Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Improved Prognosis for Advanced NK/T Cell Lymphoma
Authors: Li Zhihui , Wang Xianxuan , Yang Keyan , Wang Lei , Wen Xiaopei , Wang Jingjing , Li Jing , Song Yanzhi , Zhao Yongqiang , Zheng Qinlong , Wu Tong 
Published: December 2024

Introduction : NK/T-cell lymphoma (NKTCL) is a relatively rare type of lymphoma. The patients with advanced or relapsed/refractory NKTCL have poor prognosis.
Objective : In present study, the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the patients with advanced NKTCL were evaluated. Profiles of germline gene variants associated with hemophagocytic lymphohistiocytosis (HLH) were identified. The risk factors for transplant outcomes were also analyzed.
M ethod s : Between January 2019 and June 2024, 31 consecutive patients with advanced NKTCL who underwent allo-HSCT in our hospital were enrolled. The median age was 31.24 years (range: 3.84-57.2 years) and 54.8% of them were male. All patients were with stage III or IV NKTCL and 93.5% of them were in stage IV. 38.7% of the patients had HLH before transplantation. Five cases had central nervous system involvement. High PINK scores were reported for 17 patients. The median course of disease was16.9months（range:4.6-57.6months）. 45.2% of the patients relapsed pre-transplant. Three cases (9.7%) relapsed after autologous transplants. The median number of treatment lines was 3 (2-4), and 83.9% of them had treatment lines more than 2. 67.7% of them received PD-1 inhibitor treatment before allo-HSCT with the median 6 (1-20) cycles. Eighteen patients (58.1%) achieved complete remission (CR) or partial remission (PR) and 13 patients (41.9%) were in non-CR/PR prior to allo-HSCT. Donors were from haploidentical (48.4%) or unrelated (51.6%). Myeloablative conditioning regimens with either total body irradiation (TBI 10Gy fractionated, n=4)/teniposide (100mg/m2.d, 3 days)/fludarabine (30mg/m2.d, 5 days) or busulfan (0.8mg/kg q6h.d, 3 days, n=27)/ teniposide/fludarabine 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. The patients were analyzed for germline gene variants before transplants. Genomic DNA was extracted from blood (patients, parents) and tested using next-generation sequencing (NGS).
Results: The median follow-up was 14.7 months (95% CI: 12.9-24 months). One-year and two-year overall survival rate (OS) were 93.5%, 80.8% respectively. One-year Progression-free survival (PFS) was 93.5. One-year cumulative recurrence rate was 6.45%, and no patient had non-relapse mortality (NRM) within one year. Two-year NRM was 12.8%. Non-CR/PR before transplant was a risk factor for transplant outcome (P = 0.01). No recurrence or death post-transplant was observed in patients with CR/PR before allo-HSCT during follow-up time. For patients in non-CR/PR, one-year OS was 84.6% and the one-year cumulative recurrence rate was 15.4%. No patients had recurrent death within one year, and the two-year NRM was 21.2%. PD-1 inhibitor treatment before allo-HSCT neither increased GVHD (aGVHD, P = 0.62; aGVHD&gt; = 2, P = 1; cGVHD, P = 0.613) nor impacted survival (OS, P = 0.7; cumulative recurrence rate, P = 0.32; NRM, P = 0.62). Seventeen of 31 patients (54.84%) were found with heterozygous HLH-related gene variants. The more frequent tier I gene variants were MPEG1 (19%) and PRF1 (6%), and the more frequent tier II gene variants were LYST (23%), MPEG1 (10%), SLC7A7 (6%), STXBP2 (6%), UNC13D (6%), XIAP (6%), CTPS1 (3%), LAMP1 (3%), and PRF1 (3%). The patients with HLH had higher LYSTgene variants (5/12 vs 2/19, P = 0.058) and similar OS compared with that without HLH (P = 0.61). NRM was significantly higher in the patients with HLH than that without HLH (35.7% vs. P = 0.047). All relapsed patients after allo-HSCT received biopsy for pathology and gene variants analysis. High P53 expression in pathology were seen in all relapsed cases even if some of them were no P53 expression before allo-HSCT, and 45% of them were accompanied by TP53 gene variants.
Conclusions: Under current protocol, allo-HSCT has remarkably improved the prognosis of the patients with advanced NKTCL. Non-CR/PR is a risk factor for transplant outcomes. The patients with HLH have significant higher NRM. P53 high expression and TP53 gene variants were highly associated with relapse after allo-HSCT. Our study has identified the profiles of HLH-related gene variants in advanced NKTCL and found LYST gene variants is the most frequent one related to HLH.