For patients in need of hematopoietic cell transplants, successful HLA matching with donors has always been a prerequisite for success. Perhaps for not much longer.Credit: Andrew Aitchison/Alamy
For many patients with advanced hematological diseases and disorders, survival depends on a successful blood stem cell transplant, more formally known as hematopoietic cell transplant (HCT). Donors and recipients are typically matched according to molecular criteria, but donor registries are not as ethnically diverse as needed, leaving some patients much less likely to find a donor.
Jeffery Auletta, MD, is the Senior Vice President of Patient Outcomes and Experience at the National Marrow Donor Program (NMDP)/Be The Match and Chief Scientific Director of the Center for International Blood and Marrow Transplant Research (CIBMTR), a research collaboration between the NMDP/Be The Match and the Medical College of Wisconsin. He discusses new research that could open access to HCT for all patients in need.
What is hematopoietic stem cell transplant?
Essentially, HCT uses a donor’s stem cells [allogeneic] to repopulate unhealthy bone marrow in patients who may have malignant diseases, such as acute myelogenous leukemia, or non-malignant diseases like aplastic anemia or sickle cell disease.
What kinds of obstacles might prevent access to a HCT?
We usually talk about donor availability, disease remission and access barriers. Access barriers encompass logistical, psychological or socioeconomic challenges. Disease barriers refer to the need for patients with malignant diseases to reach a certain level of remission before undergoing transplant. Donor availability barriers relate to the identification of suitable donors, specifically the need to match human leukocyte antigen (HLA) proteins between donor and recipient. Our recent studies focus on that.
Why is HLA matching important?
One of the primary barriers to transplant is the need to match certain class I (A, B, C) and class II (DRB1) HLA proteins between donor and recipient. HLA proteins help the immune system recognize which cells belong to the body. When donor immune cells don’t recognize the HLA proteins expressed on the recipient’s hematopoietic or non-hematopoietic cells, the donor cells attack the recipient’s body and organs, a process called graft-vs-host disease (GvHD).
Research has shown that for each donor/recipient HLA mismatch, patient survival decreases significantly, primarily due to GvHD, and associated complications such as infections and organ dysfunction. At the NMDP/Be The Match, we can match donors and recipients rather successfully. However, the pattern of HLA proteins in each person is closely related to genetic ancestry, so matching is dependent upon ethnicity. The Be The Match Registry® is heavily comprised of people who are white. That leaves ethnically diverse patients at a disadvantage when seeking an HLA-matched unrelated donor. For example, currently Black and African American patients have a 29% chance of finding a matched, available donor on the Be The Match Registry.
Can graft-vs-host disease be avoided?
One way to decrease the odds of GvHD is to suppress the recipient’s immune system prior to the transplant. Drugs that decrease immune cell activity, namely those that suppress T cell function, are used to induce an immune tolerant environment. After transplant, patients usually receive a combination of calcineurin inhibitors, like cyclosporine and tacrolimus, and methotrexate, which helps eliminate rapidly dividing donor cells, including the activated T cells that mediate GvHD.
What is post-transplant cyclophosphamide and how could it improve access to HCT?
Similar to methotrexate, post-transplant cyclophosphamide (PTCy) prevents GvHD by eliminating or inhibiting rapidly dividing donor T cells that cause GvHD. Other mechanisms of action include induction of regulatory T cells that suppress alloreactive T cells.
PTCy has allowed us to get beyond the HLA barrier. We can now use haploidentical donors—or donors who are only 50% HLA matched between donor and recipient. We have studied the use of PTCy in the mismatched unrelated donors (MMUD) setting, and the results are exciting. For example, with the use of PTCy and MMUDs, it appears we can raise the donor match rate to nearly 99% for Black and African American patients.
What’s next?
We likely haven’t optimized the MMUD transplant approach, nor do we have long follow-up data for these patients. We’ve published some work on this, including a study of about 10 transplant centres using MMUDs in 80 patients with hematologic malignancies. 48% of ethnically diverse patients were enrolled, and the one-year overall survival rate was 76%‒similar to a haploidentical comparator data set from the CIBMTR.
Our current study, known as the ACCESS trial, will involve about 30 transplant centres and 180 patients, including pediatric patients, and aims to verify those results. Future studies may address cyclophosphamide dosing, alternative prophylactic agents to cyclophosphamide, the type of stem cell collection methods used, and pre-transplant conditioning types as potential optimizations of the MMUD platform. There is much to come in our research, but we are well-positioned to transform HCT outcomes for all patients in need.