100.
5 Spitzer TR, McAfee SL, Dey BR, et al. Non-myeloablative haploidentical stem cell transplantation using anti-CD2 monoclonal antibody(MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation 2003; 75:1748-1751.

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