Promising Results for Peripheral Blood Stem Cell Tranplants from MIsmatched Donors

A phase 2 trial has shown that peripheral blood stem cells can be used as a source of stem cells from donors that are unrelated and have less histocompatibility with the transplant recipients.

Results published in the Journal of Clinical Oncology earlier this month show favorable results as measured by overall survival at one year and the occurrence of graft-vs-host disease (GVHD).

Monzr M Al Malki, M.D.

Their results provide evidence that post-transplant cyclophosphamide (PTCy) effectively controls GVHD despite the use of peripheral blood stem cells, which will simplify stem cell transplants, “rendering it easier and safer for donors,” wrote lead author Monzr M. Al Malki, M.D., and his colleagues.

Malki and his colleagues wrote that one of their main reasons for conducting this study was to provided enough evidence in favor of MUDD donors to justify a phase 3 trial comparing MUDD donors to donors that are more closely matched to recipients.

Stem cells for transplants can come from bone marrow or be filtered out of the bloodstream in a process called apheresis. Harvesting stem cells from bone marrow has drawbacks for the donors, suppressing blood cell counts and involving procedural and anesthesia risks. Peripheral blood stem cell donation is easier and safer for the donors but has the tradeoff of increasing the risk of acute and chronic GVHD, Malki and his colleagues explained. All the 145 patients enrolled in this trial received peripheral blood stem cells.

There are other important variables in allogeneic (from another person) stem cell transplants. One is histocompatibility — how closely the recipient and donor are matched with respect to human leukocyte antigen (HLA), proteins on the surface of cells. The lack of a match can spur GVHD. But stem cell transplant researchers and transplant specialists have been finding ways — such as the addition of PTCy — to make stem cell transplants from HLA-mismatched unrelated donors (MMUDs) more successful. There’s a health equity aspect to expanding stem cell transplants to include MMUDs because, as Al Malki and his colleagues explain, patients in marginalized racial and ethnic groups are far less likely than non-Hispanic Whites to have HLA-matched donors in worldwide donor registries. All of the patients enrolled in this study had received their first stem cell transplants from MMUDs.

A third variable in stem cell transplant is the intensity of the chemotherapy and radiation of the “conditioning regimen” prior to the stem cell transplant. The conditioning regimen is designed to attach the cancer and also suppress the immune system to increase the chances of the stem cell transplant being successful and reducing the risk of GVHD. High-intensity regimens called myeloablative conditioning (MAC) because they kill bone marrow cells. Less intense regimens are referred to as reduced-intensity or nonmyeloablative (RIC/NMA). In this study, 75 patients received MAC and 70, RIC/NMA. Patients in the MAC group were treated with fludarabine and busulfan or fludarabine and total body irradiation. Those in the RIC/NMA group were treated in one of three ways: with fludarabine and busulfan, with fludarabine and melphalan, or with fludarabine, cyclophosphamide and low-dose total body irradiation.

All the patients in the study received the same GVHD prophylactic regimen of cyclophosphamide, tacrolimus and mycophenolate mofetil.

Overall survival

The patients were enrolled at 21 centers in the United States between September 2021 and August 2023. An additional five patients were enrolled in the MAC group because of the timing of the consent. Acute myeloid leukemia was the most common diagnosis.

The primary end point was overall survival one year after the stem cell transplant. Al Malki and his colleagues reported separate results for the MAC and the RIC/NMA groups. Their results showed that overall survival one year after the transplant was 83.8% in the MAC group compared with 78.6% in the RIC/NMA group. They also reported a number of secondary outcomes. Grades 2 to 4 acute GVHD at six months after transplant affected 30.7% of the MAC group patients compared with 44.3% of the RIC/NMA group. Moderate-to-severe chronic GVHD affected 10.3% of the MAC group compared with 8.6% of the RIC/NDA group.

An exploratory analysis showed that overall survival did not differ significantly by HLA level. Al Malki and his colleagues cautioned that the analysis was underpowered and not definitive but also said it supported searching for MUDDs for recipients who could benefit from a stem cell transplant. Loosening the criteria for HLA matching would increase the likelihood of identifying a potential unrelated donor to virtually 100% of patients, regardless of their ancestry, they note, and would allow for making other donor characteristics a priority, such as a young age.