Abstract: Nucleophosmin1 ( NPM1 ) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1 ‐mutated AML. Although patients with NPM1 ‐mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A ( DNMT3A R882 mutations) were a strong predicative factor indicating poor prognosis in all AML ( p   〈  0.0001) and NPM1 ‐mutated AML cases ( p  = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A R882 mutations and the co‐occurrence of internal tandem duplication in FMS‐like tyrosine kinase 3 ( FLT3 ‐ITD), NPM1 mutations, and DNMT3A R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A R882 mutations and triple mutations on prognosis and according to the classification of NPM1 ‐mutated AML into three risk groups based on DNMT3A R882 / FLT3 ‐ITD genotypes, we achieved the improved stratification of prognosis ( p   〈  0.0001). We showed that DNMT3A R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Abstract: Background and objectives: Total body irradiation (TBI) combined with cyclophosphamide (CY) is one of the most common myeloablative conditioning regimens used in allogeneic hematopoietic stem-cell transplantation (HSCT) for treating hematological malignancies. However, it remains unclear whether the order of administrating TBI and CY has an effect on the outcome in clinical transplantation. The aim of this study is to clarify the effects of the order of TBI and CY administration on the outcome of allogeneic HSCT. Patients and Methods: We retrospectively investigated the clinical outcome of 504 adult patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and myelodysplastic syndrome who received allogeneic HSCT with myeloablative conditioning regimens consisting of TBI and CY at the transplant centers participating in the Kanto Study Group on Cell Therapy between January 2001 and August 2012. Patients were divided into two groups based on the order in which TBI and CY were administered. The outcome of HSCT and incidences of acute and chronic GVHD, sinusoidal obstruction syndrome / veno-occlusive disease, and idiopathic pneumonia were compared between the two groups.Patients who underwent HSCT during the first or second remission of acute leukemia or refractory anemia of myelodysplastic syndrome were considered as having standard-risk disease. All other conditions were considered as high-risk disease. Results: A total of 218 patients received CY before TBI (CY-TBI) and 286 received CY after TBI (TBI-CY). AML was more common in the CY-TBI group (62.8%) compared with the TBI-CY group (51.0%), and ALL was less common in the CY-TBI group (25.7%) compared with the TBI-CY group (37.8%; P = 0.013). High-risk disease was more frequent in the CY-TBI group (38.5%) compared with the TBI-CY group (23.4%; P 〈 0.001). The proportion of unrelated bone marrow (54.6% vs. 43.4%) and cord blood transplantation (22.9% vs. 17.8) were higher among patients in the CY-TBI group than in the TBI-CY group (P = 0.0014). TBI was administered at a dose of 12 Gy in 212 patients (97.2%) in the CY-TBI group and 266 patients (93.0%) in the TBI-CY group (P = 0.013). More patients received TBI administered in six fractions in the CY-TBI group (72.9%) than in the TBI-CY group (53.1%; P 〈 0.001). Female to female transplantation was lower in the CY-TBI (13.3%) group compared with the TBI-CY group (24.1%; P = 0.023). Age, gender, GVHD prophylaxis, and blood mismatch were not significantly different between the two groups. The order in which TBI and CY was administered did not affect the incidence of grades II–IV acute GVHD (45.3% vs. 49.3% at day 100; P = 0.28) and chronic GVHD (36.0% vs. 43.8% at 2 years; P = 0.10), overall survival (52.4% vs. 53.4% at 5 years; P = 0.44), disease-free survival (50.5% vs. 51.5% at 5 years; P = 0.58), relapse rate (30.2% vs. 31.8% at 5 years; P = 0.96) and non-relapse mortality (19.3% vs. 16.7% at 5 years; P = 0.52) in the two groups (CY-TBI and TBI-CY, respectively) by univariate analysis. Moreover, the cumulative incidences of sinusoidal obstruction syndrome / veno-occlusive disease (4.1% vs. 3.8%; P = 0.81) and idiopathic pneumonia were comparable (3.1% vs. 3.4%; P = 0.87) between the two groups (CY-TBI and TBI-CY, respectively). Conclusions: This study demonstrates that the order of administration of TBI and CY does not have an effect on the outcome of allogeneic HSCT. Further studies are warranted to confirm this result. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning. Conversely, for those who prefer allo-SCT with myeloablative conditioning (MAC) and has a low HCT-CI score, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each MAC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with cyclophosphamide/total body irradiation (Cy/TBI) or busulfan/cyclophosphamide (Bu/Cy). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy (KSGCT). The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin, liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein (CRP), stem cell source, donor type, antithymocyte globulin use, performance status, recipient/donor sexes, time interval from diagnosis to transplant, and HCT-CI score. To identify a set of variables for Cox proportional hazards, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Cox proportional hazard models. The identified model's discriminative ability was assessed by Harrell's C-statistic calculated using the bootstrap method. Results Among the 555 patients analyzed, 338 received Cy/TBI, and 217 received Bu/Cy. In Cy/TBI and Bu/Cy, the median age was 39 (11-60) and 44 (18-62) years, the HCT-CI score ≤ 2 was observed in 82.1% and 87.6%, and 2-year NRM was found in 13.5% and 16.0% of the patients, respectively. Before transplantation, the most dominant parameters in Cy/TBI were abnormal liver function (AST/ALT or bilirubin & gt;upper limit of normal) and albumin value & lt; 4.5g/dL, whereas those in Bu/Cy were age & gt;40 years, EF & lt; 65 %, and CRP ≥ 0.2 mg/dL. Internal validation with bootstrap resampling showed good discrimination, with C-statistic values of 0.70 (95% CI: 0.69-0.71) in Cy/TBI and 0.68 (95% CI: 0.67-0.69) in Bu/Cy. Each of the abovementioned parameters, including age & gt;40 years, was scored as 1 point. To evaluate the 2-year NRM, we divided the total scores into three risk groups. In the Cy/TBI group, the NRM was 6.9% in low (score 0-1, n = 186), 19.5% in intermediate (score 2, n = 127), and 35.3% in high (score 3, n = 25) scores. In the Bu/Cy group, the NRM was 8.3% in low (score 0-1, n = 93), 21.7% in intermediate (score 2, n = 98), and 29.8% in high (score 3, n = 26) scores (Figure). Higher scores were strongly associated with worse NRM and survival. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each MAC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1 Disclosures Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria. Fujisawa:Takeda Pharmaceutical Company Limited.: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen Pharmaceutical K.K: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Kanda:Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Shionogi: Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria.

Abstract: Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignancy of plasmacytoid dendritic cells as classified by the World Health Organization (WHO), and is characterized by distinct clinical, pathological and genetic features. BPDCN used to be diagnosed as blastic NK-cell lymphoma or CD4+/CD56+ hematodermic neoplasm. Its prognosis is extremely poor with a median overall survival (OS) of about 1 year. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in remission has shown encouraging results for patients with BPDCN. However, the role of high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has not been reported. Methods: We surveyed the data of the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation and identified 109 patients with an original diagnosis of BPDCN, blastic NK-cell or lymphoblastic lymphoma of NK-cell lineage. These diagnoses had been made by a pathologist at each institution in accordance with the WHO classification or previous lymphoma classification systems. Then, we sent out questionnaires to collect additional data on clinical presentation, prior therapies and update of follow-up, in addition to pathology and flow cytometry reports. The diagnosis of BPDCN was made with clinicopathological review by a consensus panel. Results: Of the 109 identified patients, additional data were obtained for 83. After central clinicopathological review, 58 patients were excluded from analysis due to disease other than BPDCN or the absence of important clinical data. Finally, the diagnosis of BPDCN was confirmed in 25 patients (allo-HSCT, N = 14; HDT/ASCT, N = 11). The median age at HSCT was 58 (range, 17-67) years and male patients