Clinical Utility of the Detection of the Loss of the Mismatched HLA in Relapsed Hematological Patients After Haploidentical Stem Cell Transplantation With High-Dose Cyclophosphamide

Abstract

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with high-dose cyclophosphamide (PTCy) has resulted in a low incidence of graft-vs.-host disease (GVHD), graft failure, and non-relapse mortality. However, post-transplantation relapse remains a common cause of treatment failure in high-risk patients. Unraveling the mechanisms of relapse is therefore crucial for designing effective relapse treatment strategies. One of these mechanisms is the loss of the mismatched HLA on the recipient's leukemic cells. To study the incidence and clinical relevance of this phenomenon, we analyzed 181 patients treated with Haplo-HSCT with PTCy (2007–2019), of which 37 relapsed patients after transplantation. According to the kit employed for HLA-loss analysis, among 22 relapsed patients, we identified HLA loss at relapse in 6 of the 22 patients (27%) studied. Based on the results obtained, the genomic loss of HLA was more common in females than males (66 vs. 33%) and HLA-loss relapses occurred later than classical relapses (345 vs. 166 days). Moreover, the patients with HLA-loss had a greater presence of active disease at the time of transplantation and had undergone a larger number of treatment lines than the group with classical relapses (66 vs. 43% and 66 vs. 18%, respectively). Four of these relapses were studied retrospectively, while two were studied prospectively, the results of which could be considered for patient management. Additionally, two relapsed patients analyzed retrospectively had myeloid neoplasms. One patient had not undergone any treatment, and three had undergone donor lymphocyte infusions (DLIs) and chemotherapy. All presented severe GVHD and disease progression. In contrast, the two patients studied prospectively had a lymphoid neoplasm and were not treated with DLIs. One of them was treated with chemotherapy but died from disease progression, and the other patient underwent a second Haplo-HSCT from a different donor and is still alive. We can conclude that the detection of HLA-loss at the onset of relapse after Haplo-HSCT with PTCy could help in clinical practice to select appropriate rescue treatment, thereby avoiding the use of DLIs or a second transplantation from the same donor.

Assessment of Patient-Specific Human Leukocyte Antigen Genomic Loss at Relapse After Antithymocyte Globulin–Based T-Cell–Replete Haploidentical Hematopoietic Stem Cell Transplant

“…Unlike previous studies of myeloid conditions, 12,26 we found that the pretransplant BMI of patients was associated with HLA loss; patients with lower BMI were less likely to lose unshared HLA at relapse. A previous study 30 found that underweight patients had a higher rate of posttreatment relapse, which suggests underweight status could reflect the biological aggressiveness of leukemia.…”

“…The results of the present study suggested that male patients with lymphoid leukemia were less likely to have HLA loss at relapse, which was consistent with the findings of a recent study. 26 Although sex is associated with many autoimmune disorders, the difference in immune regulation based on sex is unclear. One study 27 found that sex can have implications for the selection and expansion of HLA-associated T cells.…”

“…Among patients with lymphoid leukemia, the possibility of HLA loss at relapse can be inferred based on the patient’s sex, the time from HSCT to relapse, the occurrence of MRD positivity, and the presence of chronic GVHD. The results of the present study suggested that male patients with lymphoid leukemia were less likely to have HLA loss at relapse, which was consistent with the findings of a recent study . Although sex is associated with many autoimmune disorders, the difference in immune regulation based on sex is unclear.…”

The prophylaxis of severe hemophilia A with inhibitors in children in the Republic of Belarus: a 12-year experience

“…При острых лейкозах рецидив с потерей HLA происходит позже, чем классический вариант реци-дива [21,22]. В предыдущей работе нашего научного коллектива медиана развития рецидива с потерей HLA у детей с острыми лейкозами составила 8 мес [11].…”

“…В качестве факторов риска, ассоциированных с потерей по генам HLA, могут выступать неблагоприятная цитогенетика, ABO-несовместимость, активное заболевание на момент алло-ТГСК, развитие острой и хронической РТПХ [11,21,22]. Биология лейкоза, отсутствие ремиссии перед алло-ТГСК, а также развитие РТПХ могли способствовать клональной эволюции опухоли после алло-ТГСК с последующей потерей HLA-гаплотипа.…”