ALBERT

Description: Key Points Expression of ITGA2B (CD41) and MPL positively correlates with that of EVI1 in acute myeloid leukemia patients. Thrombopoietin/MPL signaling enhances growth and survival of CD41+ Evi1 leukemia cells with a high leukemia-initiating capacity.

Description: [Background] Philadelphia chromosome positive (Ph+) leukemia is characterized by highly proliferative nature and clone instability that evokes the emergence of mutated clones, including BCR-ABL1 T315I mutated clone. Established evidence on the use of tyrosine kinase inhibitors (TKIs) after allogeneic hematopoietic stem cell transplantation (HSCT) is still lacking. The use of second-generation TKIs as a maintenance treatment after HSCT has been studied, and it is expected that their use would improve the prognosis by suppressing recurrence. The advent of ponatinib (PON), a potent inhibitor of tyrosine kinase including T315I mutated BCR-ABL1, is expected to improve clinical outcome of Ph+leukemia. However, there are few reports of a maintenance treatment using PON after HSCT. [Methods] We retrospectively reviewed data of 13 patients (pts) who received PON for Ph+leukemia after HSCT while in hematological complete remission (CR) between April 1, 2016 and July 15, 2019. Prophylactic treatment (Pro) was defined as post-transplant administration of PON while in minimal residual disease (MRD) negative CR. Pre-emptive treatment (Pre) was defined as starting PON when the bcr-abl transcript was detected by either quantitative or nested qualitative PCR after HSCT. ABL1 mutation was analyzed through the direct sequencing method. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Overall survival (OS) was estimated using Kaplan-Meier method. Non-relapse mortality (NRM) and cumulative incidence of hematological relapse (CIR) were calculated using Gray's test. This study protocol was approved by the ethics committee of Tokyo Metropolitan Komagome Hospital. [Results] Underlying diseases were Ph+ALL in 8 pts (5 in CR, 3 in non-CR at HSCT), CML in 5 (all in second chronic phase). ABL1 mutations were analyzed in 12 pts and T315I mutation was detected in 4 pts with Ph+ALL and 2 with CML. Furthermore, compound mutations (CMs) in BCR-ABL1 were detected in 4 pts before HSCT. PON was used in 6 only after HSCT, and in 7 both before and after HSCT. During the median observation after HSCT of 584 days (range, 116-1,110) for survivors, no vascular occlusion event occurred. With regard to adverse events (AEs), grade 3 AEs occurred in 2 pts (15.4%) and no grade 4 AE was observed. Two had liver dysfunction and one of them discontinued PON due to grade 3 abnormalities in liver function tests. One suffered from grade 3 thrombocytopenia. Four had skin rashes lower than grade 3 that were indistinguishable from skin graft-versus-host disease, and all of them resolved through topical steroid therapy. Of all, 6 were in Pro group and 7 were in Pre group. The initial dose of PON was median 15mg (range 45mg/twice a week - 15mg/day) in Pro and median 30mg (range, 15-45mg) in Pre. The median days from HSCT to the start of PON was 107 days (range, 32-174) in Pro and 208 days (range, 50-364) in Pre. The median duration of PON treatment was 297 days (range, 20-699) in Pro and 188 days (range, 5-608) in Pre. At final observation in Pro group, 2 pts relapsed and died during the salvage therapy, 1 pt discontinued PON due to hepatic adverse event, and 3 pts were still on PON. Meanwhile, in Pre group, 5 pts achieved MRD negative CR after PON administration (1 pt also received donor lymphocyte infusion and stop PON due to liver dysfunction, 1 discontinued PON by the patient's request, and 3 of them were still on PON). One pt with CM relapsed but achieved CR through salvage therapy and 1 pt with low performance status (KPS 60) died at home of unknown cause six days after taking PON 30mg daily. For all the 13 pts receiving PON maintenance therapy, OS was 74.6% (95%CI; 39.8-91.1), CIR was 23.1% (95%CI; 5.1-48.5), and NRM was 7.7% (95%CI; 0.4-30.6) at 1 year after transplant (Figure 1). Two out of 4 pts with CMs (V299L/F317L and E255K/T315I/F317L) remains in MRD negative CR. The other 2 with CMs (E255K/T315I and D276G/T315I) had progressed to hematological relapse, suggesting the resistance to PON. In contrast, only one out of 9 without CMs relapsed on PON treatment. [Conclusion] Our results suggested that post-transplant maintenance treatment using PON was tolerable in the majority of patients with Ph+leukemia, although the optimal dose or the initiation strategy (Pre or Pro) are still undetermined. Furthermore, some patients with T315I-inclusive CMs seemed to be resistant to PON. The longer observation in a larger cohort is warranted. