What Is the Optimal Dose of MMF in Single Cord Blood Transplantation?: A Single-Center Analysis of MMF Dosage for GVHD Prophylaxis and Its Impact on Outcomes
Authors: Yamamoto Jotaro , Yamamoto Hisashi , Kuno Mika , Watanabe Otoya , Yamaguchi Kyosuke , Kageyama Kosei , Kaji Daisuke , Taya Yuki , Nishida Aya , Takagi Shinsuke , Ishiwata Kazuya , Yamamoto Go , Asano-Mori Yuki , Wake Atsushi , Uchida Naoyuki 
Published: December 2024

Introduction: Umbilical cord blood transplantation (UCBT) is a valuable treatment option with the potential for curative outcomes in patients with myeloid malignancies in non-remission status, but relapse and early non-relapse mortality (NRM) remain significant barriers. Tacrolimus and mycophenolate mofetil (MMF) are widely used as graft-versus-host disease (GVHD) prophylaxis in UCBT, but there is no consensus on the appropriate MMF dose for GVHD prophylaxis. We conducted a retrospective analysis to investigate the impact of MMF dose on outcomes in patients undergoing single UCBT with tacrolimus and MMF at our institution.

Methods: We reviewed patients with myeloid malignancies who received their first single UCBT in non-remission status at our center between April 2010 and March 2023, administered tacrolimus and MMF for GVHD prophylaxis. Patients with poor performance status (ECOG PS 3-4) were excluded. The initial MMF dose was divided into three groups: MMF-Lo (&lt;17 mg/kg), MMF-Int (17-23 mg/kg), and MMF-Hi (≥23 mg/kg). Primary endpoint: disease-free survival (DFS). Secondary endpoints: overall survival (OS), relapse incidence, NRM, neutrophil engraftment, acute GVHD, and severe preengraftment immune reactions (PIR). DFS and OS probabilities were estimated using the Kaplan-Meier method; differences were evaluated using the log-rank test. Cox regression analysis examined the independent effect of MMF dose on outcomes, calculating hazard ratios (HRs) with 95% confidence intervals (CIs). The Fine-Gray model was used to evaluate relapse, NRM, neutrophil engraftment, acute GVHD, and severe PIR, accommodating competing risks.

Results: A total of 574 patients were enrolled, median age 63 years (range 16-79), 48% female. Diagnoses included AML (n=436), MDS (n=107), and MPN (n=31). 79.8% received myeloablative conditioning regimens. Median numbers of TNC and CD34-positive cells were 2.45x10^7/kg and 0.84x10^5/kg, respectively. MMF groups: 95 patients (16.6%) in MMF-Lo, 358 (62.4%) in MMF-Int, and 121 (21.1%) in MMF-Hi. MMF administration began the day before transplantation, median duration 41 days. Mean ages for MMF-Lo, MMF-Int, and MMF-Hi groups were 54, 63, and 66 years, with p-values &lt;0.01 across groups. The 3-year OS and DFS were 39.6% and 37.5%. The 3-year NRM and relapse rates were 42.4% and 22.9%, with a cumulative neutrophil engraftment rate of 92.1% (median engraftment time 21 days). Significant differences in 3-year DFS were observed between MMF-Lo and MMF-Hi (p=0.03). OS rates were 53.0%, 37.9%, and 34.2%, with significant differences between MMF-Lo and MMF-Int (p=0.04) and MMF-Lo and MMF-Hi (p=0.02). No significant differences were observed in relapse rates. The 3-year cumulative incidence (CI) of NRM was 31.3%, 44.6%, and 45.2%, with significant differences between MMF-Lo and MMF-Int (p=0.03) and MMF-Lo and MMF-Hi (p=0.04). Neutrophil engraftment rates were 97.9%, 92.7%, and 86.0%, with significant differences between MMF-Lo and MMF-Hi (p&lt;0.05). Severe PIR incidence showed no significant differences. The 100-day CI of grade 2-4 acute GVHD was 68.4%, 63.1%, and 62.8%, with no significant differences. Multivariate analysis revealed age as a significant factor affecting OS, DFS, and NRM (p&lt;0.01), while differences among MMF dose groups were not significant after adjustment. Subgroup analysis by age (≥60 and &lt;60) and by disease showed no significant differences in DFS, OS, NRM, or relapse among the MMF dose groups. However, the MMF-Hi group had a significantly lower engraftment rate compared to the MMF-Lo group (HR=0.69, p=0.01). Other factors contributing to engraftment rate included the number of CD34-positive cells (HR=1.50, p=0.02) and female recipient sex (HR=1.21, p=0.04). Among 45 patients not achieving neutrophil engraftment, 36 died before engraftment. Nine experienced engraftment failure, with one case of hemophagocytic syndrome and the rest due to graft rejection.Discussion: MMF dose did not affect DFS, OS, NRM, relapse, or acute GVHD incidence, but an MMF dosage of more than 23 mg/kg was detrimental to neutrophil engraftment. Graft rejection was predominant among neutrophil engraftment failure cases, suggesting excessive donor cell suppression due to a higher dose of MMF might have lead to graft rejection and increased NRM. Therefore, an MMF dosage of less than 23 mg/kg is recommended.