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3485 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

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment, and Acute Toxicities: Poster II
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, MDS, Clinical Practice (Health Services and Quality), MPN, Clinical Research, CML, Chronic Myeloid Malignancies, Diseases, Real-world evidence, Treatment Considerations, Myeloid Malignancies, Human
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Jotaro Yamamoto1*, Hisashi Yamamoto, MD, PhD2*, Mika Kuno, MD2*, Otoya Watanabe, MD2*, Kyosuke Yamaguchi, MD3*, Kosei Kageyama, MD3*, Daisuke Kaji, MD, PhD2*, Yuki Taya, MD, PhD2*, Aya Nishida, MD2*, Shinsuke Takagi, MD, PhD2*, Kazuya Ishiwata, MD3*, Go Yamamoto, MD, PhD2*, Yuki Asano-Mori, MD4, Atsushi Wake, MD, PhD3 and Naoyuki Uchida2

1Department of Hematology, Toranomon Hospital, Minato City, Japan
2Department of Hematology, Toranomon Hospital, Tokyo, Japan
3Department of Hematology, Toranomon Hospital Kajigaya, Kanagawa, Japan
4Department of Transfusion and Cell Therapy, Toranomon Hospital, Tokyo, Japan

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 (<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 <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<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<0.01), while differences among MMF dose groups were not significant after adjustment. Subgroup analysis by age (≥60 and <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.

Disclosures: Yamamoto: JCR Pharmaceuticals Co.,Ltd.: Honoraria; MSD KK (Merck & Co.) Inc.: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; AstraZeneca: Honoraria; Novartis Pharma Co.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Janssen Pharmaceutical KK: Honoraria; CSL Behring K.K: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Sumitomo Pharma CO.,Ltd.: Honoraria. Yamaguchi: Nippon Shinyaku Co.: Honoraria; AbbVie GK.: Honoraria. Kaji: AbbVie GK.: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Meiji Seika Pharma Co.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Eisai Co.: Honoraria; Genmab: Honoraria; Bristol Myers Squibb K.K.: Honoraria; AstraZeneca: Honoraria; Takeda Pharmaceutical Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Sanofi K.K.: Honoraria; Pfizer Japan Inc.: Honoraria; Ono Pharmaceutical Co.: Honoraria. Takagi: Otsuka Pharmaceutical Co.: Honoraria; Novartis Pharma Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; MSD KK (Merck & Co. Inc.): Honoraria; Kyowa Kirin Co.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; GlaxoSmithKline KK.: Honoraria; Daiichi Sankyo Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Astellas Pharma Inc.: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Amgen KK.: Honoraria; AbbVie GK.: Honoraria; The Japanese Society of Hematology: Research Funding; Okinaka Memorial Institute for Medical Research: Research Funding; Pfizer Japan Inc.: Honoraria; Sumitomo Pharma Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria. Yamamoto: Novartis Pharma Co.: Honoraria; Nihonkayaku Co.: Honoraria; Mundi Pharma Co.: Honoraria; Meiji Seika Pharma Co.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; AstraZeneca: Honoraria; Genmab: Honoraria; Bristol Myers Squibb K.K.: Honoraria; Eisai Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Daiichi Sankyo Co.: Honoraria; Ono Pharmaceutical Co.: Honoraria; Pfizer Japan Inc.: Honoraria; Sanofi K.K.: Honoraria; Takeda Pharmaceutical Co.: Honoraria. Wake: Pfizer Japan Inc.: Honoraria; Sanofi K.K.: Honoraria; Alexionpharma: Honoraria; Nihonkayaku Co.: Honoraria; Novartis Pharma Co.: Honoraria; Daiichi Sankyo Co.: Honoraria; Janssen Pharmaceutical KK.: Honoraria; GlaxoSmithKline KK.: Honoraria; SymBio Pharmaceuticals: Honoraria; Astellas Pharma Inc.: Honoraria; Ono Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria; Mundi Pharma Co.: Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Eisai Co.: Honoraria; Meiji Seika Pharma Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Amgen KK: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Bristol Myers Squibb K.K: Honoraria; AstraZeneca: Honoraria. Uchida: Chugai Pharmaceutical Co.: Research Funding; Sumitomo Pharma Co.: Research Funding; Fuji Pharma Co.: Research Funding; AstraZeneca: Honoraria; Asahi Kasei Pharma Co.: Honoraria; Astellas Pharma Inc.: Honoraria; Nippon Boehringer Ingelheim Co.: Research Funding; JCR Pharmaceuticals Co.: Research Funding; CSL Behring: Honoraria; MSD (Merck & Co. Inc.): Honoraria; AbbVie GK: Honoraria; Otsuka Pharmaceutical Co.: Honoraria; Kyowa Kirin Co.: Honoraria; SymBio Pharmaceuticals: Honoraria; Daiichi Sankyo Co.: Honoraria; Takeda Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co.: Honoraria; Nippon Shinyaku Co.: Honoraria; Takeda Pharmaceutical Co.: Consultancy; Astellas Pharma Inc.: Consultancy; Novartis Pharma Co.: Honoraria.

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