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curable treatment for various hematological malignancies, some serious comorbidities are still problematic, and acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality. The gut microbiota and its metabolites have been reported to play pivotal roles in both intestinal inflammation and the immune system. Also in allo-HSCT, it is increasingly evident that imbalance in the gut microbiota (dysbiosis) related to the development of aGVHD. Short chain fatty acids (SCFAs), which are produced as fermentation products by gut microbiota, are among the most studied metabolites. Of them, butyrate has been reported to strengthen the mucosal barrier, induce the differentiation of colonic regulatory T cells (Natue. 2013; 504: 446-450). Actually, both butyrate and butyrate high-producing bacteria mitigate aGVHD in a mouse model (Nat Immunol. 2016; 17: 505-513) and furthermore, some dietary ingredients are known to increase SCFAs in the colon. Resistant starch (RS) is the starch portion that is not absorbed in the small intestine but is fermented in the large intestine, and converted into butyrate. GFO is an enteral supplement comprising glutamine, fiber, and oligosaccharides, and has been reported to be alleviate the mucosal injury in HSCT (Case Rep Oncol. 2014; 7: 692-699). Based on these results, we conduct a prospective study to evaluate the clinical impact of these prebiotics on transplant outcomes. Methods Forty-nine patients who underwent allo-HSCT in our hospital were enrolled in this study (prebiotics group). As a control group, 142 patients were selected because both the clinical and micorobial data were available. We used commercially available RS (Amylofiber SH®, J-Oil Mills Inc., Tokyo, Japan) and GFO (GFO®, Otsuka Pharmaceutical Factory Inc., Tokushima, Japan). Amylofiber SH® is corn starch which contains 70% of RS. Eight grams of RS were provided for patients at lunch and dinner, and one pack of GFO®, which contains 3 g of glutamine, 4.7 g of polydextrose , 1.45 g of oligosaccharides, was provided at breakfast. Patients ingested RS and GFO® from the start of conditioning regimen to +day 28. To evaluate the efficacy of prebiotics, the incidence of aGVHD, and severity of oral mucositis and diarrhea were compared. Moreover, sequencing of 16s ribosomal RNA gene was performed using feces samples before and day 28 after allo-SCT in both groups. Results The patient characteristics of the two groups were no significant differences except for the rate of female to male transplantation (4 % vs 17 % p=0.028). Median intake of prebiotics was 51%; 45% in RS and 68% in GFO, respectively. There was clear positive correlation between RS and GFO intakes. No adverse events obviously attributable to intake of prebiotics were observed. The cumulative incidence of all grade (63.3% vs. 75.4%, p=0.02) and Grade II-IV aGVHD (32.9% vs 47.9% p=0.03) was significantly lower in the prebiotics group compared with the control group. Interestingly, the incidence of skin aGVHD was significantly lower in the prebiotics group compared with the control group (53.8% vs 64.8% p=0.04 in all grade; 12.7% vs. 26.9% p=0.03 in ≥stage 3).In a multivariate analysis, prebiotics intake was associated with a decreased risk of grade II-IVaGVHD (p=0.04, HR: 0.58[95% CI: 0.35-0.97]).Oral mucositis was significantly less severe in prebiotics group in the early period (day 0 to +9) of allo-HSCT. With regard to diarrhea, the duration of diarrhea in the prebiotics group was shorter than that in the control group (median 7 days vs. 9 days, p=0.049). In microbial analysis, the diversity of the gut microbiota was well conserved, or improved in some cases, in the prebiotics group compared to that in the control group. Conclusions Our results indicate that prebiotics treatment could reduce post-transplant complications, including GVHD by conserving the intestinal microbial diversity in transplant patients. Further evaluation will be needed to confirm them. Disclosures No relevant conflicts of interest to declare.

