Impact of Different Doses of Fludarabine in Fludarabine-Based Conditioning Regimen for Unrelated Bone Marrow Transplantation
Authors: Kuriyama Kodai , Fuji Shigeo , Doki Noriko , Katayama Yuta , Shiratori Souichi , Ozawa Yukiyasu , Ashida Takashi , Kanda Junya , Fukuda Takahiro , Atsuta Yoshiko , Ogata Masao 
Published: November 2019

Background:
The purine analog fludarabine (Flu) is recognized as an agent having strong immunosuppressive effects and plays a central role in reduced-intensity conditioning (RIC) and myeloablative reduced-toxicity conditioning (RTC) regimens because of limited nonhematologic toxicities. Combinations of Flu and busulfan (Bu) (FB group) or melphalan (Mel) (FM group) are the commonly used as RIC and RTC regimens.
Flu inhibits lymphocyte proliferation, induces apoptosis of hematologic malignant cells and has a synergistic tumor-killing effect with alkylating agents such as Bu and Mel. Few reports assess the impact of different dose of Flu on the clinical outcome.
In this study, to compare the impact of Flu doses in RIC or RTC, we retrospectively analyzed clinical outcomes in patients who received FB or FM conditioning by using nationwide registration data of Japan Society for Hematopoietic Cell Transplantation.
Method:
Patients aged 16 years of older with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia and malignant lymphoma, who received FB or FM conditioning regimen, and who underwent bone marrow transplantation from an unrelated donor between 2007 and 2016 were included in this study. We excluded patients who received oral Bu. Also, patients who had renal dysfunction in Hematopoietic Cell Transplantation-Comorbidity Index was excluded because Flu dose needs an adjustment due to renal function. As a result, 2809 patients were included in this study. All transplantation data in the present study were obtained from the Transplant Registry Unified Management Program (TRUMP), which included clinical data of hematopoietic cell transplantation performed in Japan.
Result:
In the FB group (n=1647), high-dose Flu (180 mg/m2; HFB) and low-dose Flu (150/125 mg/m2; LFB) were used in 1334 and 313 patients, respectively. The probabilities of 3-year OS and PFS in the HFB group were significantly higher than that in the LFB group (49% vs 38%, P<0.001; 44% vs 35%, P=0.007). The cumulative incidences of relapse at 3 years were 30.4% and 36.6% (P=0.058), and NRM at 3 years were 25.1% and 28.1% (P=0.24) in the HFB and LFB groups, respectively. In multivariate analysis for OS and relapse, Flu doses was identified as an independent prognostic factor (HR 0.82, P=0.03; HR 0.8, P=0.043). In the FM group (n=1162), high-dose Flu (180 mg/m2; HFM) and low-dose Flu (150/125 mg/m2; LFM) were used in 118 and 1044 patients, respectively. There was no significant difference in the OS, relapse and NRM rates between HFM and LFM (at 3 years, 51.4% vs 48.5%, P=0.596; 22.4% vs 27.0%, P=0.362; 30.7% vs 30.3%, P=0.783).
Conclusion:
In this large study, we suggested that high-dose Flu was associated with favorable outcome in the FB group, but not in the FM group. Prospective studies and further investigations are needed to clarify the benefit of high-dose Flu in the setting of FB regimen.

Disclosures
Ozawa: Kyowa-Hakko Kirin: Honoraria; Astellas Pharma Inc.: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis: Honoraria. Kanda:Daiichi Sankyo Company: Honoraria; Bristol-Meyers Squib: Honoraria; Celgene: Honoraria; MSD: Honoraria; JCR Pharmaceuticals: Honoraria; Takeda: Honoraria; Otsuka: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai: Honoraria; Astellas: Honoraria; Novartis: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392. Atsuta:Kyowa Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria.