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.
Highlights
Allogeneic hematopoietic stem cell transplantation is the only curative option for many high-risk hematological malignancies [1]
A deeper understanding of the mechanisms by which patients relapse could help in selecting the best treatment, increasing its effectiveness and reducing the toxicity of such treatment and thereby offering a personalized medical approach
We have examined the largest cohort of patients with HLA-loss at relapse after HaploHSCT with posttransplantation cyclophosphamide (PTCy) and we described HLA-loss for lymphoid neoplasms, which to our knowledge has not been reported to date
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for many high-risk hematological malignancies [1]. The success of the transplant lies in the donor immune system’s capacity to remove residual leukemia cells via a graft-vs.leukemia effect (GVL) based on the HLA disparity between donor and recipient, where donor T cells recognize patientspecific HLA molecules and eliminate leukemic cells. This effect is usually accompanied by an autoimmune and alloimmune disorder called graft-vs.-host disease (GVHD) [8]. The genomic loss of HLA (copy neutral loss of heterozygosity), the epigenetic downregulation of class II HLA and the epigenetic upregulation of inhibitory molecules (PDL1, B7H3, PVR or PVRL2) are the three known tumor-intrinsic mechanisms [14]
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