Description: Background: Sarcopenia, the loss of muscle mass, has been recognized as a prognostic factor for cancer patients. For example, low body mass index (BMI) was reported to be a risk of poor overall survival (OS) among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. However, low BMI was not associated with high non-relapse mortality (NRM) rate, and BMI may not directly reflect the physical condition. (Bone Marrow Transplant. 2014;49:1505-12). To evaluate the clinical impact of the muscle volume on the prognosis of allo-HSCT recipients, other biomarkers that directly reflect muscle mass may be warranted. Urinary creatinine excretion (UCE) has been reported to estimate muscle mass and have prognostic value for kidney transplant patients (Transplantation. 2008;86:391-8.). There is no report to evaluate clinical impact of UCE on the prognosis of allo-HSCT recipients. Therefore, we retrospectively analyzed the association between pre-transplant UCE and the transplant outcomes. Methods: We included 173 adult patients with acute myeloid leukemia (AML) in complete remission (CR) who underwent first allo-HSCT from 2006 to 2017 at our institute and measured UCE before allo-HSCT. Concerned the possibility of urine storage failure, two patients with low total daily urine volume (

Description: Key Points FMT was safely performed in SCT patients, with 3 complete responses and 1 partial response. Temporal microbiota dynamics seem linked to gut condition and effector regulatory T cells also increased during response to FMT.

Description: Background Myelodysplastic syndromes (MDS), commonly seen in elderly patients, represent a heterogeneous group of clonal hematopoietic stem cell disorders caused by the accumulation of gene mutations. By contrast, congenital bone marrow failure syndromes and genetic predispositions associated with MDS are known in pediatric patients. However, little is known about the pathogenesis of MDS in adolescent and young adult (AYA) patients. Previous reports showed the patients with MDS aged under 40 or 41.5 years at allo-HSCT were associated with good survival compared to those among the older population (N Engl J Med. 2017;376:536-547, Blood. 2017;129:2347-2358). However, AYA-MDS is rare, and its clinical features and genetic abnormalities have not been analyzed enough. It is suspected that the clinical and genetic features of AYA-MDS patients might be different from those of elderly patients or pediatric patients. Therefore, we investigated the gene abnormalities of AYA-MDS patients and aimed to elucidate the genetic characteristics associated with the good outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We analyzed the patients younger than 50 years of age in order to reduce the variation of patient-related factors. Methods We analyzed the outcomes of all consecutive patients aged under 50 years who were diagnosed with MDS or acute myeloid leukemia evolving from MDS in our hospital between January 2005 and July 2018. The study was approved by the institutional review board, and patients gave written informed consent for the study, according to the Declaration of Helsinki. Cytogenetic analysis and genomic DNA extraction were carried out using diagnostic bone marrow samples. We performed targeted next-generation sequencing to identify mutations in 68 driver genes using AmpliSeq for Illumina Myeloid Panel and On-Demand Panel on the MiniSeq system (Illumina). Gene variants were detected by in-house analysis pipeline. Overall survival (OS) was analyzed for all patients, and the Kaplan-Meier survival curve was used to assess OS using the log-rank test. Additionally, the cumulative incidence of relapse (CIR) was analyzed for patients who underwent allo-HSCT. Gray's test was used to evaluate the CIR. Results A total of 85 patients with MDS aged under 50 years (U40 between 15 and 39 years old: N=37, 40s between 40 and 49 years old: N=48) were analyzed. The median