Potential Influence of Hematological or Immunological Hereditary Predisposition Genes on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematological Malignancies

Introduction: The development of hematological malignancies may be relevant to hereditary predisposition and harmful external environment. Germ line predisposition to myeloid neoplasms has been incorporated in the WHO 2016 classification of myeloid neoplasms. Hereditary predisposition genes may also play a certain role in the complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Objective: In present clinical study, we investigate whether hematological and immunological hereditary predisposition genes have influence on the outcomes of allo-HSCT in patients with hematological malignancies.

Methods: Between January 2018 and May 2019, ninety-one patients with hematological malignancies who underwent allo-HSCT with the same protocols in our hospital were enrolled. The median age was 20 (2 to 66) years old. Male to female was 1.53:1. The diagnosis included AML (n=32, 35.2%), ALL (n=47, 51.6%) and NHL (n=12, 13.2%). The disease status before transplants was CR1 in 31 cases (34.1%), CR2 in 45 cases (49.5%), PR in 5 cases (5.5%), and NR in 10 cases (11.0%). Hematological and immunological hereditary predisposition genes of the patients, their parents and potential related donors were prospectively detected before transplant with whole exon sequencing and validation by sanger sequencing. Donors were from haploidentical family members (n=74, 81.3%) or identical siblings (n=6, 6.6%) or unrelated volunteers (n=11, 12.1%). Myeloablative conditioning regimens with either TBI/Fludarabine or Busulfan/Fludarabine were applied. Anti-thymocyte globulin (ATG) was used in haploidentical and unrelated transplants. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine, short-term methotrexate and mycophenolate mofetil. Prevention of fungal, pneumocystis carinii and herpes virus infections was routinely administrated. Chi-square test was used to analyze whether hereditary predisposition genes were associated with major complications after allo-HSCT. The study used the IBM SPSS Statistics software for analysis. P value <0.05 was considered to be statistically significant.

Results: Thirty-one (34.1%) cases carried primary hemophagocytic lymphohistiocysis (HLH) related gene variants and the average number of gene variants was 1.2 (range 1 to 2). More frequent HLH gene variants were in UNC13D, LYST, PRF1, AP3B1 and STX11. Forty-four (48.4%) cases carried Fanconi anemia (FA) related gene variants and the average number of gene variants was 1.27 (range 1 to 3). More frequent FA gene variants were in BRCA2, FANCA, PALB2, FANCD2, BRCA1, FANCL, FANCI and SLX4. Ninety (98.9%) cases carried immunodeficiency related gene variants and the average number of gene variants was 3.25 (range 1 to 10). More frequent immunodeficiency gene variants were in IFIH1, CHD7, TYK2, LRBA, NFAT5, IL7R, NLRP12, POLE, TNFRSF13B, ATM, IGLL1, ORAI1, RNF31, C8A, CBLB, IRF8, LIG1, NCF2, NCF4, STIM1 and TCF3 .The incidence of acute GVHD (aGVHD) in patients carried HLH gene variants was significantly higher than that without HLH gene variants (45.1% vs. 21.6%, p=0.020). Bacterial infections occurred more frequent in patients with FA gene variants than that without FA gene variants (47.7% vs. 21.3%, p = 0.008). There was a trend of higher relapse rate in patients with more than 3 immunodeficiency gene variants than that with less than 3 immunodeficiency gene variants but without statistical significance (23.8% vs. 11.4%, p > 0.05).

Conclusions: Our preliminary results have shown that hematological and immunological hereditary predisposition genes have potential influence on major complications of allo-HSCT in patients with hematological malignancies. HLH gene variants increase the risk of aGVHD, and FA gene variants increase bacterial infections after allo-HSCT. The patients with multiple immunodeficiency related gene variants may increase relapse rate post-transplant. A larger cohort and longer follow-up are needed to address this issue.