Stem cell transplantation, often called a bone marrow transplant, is a treatment for blood cancers (such as leukemia and lymphoma), immune system disorders, and genetic diseases. This procedure replaces a patient’s diseased bone marrow with healthy blood-forming stem cells from a donor. Finding a donor with a close immune system match has historically been challenging, but the development of the haploidentical transplant has changed this. Haploidentical stem cell transplantation (Haplo-SCT) allows a patient to successfully receive stem cells from a partially matched family member.
Defining the Haploidentical Match
The success of a stem cell transplant depends on the genetic compatibility between the donor and the recipient, determined by Human Leukocyte Antigens (HLAs). HLA proteins regulate the immune system’s recognition of foreign material and are found on the surface of most cells. A patient inherits one set, or haplotype, of HLA genes from each parent; a full match requires sharing both haplotypes, typically a 10/10 match.
The term “haploidentical” means “half-identical” and describes a donor who shares exactly one of the two HLA haplotypes with the patient. This results in a 50% genetic match, as the donor and recipient are mismatched for the unshared haplotype. Parents and children are always a haploidentical match, and full siblings have a 50% chance of being haploidentical.
Solving the Donor Availability Crisis
Historically, the preference for allogeneic stem cell transplantation was an HLA-identical sibling, but only 20% to 30% of patients have such a donor. If a matched sibling is unavailable, the search turns to a fully matched unrelated donor (MUD) found through international registries. However, the probability of finding a perfect MUD is low, particularly for patients from diverse ethnic backgrounds.
The clinical advantage of Haplo-SCT is the expansion of the potential donor pool, as almost every patient has a haploidentical family member—a parent, child, or sibling—who can serve as a donor. This availability dramatically reduces the time spent searching for a donor, allowing patients with rapidly progressing diseases to receive treatment sooner. Haplo-SCT has effectively eliminated the lack of a suitable donor as a barrier to transplantation for most patients.
Navigating the Transplantation Process
The transplant process begins with conditioning, which prepares the patient’s body to receive the new stem cells. This step involves high-dose chemotherapy, and sometimes total body irradiation, delivered over several days. Conditioning serves two purposes: to eradicate the patient’s diseased cells and to suppress the existing immune system to prevent rejection of the donor cells.
Following conditioning, healthy stem cells are collected from the haploidentical donor, usually from the peripheral blood via apheresis. The collected stem cells are then infused into the patient intravenously through a central line, similar to a standard blood transfusion. The infusion is not a surgical procedure, and the patient remains awake throughout.
The stem cells circulate in the bloodstream and migrate to the bone marrow space where they begin to grow and multiply. This process is known as engraftment, which signals the new cells are successfully establishing themselves. Engraftment is confirmed when the patient’s blood counts (white blood cells, red blood cells, and platelets) begin to rise, typically two to six weeks after the infusion.
Preventing Immune System Attack
The challenge of using a half-matched donor is the high risk of Graft-versus-Host Disease (GvHD), where the donor’s immune cells recognize the recipient’s body as foreign and attack. This risk is due to the significant HLA mismatches between the haploidentical donor and the recipient. To manage this immune mismatch, a strategy involving high-dose Post-Transplant Cyclophosphamide (PTCy) was developed.
PTCy is administered a few days after the stem cell infusion, typically on days +3 and +4. Cyclophosphamide is a chemotherapy agent, but at this specific timing, it acts as a selective immunosuppressant. It works by targeting and destroying the rapidly dividing, mismatched T-cells from the donor, which are responsible for causing GvHD.
T-cells activated by the recipient’s mismatched HLA antigens proliferate quickly after the transplant, making them susceptible to the cyclophosphamide. Stem cells, which are not rapidly dividing, and beneficial immune cells are relatively spared from this destruction. This selective elimination of alloreactive T-cells, while preserving hematopoietic stem cells, makes Haplo-SCT a viable treatment option.
Applications and Clinical Results
Haplo-SCT is utilized to treat hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS). The technique is also used for non-malignant conditions like severe aplastic anemia. The rapid availability of a donor allows for transplants to be performed promptly, which is important for patients with aggressive diseases.
Thanks to PTCy-based strategies, the clinical outcomes for Haplo-SCT are comparable to those achieved with fully matched related or unrelated donors. Overall survival rates in patients receiving Haplo-SCT are similar to those of matched sibling donor transplants. The use of PTCy has been effective in reducing the incidence of severe acute and chronic GvHD, which were historical drawbacks of using a mismatched donor.
In some studies, Haplo-SCT with PTCy has shown superior outcomes in terms of GvHD-free and relapse-free survival compared to other donor sources. The widespread adoption of this approach has transformed the field. Stem cell transplantation is now accessible to virtually every patient who needs it, regardless of their ability to find a perfect genetic match.