Allogeneic haematopoietic cell transplantation for extranodal natural killer/T‐cell lymphoma, nasal type: a <scp>CIBMTR</scp> analysis

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL), is a rare entity characterized by extranodal involvement and association with Epstein–Barr virus (EBV). Treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like therapies alone generally does not provide durable remissions(Tse & Kwong, 2013). While chemo-radiation (for limited stage disease) or L-asparaginase-containing regimens (for advanced stage disease) have improved outcomes, ~40–50% of patients experience progression/relapse(Tse & Kwong, 2016). The median survival of advanced stage or relapsed ENKL is poor at ~6–12 months(Au et al, 2009; Suzuki, 2010). The role of allogeneic haematopoietic cell transplantation (allo-HCT) has been explored in a few small retrospective studies, which almost exclusively were comprised of Asian patients (Table SI). Studies evaluating allo-HCT for ENKL in a North American/European cohort are not available. Using the observational database of the Center for International Blood and Marrow Transplant Research (CIBMTR), we report here the largest analysis and the only study to include Caucasian patients. Adult (≥18 years) ENKL patients undergoing allo-HCT between 2000 and 2014 were included. Central biopsy report review by expert haematopathologist was required for inclusion (details of methods, study definitions and statistical analysis are provided in Supplemental Appendix). The baseline patient-, disease- and transplantation-characteristics of 82 ENKL patients undergoing allo-HCT are described in Table 1. The median age at the time of allo-HCT was 44 years (range: 20–70); 66% were male and 78% had Karnofsky performance score of ≥80%. Recipients were predominantly Caucasian (66%), 19% were of Asian ethnicity. The disease status at the time of HCT was complete remission (CR), partial remission (PR) and chemorefractory disease in 45% 30% and 12%, respectively. The majority of patients received peripheral blood grafts (89%) from matched related donors (61%). Reduced-intensity (RIC) or myeloablative conditioning (MAC) was used in 59% and 38% of cases, respectively. Table SII describes post-transplantation outcomes. With a median follow-up of 36 months (range: 1–121), the cumulative incidence of non-relapse mortality (NRM) and relapse at 3 years were 30% (95%confidence interval [CI]: 20–40) and 42% (95% CI: 32–53), respectively (Fig 1A–B). The corresponding 3-year progression-free (PFS) and overall survival (OS) were 28% (95% CI: 19–39) and 34% (95% CI: 24–45), respectively (Fig 1C–D). No disease relapse was noted beyond the 2-year mark. At last follow-up 52 patients had died, with lymphoma relapse/progression being the most common cause of death (n = 22) (Table SV). Results of univariate analysis to identify factors predicting outcomes are described in Table SIII. We also built a univariate Cox proportional hazards model for each covariate (Table SIV). Recipient race (Caucasian versus Asian) did not significantly impact PFS (Hazard ratio [HR] = 0·92, 95% CI: 0·47–1·80, P = 0·81) or OS (HR = 1·17, 95% CI: 0·59–2·32, P = 0·65). NK-prognostic index (NK-PI) (low/low intermediate-risk versus high intermediate/high-risk NK-PI) was not significantly associated with the risk of disease relapse (HR = 0·81, 95% CI: 0·28–2·35, P = 0·70), PFS (HR = 0·89, 95% CI: 0·37–2·12, P = 0·80) or OS (HR = 1·11, 95% CI: 0·44–2·80, P = 0·83). Among patients receiving late (after >1 line of prior therapy) versus upfront allo-HCT (after first-line therapy), the risk of relapse (HR = 0·86, 95% CI: 0·42–1·77, P = 0·69), PFS (HR = 1·10, 95% CI: 0·60–1·98, P = 0·77) and OS (HR = 1·20, 95% CI: 0·61–2·28, P = 0·58) were not significantly different. Remission status at the time of allo-HCT (CR versus PR versus chemoresistant disease) did not impact the relapse risk (P = 0·93), PFS (P = 0·59) or OS (P = 0·51). There was no statistically significant difference between the outcomes of patients receiving RIC versus MAC regimens in terms of relapse (HR = 0·56, 95% CI: 0·26–1·21, P = 0·14), NRM (HR = 1·72, 95% CI: 0·75–3·92, P = 0·20), PFS (HR = 0·92, 95% CI: 0·54–1·58, P = 0·77) and OS (HR = 0·95, 95% CI: 0·54–1·68, P = 0·85). Literature evaluating the role of allo-HCT in ENKL is limited to small retrospective studies, exclusively in Asian populations (Table SI). The largest previously reported study included 22 patients with ENKL, noting a 2-year PFS and OS of 34% and 40%, respectively (Murashige et al, 2005). In this study, no disease relapse was reported beyond 10 months, hinting at durable remissions with allo-HCT. In our analysis, allo-HCT in ENKL was associated with durable remission and survival in approximately one-third of the patients, with a 3-year PFS and OS of 28% and 34%, respectively and, notably, no relapses were reported beyond 2 years post-transplantation, suggesting potent graft-versus-lymphoma effects. However, disease relapse remained the main reason for treatment failure and death. This observation provides the unique opportunity for implementing better surveillance modalities in the first 2 years after transplantation or investigating novel maintenance strategies to mitigate risk of relapse(Iqbal et al, 2011; Koo et al, 2012; Tse & Kwong, 2013; Kim et al, 2015; Hari et al, 2016). Post-transplant relapse risk, NRM and survival were not affected by patient race, remission status, NK-PI, prior L-asparaginase use, timing of HCT (late vs. upfront) or conditioning intensity. The current study is the only report to evaluate allo-HCT for ENKL in a predominantly Caucasian patient cohort. The similar 3-year OS, of 35% in Caucasian and 33% in Asian patients, is noteworthy and implies the broader applicability of allo-HCT in non-Asian cohorts. In our analysis, the 3-year PFS and OS by pre-HCT remission status were similar, suggesting that even a subset of patients with chemorefractory disease can benefit from allo-HCT. The risk of disease relapse was numerically lower with MAC regimens compared to RIC (50% vs. 30%, P = 0·07), albeit not statistically significant and was offset by higher NRM associated with MAC regimens (40% vs. 23%, P = 0·12) resulting in no difference in PFS and OS by conditioning intensity. Murashige et al (2005), previously reported a 2-year NRM of 30% and 20% with MAC and RIC regimens, comparable to our findings. Being a retrospective study utilizing registry data is an inherent limitation of this analysis. The sample size limits the power to detect small differences in outcomes in our population. Notwithstanding these limitations, this CIBMTR study evaluating the role of allo-HCT in ENKL is the largest study to date and included patients only after a careful central review of biopsy reports. In conclusion, our data suggests that allo-HCT is a viable curative option in a subset of ENKL and should be considered in advanced or relapsed/refractory disease irrespective of patient race. Relapse remains a major cause of treatment-failure, highlighting the need for active surveillance and use of pre-emptive or maintenance strategies to mitigate relapse risk. CIBMTR Support List: The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. *Corporate Members. The authors thank Morgan Geronime for administrative support. Conception and design: Abraham S. Kanate and Mehdi Hamadani. Financial support: CIBMTR. Review of pathology reports: Horatiu Olteanu and Mehdi Hamadani. Collection and assembly of data: Alyssa DiGilio and Mehdi Hamadani. Data analysis: Kwang W. Ahn, Alyssa DiGilio and Mehdi Hamadani. Interpretation: All authors. Manuscript writing: First draft prepared by Abraham S. Kanate and Mehdi Hamadani. All authors helped revise the manuscript. Final approval of manuscript: All authors. No disclosures to report. Table SI. Retrospective studies evaluating allogeneic HCT for ENKL.* Table SII. Post-transplantation outcomes in extranodal NK/T-cell lymphoma. Table SIII. Univariate analysis of post-transplantation outcomes. Table SIV. Univariate Cox proportionate model of post-transplantation outcomes. Table SV. Causes of death post allogeneic transplantation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.