Haploidentical Transplantation

Karen Ballen, MD

What is a Haploidentical Transplant?

A haploidentical transplant (haplo) is a half matched stem cell transplant from a family member. Haplo donors can be parents, children, siblings, and sometimes cousins of the patient. A biologic parent or a biologic child is always a half match to the patient, based on genetics. A haplo transplant can be used when there is no matched sibling or unrelated donor. Recently there has been an increase in the number of haplo transplants, particularly in Europe (1).

What is the History of Haploidentical Transplants?

Haplo transplants have been performed for over 20 years, but initially were limited by the very high risk of graft vs host disease (GVHD), one of the immune complications of a transplant.

About a decade ago, doctors in Italy tried to limit the GVHD of haplo transplants by using complex techniques to remove the T cells (the cells that cause GVHD) from the haplo marrow (2). These techniques were successful in reducing the risk of GVHD, but led to increases in infection, and relapse of leukemia. In addition, it was difficult for other hospitals to reproduce the T cell depletion method.

What is New in Haploidentical HCT?

Strategies to limit GVHD without increasing relapse or infection are crucial to the success of haplo transplants. The use of post transplant cyclophosphamide, chemotherapy actually given after the transplant - usually on Day +4 and Day +5 after transplant - was pioneered at Johns Hopkins. This strategy has led to a low rate of GVHD and post transplant mortality.

In a recently published study, 372 patients at Johns Hopkins with leukemia and lymphoma received post transplant cyclophosphamide after a haplo transplant using reduced intensity conditioning (mini transplant). After three years, 40% of the patients were alive with no evidence of their cancer (3).

The original haplo transplants were done using bone marrow as the stem cell source. Peripheral blood stem cells (PBSC) can be safely substituted for bone marrow, with an overall survival of 48% at two years (4).

The main concern with haplo transplant is a high risk of relapse, particularly for patients with high risk diseases. An important advantage of haplo transplants is the feasibility and safety of giving a donor lymphocyte infusion (DLI) from the original donor if there is relapsed disease (5). The benefits of haplo transplants are the ready availability, low cost, and low transplant related mortality (TRM: death within the first 100 days post transplant, not due to relapsed disease). Relapse, however, may be a limiting factor.

Comparative Studies

To date there are no completed prospective studies that compare outcomes among haplo transplant, umbilical cord blood transplant, and unrelated donor bone marrow transplant.

Most retrospective studies show similar survival but different rates of GVHD, relapse, infection, and TRM. Two parallel phase 2 trials, one using haplo transplants (halpo) and the other double cord blood transplants (CBT), were completed by the United States Bone Marrow Transplant-Clinical Trials Network (6). Fifty patients were treated in each study; all patients received a reduced intensity conditioning regimen of fludarabine, cyclophosphamide, and low dose total body radiation. At one year, the TRM was higher after cord blood transplants (24% CBT vs 7% haplo), but the relapse rate was higher after haplo transplants (31% CBT vs 45% haplo). Disease-free survival in the two groups was comparable at one year (46% CBT vs 48% haplo), and again in a follow-up at three years (36% CBT vs 35% haplo) (7).

The first prospective randomized comparison of double cord blood transplants vs haplo transplants is now ongoing (BMT CTN1101 or NCT01597778).

Conclusions:

In 2015, there are many graft sources that allow almost all patients to have a transplant donor: matched sibling, fully matched unrelated donor, mismatched unrelated donor, umbilical cord blood, or haplo transplant. The table above presents a comparison of haploidentical transplants with either cord blood or a mismatched unrelated adult as the donor graft source. In fact, the choice of graft source may be less important than other factors such as the disease status and organ function of the transplant recipient. No patient should be denied a potentially curative transplant due to lack of a donor.

Karen Ballen, MD, is the Director of the Leukemia Program at Massachusetts General Hospital in Boston, and a Professor of Medicine at Harvard Medical School. Dr. Ballen studied Medicine at Dartmouth College, completed an internship and residency at Beth Israel Hospital in Boston, and a fellowship at Brigham and Women's Hospital in Boston. Her clinical and research interests focus on care of patients with leukemia and patients undergoing bone marrow or stem cell transplants, and novel therapies for leukemia and transplantation. A particular area of specialty is cord blood transplantation for those patients who do not have matched bone marrow donors. For more information: kballen@partners.org.

References:

1. Passweg JR, Baldomero H, Bader P, et al. Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplantation 2015; 50:476-482. doi:10.1038/bmt.2014.312
2. Aversa, F, Terenzi, A, Tabilio, A, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23:3447-3454. doi: 10.1200/JCO.2005.09.117
3. McCurdy SR, Kanakry JA, Showel MM, et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood 2015; 125(19):3024-31. http://dx.doi.org/10.1182/blood-2015-01-623991
4. Raj G, Pagliuca A, Bradstock K, et al. Peripheral blood hematopoietic stem cells for transplantation of hematologic diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant 2014; 20(6):890-5. http://dx.doi.org/10.1016/j.bbmt.2014.03.003
5. Zeidan AM, Forde PM, Symons H, et al. HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 2014; 20(3):314-18. http://dx.doi.org/10.1016/j.bbmt.2013.11.020
6. Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011; 118(2):282-8. http://dx.doi.org/10.1182/blood-2011-03-344853
7. Eapen M, O'Donnell P, Brunstein CG, et al. Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biol Blood Marrow Transplant 2014; 20(10):1485-92. http://dx.doi.org/10.1016/j.bbmt.2014.05.015