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Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for myelodysplastic syndrome (MDS) but is associated with high non-relapse mortality (NRM). Its use was originally limited to younger patients eligible for myeloablative conditioning (MAC). Introducing reduced-intensity conditioning (RIC), such as a combination of fludarabine with reduced doses of busulfan (Flu/Bu2), increased the number of elderly patients suitable for allo-HSCT. Additionally, a combination of fludarabine and myeloablative doses of busulfan (Flu/Bu4) was developed to retain the antitumor activity of MAC and reduce the NRM to the level of RIC. However, few published reports have compared Flu/Bu4 and Flu/Bu2 in patients with MDS. We thus retrospectively performed a nationwide study to compare the outcomes of Flu/Bu4 and Flu/Bu2 in MDS patients undergoing allo-HSCT. Methods Clinical data were obtained from the Japanese Data Center for Hematopoietic Cell Transplantation. Inclusion criteria were age ≥16 years, diagnosis of de novo MDS, first allo-HSCT between 2006 and 2018, and receiving Flu/Bu4 consisted of intravenous busulfan (12.8 mg/kg) and fludarabine (125-180 mg/m 2) or Flu/Bu2 consisted of intravenous busulfan (6.4 mg/kg) and the same dose of fludarabine. Administration of anti-thymocyte globulin and low-dose total body irradiation (TBI, total dose ≤4 Gy) was permitted. Propensity score (PS)-matched analysis was performed to minimize selection bias, and the PS was calculated by logistic regression using the following factors: age, sex, hematopoietic cell transplantation-comorbidity index, French-American-British classification at diagnosis, cytogenetic risk, International Prognostic Scoring System score at diagnosis, disease status at allo-HSCT, bone marrow (BM) blasts at allo-HSCT, days from diagnosis to allo-HSCT, stem cell source, graft-versus-host disease (GVHD) prophylaxis, administration of anti-thymocyte globulin and TBI, and year of allo-HSCT. PS matching was performed at a 1:1 ratio using the nearest neighbor-matching method; caliper width was fixed at 0.2. The primary endpoint was the 3-year overall survival (OS). Results In total, 3406 patients underwent their first allo-HSCT: 447 and 256 received Flu/Bu4 and Flu/Bu2, respectively. Among them, 202 patients were assigned to each of the Flu/Bu4 and Flu/Bu2 groups after PS matching. The PS model created comparable cohorts with balanced baseline characteristics. The median age was 61 (range, 21-75) years. At the time of allo-HSCT, BM blasts were ≥5% in 273 (67.6%) patients. Regarding stem cell source, BM, peripheral blood stem cell, and cord blood was used in 268 (66.3%), 51 (12.6%), and 85 (21.0%) patients, respectively. The median follow-up period for survivors was 1117 (range, 40-3784) days. The 3-year OS rates were 44.8% (95% confidence interval [CI], 37.1-52.1%) and 46.9% (95% CI, 39.2-54.2%) in the Flu/Bu4 and Flu/Bu2 groups, respectively (P = 0.671, Figure 1A). The 3-year GVHD- and relapse-free survival rates were 28.8% (95% CI, 22.2-35.7%) and 33.0% (95% CI, 26.2-40.0%; P = 0.357, Figure 1B); the 3-year cumulative incidence of relapse, 28.9% (95% CI, 22.6-35.6%) and 30.0% (95% CI, 23.6-36.6%; P = 0.471, Figure 1C); and the 3-year cumulative incidence of NRM, 28.2% (95% CI, 21.7-35.0%) and 27.1% (95% CI, 20.6-33.9%; P = 0.597, Figure 1D) in the Flu/Bu4 and Flu/Bu2 groups, respectively. The 100-day cumulative incidence of grade II-IV acute GVHD was significantly higher in the Flu/Bu4 group than in the Flu/Bu2 group (41.7% [95% CI, 34.8-48.4%] vs. 29.3% [95% CI, 23.2-35.7%], P = 0.012, Figure 1E). The 100-day cumulative incidences of grade III-IV acute GVHD were 11.4% (95% CI, 7.5-16.3%) and 6.5% (95% CI, 3.6-10.5%; P = 0.064), while the 1-year cumulative incidences of extensive chronic GVHD were 19.5% (95% CI, 14.2-25.4%) and 15.1% in the Flu/Bu4 and Flu/Bu2 groups, respectively (95% CI, 10.5-20.6%; P = 0.196, Figure 1F). According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens (Figure 2). Conclusion The OS did not significantly differ between the Flu/Bu4 and Flu/Bu2 groups. While the Flu/Bu4 group was at an increased risk of acute GVHD, the relapse was not significantly different between the two groups. Data from more patients are needed to determine the optimal intensity of conditioning regimens in patients with MDS. Figure 1 Figure 1. Disclosures Kanda: Sanofi: Research Funding; MSD: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding. Kako: Novartis Pharma K.K.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Bristol-Myers Squibb/Celgene K.K.: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Fuji Pharma Co., Ltd.: Honoraria; CSL Behring K.K.: Honoraria; Amgen K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Imada: Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co. Ltd.: Honoraria; Otsuka Pharmaceutical Co. Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Celgene Co., Ltd.: Honoraria. Kanda: Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Astellas BioPharma: Honoraria; TEIJIN PHARMA LIMITED.: Honoraria. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.

