Influence of Inherited and Acquired Hematological and Immunological Gene Variants on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematological Malignancies

Chromosome abnormalities and gene variants are important factors in prognosis of the patients with hematological malignancies. Our previous study showed that some germline gene mutations-related to hematological and immunological disorders may have negative impact on the complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In current study, the influence of both hematological and immunological hereditary predisposition gene variants and tumor gene variants on the outcomes of allo-HSCT in patients with hematological malignancies was studied. Between January 2018 and June 2020, 164 patients with hematological malignancies who underwent allo-HSCT in our hospital were analyzed. The median age was 14 (1 to 67) years old. The diagnosis included acute myeloid leukemia (n=68, 41.5%), acute lymphoblastic leukemia (n=67, 40.8%) and non-Hodgkin’s lymphoma (n=29, 17.7%). The disease status before transplant was CR1 in 49 cases (29.9%), CR2 in 63 cases (38.4%), PR in 22 cases (13.4%), and NR in 30 cases (18.3%). Donors were from haploidentical family members (n=125, 76.2%) or identical siblings (n=18, 11.0%) or unrelated volunteers (n=21, 12.8%). Myeloablative conditioning regimens with either total body irradiation/fludarabine-based or busulfan/fludarabine-based were applied. Anti-thymocyte globulin was used in haploidentical and unrelated transplants. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine, short-term methotrexate and mycophenolate mofetil. Before transplant, blood samples from patients, their parents and potential related donors were collected to analyze for more than 700 kinds of hematological and immunological hereditary predisposition genes with whole exon sequencing and validation by sanger sequencing. The average sequencing depth was 150×. At diagnosis or relapse, bone marrow samples from patients were obtained to detect for 339 kinds of tumor genes by Illumina sequencing. The average sequencing depth was more than 3000×. With the median follow-up 12.6 (11.2 to 17.0) months, 105 patients (64.0%) achieved durable remission after allo-HSCT. Forty-seven patients (28.7%) relapsed. Twelve patients (7.3%) died. Total 191 immunodeficiency-related hereditary predisposition gene variants were identified in this cohort (average 3.5 gene variants per patient; range, 0-10). Twenty-six of them were recurrent more than 6 times that including TYK2, IFIH1, CFTR, LRBA, IL7R, POLE, RNF31, NLRP12, TTC7A, ATM, CARD14, CHD7, N