PTCy or ATG for Matched Transplantation in Myelofibrosis

Allogeneic hematopoietic stem cell transplantation remains the only curative therapy, yet outcomes are tempered by graft failure, relapse, infectious complications, and graft-versus-host disease (GVHD) [1]. Two approaches for GVHD prophylaxis dominate: anti-thymocyte or anti-T-lymphocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy). ATG provides broad in vivo T-cell depletion and reduces GVHD risk and has been shown to improve outcomes in all donor settings [2]. PTCy, primarily used in the haploidentical setting, acts post-transplant to selectively eliminate proliferating alloreactive T cells while preserving regulatory and memory populations, potentially mitigating GVHD while supporting immune reconstitution [3]. Both strategies have shown efficacy [2, 4-7], yet their relative impact in myelofibrosis in the matched donor setting—a disease with unique transplant dynamics—remains unclear. This study aims to evaluate outcomes of HLA-matched transplantation in MF using either ATG or PTCy. This was a retrospective, non-randomized comparison in patients undergoing transplantation for myelofibrosis between 2010 and 2024. Additional GVHD prophylaxis in both arms consisted of cyclosporine A together with mycophenolate mofetil or methotrexate, depending on center standards. Patients with accelerated-phase or blast-phase MF were excluded [8]. Dose for PTCy was 50 mg/kg/day on 2 days after transplant. Patients receiving ATG included two different brands: Thymoglobulin (Sanofi, France) 3.5 mg/kg/day on 2 days before transplantation or Grafalon (Neovii, Germany) 30 mg/kg/day for matched siblings and 60 mg/kg/day for matched unrelated donors on 3 days before transplantation. To account for selection bias and potential confounding factors between groups in outcome comparisons, we employed a weighted propensity score analysis to balance baseline characteristics between patients who received ATG versus PTCY. The propensity score model was generated using the inverse probability of treatment weighting (IPTW) approach, where each patient was weighted by the inverse probability of being in the ATG or PTCY group. Weighted Cox proportional hazards models were used to assess survival outcomes, hazard ratios (wHRs), and Fine-Gray regression was used for endpoints with competing risks. A total of 539 patients were included, with 427 receiving ATG and 112 PTCy (Supplemental Table 1), and the median age was comparable between groups (58 vs. 60 years, p = 0.21). Donor type showed a trend toward more matched related donors in the PTCy group compared with ATG (38% vs. 28%, p = 0.06). Conditioning intensity differed significantly between groups: reduced-intensity regimens were predominant in the ATG group (79%), whereas nearly half of patients in the PTCy group received higher-intensity conditioning (47%; p < 0.001). Median follow-up was 4.8 years for the ATG group and 3.7 years for the PTCy group (p = 0.12). We first performed an unadjusted univariate comparison of ATG versus PTCy (Table 1). In terms of engraftment, neutrophil recovery occurred significantly earlier in patients receiving ATG compared with those given PTCy (median 14 vs. 23 days, p < 0.001; Figure 1) and primary graft failure was more frequent after PTCy (7% vs. 1%: p < 0.001). Cumulative incidence of platelet engraftment was 88% for ATG versus 73% for PTCy (p < 0.001). Relapse incidence at 4 years was lower in the ATG group (14%) compared with PTCy (33%; p < 0.001), and non-relapse mortality at 4 years was similar between groups (24% vs. 26%; p = 0.53). Overall survival at 4 years showed a trend in favor of ATG (71% vs. 64%; p = 0.08). In terms of GVHD (Figure 2), chronic GVHD was significantly more common in the ATG cohort, affecting 50% at 4 years compared with 23% in the PTCy cohort (p < 0.001). Furthermore, the severity of chronic GVHD was significantly different between the groups, with moderate–severe chronic GVHD occurring in 27% for ATG versus 10% for PTCy (p = 0.02). Rates of acute GVHD by day 180 were comparable (30% vs. 27%; p = 0.40), with severe acute GVHD grade III–IV being numerically higher for ATG (10%) versus PTCy (5%). GRFS at 4 years was 42% in the ATG group and 37% in the PTCy group, with no significant difference (p = 0.14). We next performed matched analyses. Here, relapse incidence remained higher in patients receiving PTCy versus ATG (33% vs. 20%; p = 0.15), while GRFS was comparable between groups (37% with PTCy vs. 31% with ATG, p = 0.37). In multivariable models of matched cohorts, PTCy was associated