were predominant (80%). Involvements of skin and bone marrow at diagnosis were observed in 88% and 68% of patients, respectively. The induction chemotherapy regimen was as follows: non-Hodgkin lymphoma (NHL)-like (e.g. cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]-like regimens; or ifosfamide/etoposide-based regimens) (N = 11), acute lymphoblastic leukemia (ALL)-like (N = 10) and acute myeloid leukemia (AML)-like (N = 4). The rate of initial response to induction chemotherapy was high, with a complete remission (CR) rate of 96%, except for one patient who experienced progressive disease in the central nervous system during induction therapy with an ALL-like regimen. The median time from diagnosis to HSCT was 6 months (range, 2-22). Among the patients who underwent allo-HSCT, myeloablative (MAC) and reduced-intensity (RIC) regimens were used in 8 (57%) and 6 (43%) patients, respectively. The donor of 1st allogeneic transplant was a relative in 7, unrelated bone marrow in 7 and cord blood in 1. Regarding the disease status at transplantation, all 11 patients underwent HDT/ASCT in CR1 whereas, among patients who underwent allo-HSCT, 12 were in CR1 (N=10)/CR2 (N =2) and two had disease. With a median follow-up of 53.5 months in surviving patients, OS and progression-free survival (PFS) at 4 years were 65% and 58%, respectively (Figure 1). The OS at 4 years for patients who received HDT/ASCT and allo-HSCT were 82% and 53%, respectively (P = 0.11, Figure 2). The PFS at 4 years for patients who received HDT/ASCT and allo-HSCT were 73% and 48%, respectively (P = 0.14, Figure 2). The three induction regimen groups (NHL-like, ALL-like and AML-like regimens) had similar OS rates: 62%, 70% and 67% at 4 years, respectively (P = 0.86). OS did not differ significantly between MAC and RIC groups (OS at 4 years: 45% vs. 60%, P = 0.31). There was no non-relapse mortality within 100 days after HSCT. Seven patients (28%) relapsed at a median of 10 months (range, 3-21) after HSCT (MAC allo-HSCT, N = 2; reduced-intensity conditioning allo-HSCT, N = 3; HDT/ASCT, N = 2). Notably, there was no relapse in patients without bone marrow (BM) infiltration at diagnosis in the HDT/ASCT treatment group. After allo-HSCT, grade 2-4 acute GVHD was observed in 5 patients (20%). Conclusions: As previous reports have shown, HSCT can achieve long-term survival in patients with BPDCN. In addition, the result of HDT/ASCT in CR1 seems to be promising and deserves further evaluation in the settings of prospective trials. Meanwhile, we need to clarify who could be cured by ASCT and need to improve outcome for high-risk patients, such as those with BM invasion. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction : In the past decade, the combination of high-dose melphalan (MEL) and auto-hematopoietic stem cell transplantation (auto-HCT) with novel agents substantially improved the outcomes in younger patients with multiple myeloma. However, the safety and efficacy of auto-HCT in patients aged ≥65 years remain uncertain. Large clinical trials evaluating the role of auto-HCT in multiple myeloma mostly included patients aged 〈 65 years even in the era of novel agents. Here, we examined the safety and efficacy of auto-HCT in patients with multiple myeloma who were aged ≥65 years. Methods: We examined 2,056 patients aged ≥16 years who underwent auto-HCT for multiple myeloma from 2007 to 2014; they were selected based on the following criteria: (1) first auto-HCT with peripheral blood stem cells; (2) use of MEL alone (100, 140, and 200 mg/m2) as a conditioning regimen; and (3) without planned tandem transplantation. A total of 2,056 patients met these criteria, and 287 of them were aged ≥65 years. The era of novel agents was defined as the date of transplantation after December 2006 because bortezomib was approved for public administration in Japan in December 2006. The primary end-point was 100-day treatment-related mortality (TRM), i.e., not myeloma-related or accidental deaths within 100 days after the first auto-HCT, and the secondary end-point was overall survival (OS). To adjust for a selection bias, the 100-day TRM was compared between two age groups ( 〈 65 vs. ≥65 years) by a propensity score analysis with the following factors: sex, immunoglobulin subtype, Durie-Salmon staging system and international staging system (ISS) stages at diagnosis, renal impairment at diagnosis, cytogenetic abnormalities, disease status at transplantation, conditioning regimen, and performance status (PS) at transplantation. Finally, 1:1 matched pairs were extracted. The probability of 100-day TRM was calculated using the Gray test and assessed by cumulative incidence analysis. The probability of OS was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Multivariate analysis for OS was performed using the Cox proportional hazards model. Results: The median age at transplantation was 66 (range, 65-76) and 57 (range, 18-64) years in the elderly and younger groups, respectively. The number of patients who used 100, 140, and 200 mg/m2 MEL were 17 (1.0%), 71 (4.0%), and 1,681 (95.0%), respectively, in the younger group and 19 (6.6%), 51 (17.8%), and 217 (75.6%), respectively, in the elderly group, with a significant difference (p 〈 0.001). The number of 100-day TRM and deaths due to disease relapse or progression were 13 (0.7%) and 5 (0.3%), respectively, in the younger group and 3 (1.0%) and 1 (0.3%), respectively, in the elderly group. A matched-pair analysis was performed based on the propensity score, and 263 patients were extracted from each group. The 100-day TRM probability was 0.4% (95% confidence interval [CI] : 0.0-2.0%) and 1.2% (95% CI: 0.3-3.1%) in the younger and elderly groups, respectively, without significant difference (p=0.315, Figure 1) in the propensity score-matched pair analysis. The probabilities of 5-year OS after transplantation were 62.5% (95% CI: 58.6-66.1%) and 63.5% (95% CI: 52.2-72.7%) in the younger and elderly groups, respectively, without significant difference (p=0.561, Figure 2). In the multivariate analysis, except age at transplantation ( 〈 65 or ≥65 years), gender, immunoglobulin subtype, ISS stage, unfavorable cytogenetic abnormalities, disease status at transplantation, and PS were significantly associated with OS. Conclusion: The 100-day TRM and OS were not significantly different between the younger and elderly patients who underwent auto-HCT for multiple myeloma in 2007-2014. We showed that auto-HCT is safe and effective for treating multiple myeloma in elderly patients, particularly in the era of novel agents. A comparable benefit was observed in elderly patients who underwent auto-HCT for multiple myeloma, highlighting the fact that chronologic age alone should not be used to determine transplantation eligibility. Disclosures Hanamura: CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Company, Limited: Research Funding; Bristol-Myers Squibb: Other: Lecture fee, Research Funding; Celgene: Other: Lecture fee; Takeda Pharmaceutical Company Limited.: Other: Lecture fee; Fujimoto Pharmaceutical Corporation: Research Funding. Sunami:Sanofi: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Research Funding; MSD: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Mori:Janssen: Honoraria; Eisai: Honoraria; Japan Blood Products Organization: Honoraria; Shire Japan: Honoraria; Kyowa Hakko Kirin: Honoraria; Ono: Honoraria; Celgene: Honoraria; MSD: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Pfizer: Honoraria; Novartis Pharma: Research Funding; Asahi Kasei: Research Funding; Astella Pharma: Honoraria; CHUGAI: Honoraria; SHIONOGI: Honoraria; Novartis Pharma: Honoraria; MSD: Research Funding. Iida:MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Gilead: Research Funding; Sanofi: Consultancy; Teijin Pharma: Research Funding; Toyama Chemical: Research Funding; Astellas: Research Funding; Chugai: Research Funding. Kako:Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Sawa:Celgene Corporation: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis International AG: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Mundipharma K.K.: Honoraria. Kanda:Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Ichinohe:Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Alexion Pharmaceuticals: Honoraria; Zenyaku Kogyo Co.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; MSD: Research Funding; Nippon Shinyaku Co.: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Eisai Co.: Research Funding; CSL Behring: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Novartis.: Honoraria. Takamatsu:Bristol-Myers Squibb: Research Funding; Ono: Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Takami:Chugai: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding.