Xenopax is effective for the treatment and prophylaxis of acute graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation is one of the most important curative therapeutic methods for hematologic malignancies and certain non-malignant hematopoietic disorders.1–3 Despite advancements in prophylactic strategies (eg, antithymocyte globulin or post-transplant cyclophosphamide), severe acute graft-versus-host disease (aGVHD), particularly the steroid refractory (SR) aGVHD, remains the important cause of early transplant-related mortality. Interleukin-2 receptor (IL-2R) antagonists have been widely used as the treatment for SR-aGVHD. Basiliximab (a chimeric mouse-human monoclonal antibody) and xenopax (a recombinant humanized monoclonal antibody) are 2 available IL-2R antagonists in China. Compared to basiliximab, xenopax has a longer elimination half-life (13.3 vs 7.2 d) and it may induce a weaker immune response.4 Thus far, many clinical studies have reported the clinical outcomes for basiliximab in SR-aGVHD,5,6 but data on the efficacy and safety for xenopax, approved as a category 2 therapeutic biological product by the National Medical Products Administration (NMPA) in China, are still needed. Recently, a multicenter cohort study (RELAX study) was conducted to evaluate the safety, efficacy, and prognostic factors of xenopax in patients with SR-aGVHD.7 Among the 172 SR-aGVHD patients treated with xenopax, an overall response rate (ORR) of 64.5% on day 28 was noted, with 2-year overall survival (OS) and non-relapse mortality (NRM) rates of 68.0% and 24.2%, respectively. Additionally, xenopax showed certain advantages over other second-line agents (eg, ruxolitinib). Thus, this is the first and largest study showing the safety and efficacy of xenopax for the treatment of SR-aGVHD under real-world conditions. Furthermore, the authors reported that xenopax offers better cost-effectiveness compared to basiliximab, potentially reducing the economic burden of Chinese patients with SR-aGVHD. Based on the results of the REACH2 study and several meta-analyses, ruxolitinib has been approved as a therapy for SR-aGVHD. In the REACH2 study, the 28-day ORR was 62.3%; however, the complete remission rate was only 34.4%, and the durable ORR at day 56 decreased to 39.6%. Thus, a significant proportion of patients did not achieve a satisfactory response to ruxolitinib, and there was no widely accepted salvage therapy for these patients. In the RELAX study, they observed that for patients who failed to respond to ruxolitinib-based therapies, the ORR at day 28 and at any time after xenopax treatment were as high as 69.4% and 89.8%, respectively, suggesting that xenopax may be an ideal salvage therapy for these patients. Several studies have reported that mesenchymal stem cells (MSC) combined with basiliximab show a higher ORR compared to those received basiliximab alone,8 particularly in patients with gut SR-aGVHD.9 Based on the results of RELAX study, it is reasonable to expect that xenopax combined with MSC may also yield satisfactory clinical outcomes, which requires further investigation in the future. Several groups have also used xenopax for the prophylaxis of aGVHD. In a prospective registry study (ChiCTR2200060184), Zhang et al10 identified the efficacy of xenopax as a potential alternative for methotrexate (MTX) in GVHD prophylaxis for haploidentical hematopoietic stem cell transplantation (HSCT) recipients. Participants were divided into 2 cohorts: a single-dose group (25 mg/d xenopax + MTX) and a double-dose group (50 mg/d xenopax). The double-dose cohort demonstrated a significantly lower incidence of total aGVHD (23.53% vs 42.11%; p = 0.009) and grades III to IV aGVHD (7.35% vs 18.42%; p = 0.047). Additionally, this double-dose regimen significantly reduced the rates of oral mucositis, infections, and hemorrhagic cystitis. Therefore, a double-dose xenopax regimen without MTX may be a promising strategy for aGVHD prophylaxis. Approximately 50% of the aGVHD patients showed no response to the first-line steroid treatment; however, methods to improve the ORR of first-line treatment remain unclear. Combining steroids with other immunosuppressants may be a reasonable option.11,12 In a randomized controlled trial by Lee et al13 which compared daclizumab plus steroids with steroids alone as the initial treatment for aGVHD, the study was halted after a planned interim analysis showed a significantly worse OS at 100 days (77% vs 94%; p = 0.020) and at 1 year (29% vs 60%; p = 0.002) in the combined therapy group. Both relapse- and GVHD-related mortalities contributed to the increased total mortality. Although xenopax shares similar amino acid sequence, pharmacokinetic and pharmacodynamic profiles with daclizumab, it is expressed in Chinese hamster ovary (CHO) cells instead of murine myeloma non-secreting 0 (NS0) cells, which might result in much tolerance. A prospective, single-arm study aims to evaluate the efficacy and safety of steroids combined with xenopax as a first-line treatment for aGVHD (NCT06473909). We look forward to receiving its final results. In summary, the RELAX study supported the safety and efficacy of xenopax for the treatment of SR-aGVHD, and the comparisons of the clinical outcomes between xenopax and other systemic second-line therapies could further confirm these findings. Additionally, we anticipate that xenopax can play a critical role in the prophylaxis and first-line treatment of aGVHD.