with significantly lower risk of chronic GVHD compared with ATG (HR 0.60; p = 0.001), with a trend for increased risk of relapse with PTCy (HR 1.41; p = 0.2). For GRFS, we observed no significant difference (HR 0.94; p = 0.7). Together, these findings indicate that in the propensity score-matched cohort, no differential impact on GRFS was detected for either prophylaxis strategy, with nuanced results for GRFS components indicating higher risk for relapse but lower risk for chronic GVHD with PTCy compared with ATG (Supporting Information). GVHD remains a major obstacle in allogeneic transplants for myelofibrosis: in a recent study, acute GvHD grade III–IV was reported to occur in 22% of MF patients, with a higher rate of liver involvement [9]. ATG has been shown to reduce GVHD in patients with hematologic malignancies and to increase the proportion of recipients free of immunosuppressive therapy at 2 years [2, 7]. Engraftment is another key issue for MF patients following an allogeneic transplantation, given that these patients tend to be at onset higher risk for late engraftment, graft failure, or poor graft function [10, 11]. Identifying the right GVHD prophylaxis therefore becomes crucial for these patients receiving matched transplants, where graft failure rates would be expected to be low [12]. Our findings of delayed engraftment and higher graft failure rates with PTCy are in line with recent studies [6]. Future studies should investigate whether optimization of PTCy dose or a combination of ATG and PTCy can mitigate graft failure risk without compromising GVHD protection. Relapse also remains a relevant problem overall after transplant, and specifically in MF patients [13]. One of the key questions in the transplant field is whether GVHD protection with PTCy dissociates from a graft-versus-leukemia effect. While some studies suggested no increased relapse with PTCy [14, 15], others have shown in the particular setting of MF that there is a nuanced association between GVHD and relapse [9, 16]. The present study is underpowered to investigate the potential association of relapse and GVHD in the PTCy setting in a robust fashion. Of note, one particular difference between MF and other myeloid diseases is the type of relapse and its assessment (molecular vs. hematological vs. both) [17]. One reason for higher relapse in our group could be due to close post-transplant follow-up and clinical evaluation while most registry studies have no access to reliable relapse assessment, which could impact relapse rate interpretations. However, the results seen for PTCy are closely correlated with most recent reports [6]. This study has inherent limitations related to its retrospective, non-randomized design, which precludes full control for unmeasured confounders. In addition, the use of PTCy versus ATG was largely center-specific rather than evenly distributed across contributing institutions, introducing potential institutional practice effects that cannot be entirely excluded despite broadly homogeneous transplant approaches for myelofibrosis across centers. Detailed, standardized data on the timing and intensity of post-transplant immunosuppression tapering and discontinuation were not available, precluding analysis of potential differences between the PTCy and ATG groups. Given the observed trade-off between graft-versus-host disease and relapse in this study, the impact of prophylaxis duration on these outcomes warrants prospective investigation. Finally, a cautious analytic approach was adopted: because detailed post-transplant monitoring data (including transfusion requirements and relapse-directed therapies) were not consistently available, and other modalities such as chimerism assessment were not uniformly performed across the cohort and are technology-dependent, these variables were not included in the analysis to limit heterogeneity and reduce the risk of biased or overinterpreted findings. Future studies should assess the potential for early molecular targeted intervention to reduce incidence or burden of relapse, particularly in the PTCy setting [18, 19]. In conclusion, PTCy was associated with reduced chronic GVHD but increased risk of relapse and graft failure in myelofibrosis undergoing HLA-matched allogeneic transplantation, with similar GRFS and overall survival compared with ATG. The authors have nothing to report. Has been obtained by each center. Has been obtained by each center. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1: ajh70244-sup-0001-Supinfo.docx. 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.