Page 307 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
Mycophenolate mofetil is associated with inferior overall survival in cytomegalovirus-seropositive patients with acute myeloid leukemia undergoing hematopoietic cell transplantation
A combination of a calcineurin-inhibitor (CNI) with myco- phenolate mofetil (MMF) or methotrexate (MTX) is commonly used as graft-versus-host disease (GvHD) prophylaxis for HLA-matched donor hematopoietic cell transplantation (HCT). However, the use of MMF, which targets both T- and B-lymphocytes, is associated with a higher risk of cytomeg- alovirus (CMV) reactivation as compared to MTX.1 Moreover, CMV reactivation is associated with an increased risk of non-relapse mortality (NRM) and worse overall survival (OS).2 We, therefore, postulated that the use of MMF as compared to MTX may increase these risks, especially in CMV-seropositive recipients. To investigate this hypothe- sis, we compared the HCT outcomes of four groups: MTX/ CMV– (n=916), MTX/CMV+ (n=1,527), MMF/CMV– (n=267), and MMF/CMV+ (n=395).
We used an existing Center for International Blood and Marrow Transplant Research (CIBMTR) publicly available dataset3 from a previous publication.4 Our study population included patients ≥18 years with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodys- plastic neoplasm (MDS) who underwent HCT with peripheral blood grafts from 10/10 HLA-matched unrelated donors between 2008 and 2017. All patients received tacrolimus with either MMF or MTX. Patients who received ex-vivo T-cell-depleted/CD34+ cell-selected grafts or post-trans- plant cyclophosphamide (PTCy) were excluded. Our primary outcome of interest was OS. Secondary outcomes includ- ed grades III-IV acute GvHD, chronic GvHD, relapse, and NRM. The Kaplan-Meier method was used to estimate OS probability. The cumulative incidence method accounting for competing risks was used to estimate the incidence of GvHD, NRM, and relapse. Competing risks considered were death or disease relapse for GvHD; disease relapse or relapse-related deaths for NRM; and death before relapse (NRM) for relapse. Predictors in univariate and multivariable analyses were evaluated using Cox proportional hazards regression for OS, and Fine-Gray regression accounting for competing risks for GvHD, NRM, and relapse. Factors significant at the 5% level (P≤0.05) were retained in the final model, except the main effect (GvHD prophylaxis/ recipient CMV serostatus), which was retained in the final model irrespective of the level of statistical significance. Bonferroni-adjusted P values are reported for multivariate analyses for the main effect to account for multiple testing.
Interaction effects between the main effect and other sta- tistically significant co-variables were tested and account- ed for as indicated in multivariable regression analyses. All reported outcomes are at 3 years, except acute GvHD which is at day 180. The proportionality of hazards assump- tion was tested graphically and statistically. All statistical analyses were performed using STATA/IC 16.1 (StataCorp LLC, College Station, TX, USA). As the data analysis was carried out at The MD Anderson Cancer Center, the local Institutional Review Board approved this study (protocol: 2022-0684), which was conducted in accordance with the Declaration of Helsinki. The dataset is publicly available3 for data sharing, in accordance with CIBMTR guidelines. The study population’s baseline characteristics are shown in Table 1. In patients with AML (n=1,572), OS was signifi- cantly (P<0.001) inferior in CMV+ recipients who received MMF prophylaxis. Overall survival at 3 years was only 31% (95% confidence interval [95% CI]: 25-37) in the MMF/CMV+ group, compared with 54% (95% CI: 45-63) in the MMF/ CMV– group, 51% (95% CI: 48-55) in the MTX/CMV+ group, and 58% (95% CI: 53-63) in the MTX/CMV– group (Figure 1A). This effect persisted in multivariate analysis: compared to the overall mortality in the MTX/CMV– group, the risk was 1.8-fold higher in the MMF/CMV+ group, while it did not differ significantly in other groups (Table 2, Online Sup- plementary Table S1). Inferior OS in the MMF/CMV+ group was driven by a higher risk of NRM (Figure 1B). The risks of relapse (Figure 1C) and grade III-IV acute and chronic GvHD (Figure 1D) did not differ significantly between the groups. In MDS patients (n=1,080), GvHD prophylaxis/recipient CMV serostatus had no significant association with OS, or the risk of relapse, but NRM varied by the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score (Table 2, Online Supplementary Figure S1A). Among those with an HCT-CI score ≥3, the MTX/CMV+ group had a higher risk of NRM than had the MTX/CMV– group, while no sta- tistically significant differences were seen in patients with an HCT-CI score 0-2. The risk of chronic GvHD was higher in the MMF/CMV– group than in the MTX groups.
In ALL patients (n=453), GvHD prophylaxis/recipient CMV serostatus had no significant associations with OS, NRM, or relapse (Table 2, Online Supplementary Figure S1B). The risk of chronic GvHD was higher in the MMF/CMV– group than in the MTX groups.
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