Background High dose melphalan with autologous stem cell transplantation (ASCT) is a standard treatment for eligible patients with systemic light chain (AL) amyloidosis. Treatment-related mortality (TRM) of ASCT for AL amyloidosis was previously reported being as high as 40%; however, risk-adapted melphalan dosing reduced TRM to about 10% or less in experienced institutes. Several ways to determine the dose of melphalan have been proposed. They were focusing on organ failures especially cardiac dysfunction shown by ejection fraction (EF). EF represents contractile function of the heart; however, in AL amyloidosis, EF is known to be maintained until late stage whereas diastolic function is damaged earlier. We here present the outcomes of AL patients who received ASCT following risk-adapted melphalan with our criteria including B type natriuretic peptide (BNP) which is a practical marker for diastolic function of the heart and less affected by the renal function than NT-proBNP. Patients and Methods A total of 12 patients with primary systemic AL amyloidosis treated with HD-Mel with ASCT at Sapporo Medical University Hospital between 2004 and 2012 were evaluated. Patients with age older than 65 years, poor performance status or severe organ dysfunction were determined not to eligible for ASCT. The dose of melphalan for conditioning regimen was modified due to patients' condition. A dose of 200 mg/m2 was administered to patients in performance status (ECOG) 0 or 1, number of organ involvement 2 or less, serum creatinine 50%, and BNP Results Twelve patients were included in this study, 4 were women. The median age at transplantation was 54 years (range, 32 - 65 years). Involvement of 1 organ was present in 1 patient (8.3%), 2 organs were involved in 8, and 3 or more organs in the remaining 3. Ten patients had a lambda monoclonal protein, and the median percentage of plasma cells in the bone marrow was 2.5% (range, 0.2% - 9.6%). No patients received treatment before HDM/ASCT, except 2 patients treated high-dose dexamethasone or 1 course of VAD regimen before referring to our hospital. Six patients received 200 mg/m2 of melphalan and remaining six received reduced dose based on the criteria in Patient and Methods. Notably, it was possible to screen patients with only the value of BNP; i.e., all the patients who received 140 mg/m2 of melphalan by the criteria had a high level (more than 200 pg/ml) of BNP. The median time from diagnosis of AL to ASCT was 95 days (range, 47 to 195 days). The median number of CD34-positive cells infused was 3.55 x106/kg, and all patients were engrafted. The hematologic CR was achieved in 5 patients and PR in 2. The organ response was observed in 2 patients who achieved hematologic CR. The median EFS of all patients was 21.1 months (range, 3.4 to 70.8 months), and median OS was 21.1 months (range, 3.4 to 112.5 months). EFS and OS were significantly longer for patients who received 200 mg/m2 of melphalan that are same with patients who had BNP less than 200 pg/ml, compared with a lower dose of melphalan and higher level of BNP (EFS: 15.0 months vs not reached, p=0.0166; OS: 15.0 months vs not reached, p=0.0166). No TRM was observed. Conclusions AL patients with less than 200 pg/ml of BNP can be safely performed HD-Mel with ASCT and expected longer survival. Disclosures: No relevant conflicts of interest to declare.