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.

Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) with the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen is an essential therapeutic strategy for acute lymphoblastic leukemia (ALL) in adults. Medium‐dose etoposide (VP16, 30‐40 mg/kg) can be added to intensify this CY/TBI regimen and reduce relapse; however, differences in prognosis between the VP16/CY/TBI and CY/TBI regimens have not yet been fully analyzed. We conducted a retrospective cohort study using a Japanese transplant registry database to compare the prognosis between the VP16/CY/TBI (VP16, total 30‐40 mg/kg) ( N  = 376) and CY/TBI ( N  = 1178) regimens in adult patients with ALL transplanted at complete remission (CR) between January 1, 2000 and December 31, 2014. Our analyses indicated that VP16/CY/TBI significantly reduced relapse compared with CY/TBI (risk ratio, 0.75; 95% confidence interval [CI], 0.56‐1.00; P  = .05) with a corresponding improvement in leukemia‐free survival (hazard ratio [HR], 0.76; 95%CI, 0.62‐0.93; P  = .01), particularly in patients transplanted at CR1 with advanced‐risk (positive minimal residual disease, presence of poor‐risk cytogenetics, or an initial elevated leukocyte count) (HR, 0.75; 95%CI, 0.56‐1.00; P  = .05) or those transplanted beyond CR2 (HR, 0.58; 95%CI, 0.39‐0.88; P  = .01). The addition of VP16 did not increase post‐transplant complications or nonrelapse mortality (HR, 0.88; 95%CI, 0.65‐1.18; P  = .38). This study is the first to reveal the efficacy of the addition of medium‐dose VP16 to CY/TBI in high‐risk ALL. To establish new myeloablative conditioning regimens including VP16, a large‐scale prospective study is necessary.

Abstract: The optimal treatment strategy with the use of hematopoietic stem cell transplantation (HSCT) for relapsed and refractory Hodgkin lymphoma (HL) remains unclear. We performed a retrospective analysis using registry data from the Japanese Society for Hematopoietic Cell Transplantation. Adult patients with HL who underwent a first autologous or a first allogeneic HSCT between 2002 and 2009 were included. Patients who underwent HSCT in first complete remission (CR) were excluded. Autologous and allogeneic HSCT were performed in 298 and 122 patients, respectively. For autologous HSCT, overall survival at 3 years (3yOS) was 70%, and sex, age, disease status, and performance status (PS) at HSCT were prognostic factors. OS was favorable even in patients who underwent autologous HSCT in disease status other than CR. For allogeneic HSCT, 3yOS was 43%, and sex and PS at HSCT were prognostic factors. Disease status at HSCT, previous autologous HSCT, and conditioning intensity did not affect OS. Moreover, graft‐versus‐host disease did not affect progression‐free survival or relapse/progression rate. A first allogeneic HSCT without a previous autologous HSCT was performed in 40 patients. 3yOS was 45%, and was significantly inferior to that in patients who underwent their first autologous HSCT. This result was retained after the correction by the different patient characteristics according to the type of HSCT. In conclusion, autologous HSCT is effective in prolonging survival in patients with relapsed and refractory HL. Allogeneic HSCT might be beneficial even to relapsed HL after autologous HSCT, although establishing the role of allogeneic HSCT remains a challenge. Am. J. Hematol. 90:132–138, 2015. © 2014 Wiley Periodicals, Inc.

Abstract: [Background] CD34-positive monocytes (CD34+mono) have recently been identified following mobilization by granulocyte-colony stimulating factor (G-CSF), and have been suggested to have a potential to modulate immune functions in animal models. However, the biological feature of CD34+mono in humans still remains unclear. Thus, we explored the difference between CD34+mono, CD34+cells, and monocytes through the analyses of gene expression profiles (GEP). [Methods] CD34+mono　(Lin-CD34+CD33+CD14+CD11b+, Figure1), CD34+cells (Lin-CD34+CD33-CD14-CD11b- ), and monocytes (Lin-CD34-CD33+CD14+CD11b+) were directly sorted into tubes from cryopreserved grafts from three healthy donors. After the extraction of total RNA, microarray analyses were performed with GeneChip™ 3' IVT Pico Kit and analyzed according to the algorithm of Transcriptome Analysis Console (Thermo Fisher Scientific). Condition false discovery rate (FDR) F-test was used for filtering genes, and the threshold was 〈 0.0005 for hierarchical clustering without considering fold changes. In addition, enrichment analyses were performed for gene ontology (GO) and pathways by the Kyoto Encyclopedia of Genes and Genomes (KEGG) through Database for Annotation, Visualization and Integrated Discovery (DAVID). The differentially expressed genes with 〈 0.05 of F-test values and 2 or more fold changes in CD34+mono compared with CD34+cells and monocytes were selected for the enrichment analyses. Thereafter, the protein-protein interaction (PPI) network in CD34+mono was constructed through Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which is a biological database. This study was approved by the institutional review board of Jichi Medical University and all subjects gave their written informed consent for the cryopreservation and analysis of the blood samples in accordance with the Helsinki Declaration. [Results] CD34+mono resembled con-mono in the appearance, although it might look slightly immature. In fact, the number of differential expressed genes was smaller in the pair of CD34+mono vs. monocytes (n=605) compared with the other pair (n=2136), suggesting that CD34+mono might stand nearby monocytes. However, a principle component analysis of GEP demonstrated that CD34+mono would be categorized into an independent cell type entity. In addition, the hierarchical clustering heat map suggested that CD34+mono would have the interim gene expressions between CD34+ cells and monocytes (Figure 2). GO analysis was also performed using the 203 genes which were differentially expressed in CD34+mono compared with CD34+cells and monocytes. The differentially expressed genes seemed to be significantly involved in the "immune system process" of biological process, followed by "locomotion", "metabolic process" and "response to stimulus", because pro-inflammatory genes in CD34+mono like IL6, CCL3, IL8, VEGFA, and IL1A were increased. In addition, PPI analyses indicated that 128 of the 203 differentially expressed genes in CD34+mono had close connections with each other. Especially, IL6, VEGFA, IL8, NFkB1, EGR1, CDKN1A (p21), and CYCS could be considered as a hub gene in CD34+mono. Of them, IL6, IL8, and VEGFA are considered to be pro-inflammatory cytokines. NFkB1, and EGR1 are transcriptional factors, and CDKN1A, and CYCS are considered to regulate cell cycle or apoptosis. Furthermore, simultaneously focusing on the difference in the fold changes of gene expressions between CD34+mono vs. monocytes, CD83 (a membrane protein and immunoglobulin superfamily that regulates antigen presentation) and FOSL1 (a kind of regulators of cell proliferation, differentiation, and transformation) were specifically increased in CD34+mono (Figure3). The increased expression of CD83 strongly suggests antigen presenting cells like mature dendritic cells. CD34+mono might be one of progenitors of dendritic cells, or might have a potential of antigen presentation itself. [Conclusion] In summary, the differentially expressed genes in CD34+mono would be mapped in the immune process, especially against infectious pathogens. In addition, the increased CD83 suggested that CD34+mono might play a role of antigen presentation in the immune response. Further investigations would be necessary to confirm the clinical roles of CD34+mono after transplantation. Disclosures Nakasone: Phizer: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kimura:Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. 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. Kanda:Eisai: Consultancy, Honoraria, Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Nippon-Shinyaku: Research Funding; Pfizer: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.