follow-up time of survivors was 2,041 days (range 176-5,085). There were no significant differences in patient characteristics between U40 and 40s. The 3-year OS of U40 were superior to 40s (79.9% vs. 58.1%, P=0.018), especially lower risk IPSS categories (3-year OS, 95.5% vs. 50.8%, P=0.002). In total, 69 of 85 patients (U40: N=31, 40s: N=38) had undergone allo-HSCT. U40 patients had lower percentage of bone marrow blasts at just before HSCT than 40s patients (over 10%, 12.9% vs. 36.8%, P=0.048), and better 3-year OS from HSCT in lower-IPSS (88.8% vs. 53.8%, P=0.024); but not in higher-IPSS (45.0% vs. 43.2%, P=0.834). In this cohort, at least one driver mutation was detected in 61% of allo-HSCT recipients. Frequently mutated genes (more than 10%) were ASXL1 and RUNX1; however, both of the genes did not have significant impact on the outcomes. While, only one patient in 40s had TP53 mutation. We detected 0.8 (range 0-3) and 1.8 (range 0-6) mutations at average in U40 and 40s, respectively (P=0.06). The proportions of the patients without any gene mutations were 52% in U40 and 30% in 40s. Transplanted patients with 0 or 1 mutation showed lower relapse rate than those with 2 or more mutations (3-year CIR, 23.3% vs. 45.2%, P=0.049). Conclusions The clinical outcomes of U40 patients with MDS were favorable than those in the 40s, especially in lower disease risk. The number of driver mutations in U40 tended to be lower than that in 40s. MDS in adult is regarded as a stem-cell aging disease with gene mutations; however, MDS-associated mutations were not detected in the half of U40. Moreover, TP53 mutation that is associated with extremely poor posttransplant survival was not detected in U40 patients. MDS patients with less than 2 mutations showed lower relapse rate, which maybe indicate genetic mutations have a great impact on transplant outcomes between 15 and 49 years old. Disclosures No relevant conflicts of interest to declare.

Description: Background: Erdheim-Chester disease (ECD) is a subtype of non-Langerhans histiocytic disorder that is shown to be driven by hyperactivation of MAPK pathway (most frequently caused by BRAFV600E mutation) and characterized by generalized organ dysfunction with infiltration of CD68-positive, CD1a-negative histiocytes. However, ECD is a rare entity and therefore very little is known about epidemiology of this disorder. Methods: We underwent a postal questionnaire-based, multi-center retrospective study to clarify the clinical features of ECD patients. We first sent 3850 questionnaires to various departments including orthopedics, respiratory medicine, dermatology, hematology, and pathology to cover as many ECD patients as possible, and identified 71 ECD patients in Japan. We further collected detailed clinical information and patients' samples if available. All cases were pathologically proven and the diagnoses of ECD were self-reported by each institute. DNA was extracted from each clinical sample and Sanger sequencing or allele-specific polymerase chain reaction (PCR) for BRAFV600E mutation were underwent with specific primers. Results: Among 71 patients with ECD, detailed clinical information about 38 patients were collected. The median age was 51 years old (range: 25-76 years old) and there was a male predominance (1.9:1). Major affected lesions were the bone (84 %), central nervous system (CNS; 50 %), cardiovascular lesion (37 %), skin (37 %), retroperitoneum (37 %), endocrines (37 %), lung (24 %), and digestive organ (12 %). C-reactive protein at onset was higher than upper normal limit in 24 of 29 patients (median 23.8 mg/L). The median time from the onset to diagnosis was 17 months and median survival from initial onset was 10.9 years. In the univariate analyses, age older than 60 years old at initial onset (hazard ratio [HR], 30.2; 95% CI, 5.7-159; p 〈 0.001), weight loss (HR, 5.4; 95% CI, 1.4-20.8; p = 0.014), CNS involvement (HR, 25.2; 95% CI, 3.1-203; p = 0.0024), cardiovascular lesion (HR, 3.6; 95% CI, 1.2-10.8; p = 0.021) and digestive organ disease (HR, 5.6; 95% CI, 1.6-20.2; p = 0.0085) were associated with poor prognosis. Interestingly, the bone involvement was associated with better outcome (HR, 0.20; 95% CI, 0.065-0.63; p = 0.0052). Multivariate analysis revealed that older age was an independent poor prognostic factor (HR, 18.9; 95% CI, 2.12-169; p = 0.0085). In addition, patients with CNS involvement were significantly older than patients without CNS disease (median, 63.7 vs 44.0 years old; p 〈 0.001). We also analyzed the BRAF V600E mutation status in seven cases. Allele-specific PCR identified that three of seven patients had BRAFV600E mutation. Conclusion: Our nationwide survey revealed that older age was associated with CNS involvement and poor prognosis in ECD patients. In addition, the bone, cardiovascular, CNS and digestive organ involvement might also affect clinical outcome. It is of note that the bone lesion was associated with better survival in the univariate analysis. However, larger and prospective studies are warranted. Regional disparity such as percentage of bone lesions should be also investigated. Disclosures Ogura: Payment for lectures including service on speakers bureaus: Speakers Bureau.

Description: Background Although the outcome after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for the patients with acute myeloid leukemia (AML) in complete remission has been improved, the prognosis of patients with active disease is still dismal, generally with 20 - 30% of overall survival (OS) at 2 years. Prognostic value of gene mutations detected by the next generation sequencing (NGS) for this extremely poor group remains to be evaluated. Methods A total of 120 patients with AML not in hematological remission who received the first allo-HSCT at our institute between April 2005 and December 2017 were enrolled. For each patient, genomic DNA was extracted from the frozen bone marrow sample harboring leukemic blasts which was preserved at the nearest available date before the initiation of conditioning regimen. Sequencing was performed using TruSight Myeloid Sequencing Panel® on the MiniSeq system (Illumina). Gene variants were detected by in-house analysis pipeline. Charts were retrospectively reviewed on survival, relapse, and non-relapse mortality (NRM). The Kaplan-Meier method was used to assess OS using the log-rank test. Univariate and multivariate analysis were performed to identify potential prognostic factors. The Cox proportional hazards method was used for the multivariate analysis to assess OS. Gray's test and the Fine-Gray test were used to assess the cumulative incidence of relapse (CIR). Competing risks were relapse and NRM. Results Median follow-up of survivors was 1345 days (235 - 4888 days). Median age at transplant was 51 (range 21 - 71). Grafts were from bone marrow (n = 67, 55.8%), peripheral blood (n=42, 35.0%) and cord blood (n=11, 9.2%). Refined disease risk index (Blood. 2014;123:3664-71) scored high (n=61, 51.3%) and very high (n=58, 48.7%). OS at 2 years of the whole cohort was 27.3% (95% confidence interval [CI], 19.4% - 35.7%). There was no significant difference in OS between patients in primary induction failure and in relapse (OS at 2 years: 26.5% [n=50] vs 28.7% [n=70], p= 0.293). NGS analysis revealed TP53 loss-of-function mutation in 23 (19.2%) patients. Among all detected gene mutations, TP53 mutation was the most powerful predictor of poor OS after allo-HSCT (OS at 2 years: 13.5% vs 30.5% for TP53+ [n=23] vs TP53- [n=97], p= 0.0184). Consistent with previous reports, monosomal karyotype (MK, J Clin Ocnol 2010:26;4791-7) was significantly associated with positive TP53 mutation (13.3% of non-MK vs 37.9% of MK, p=0.006). Of note, all the patients (n=11) positive for both prognostic factors died within 1 year after allo-HSCT, whereas OS of the patients without either factor (n=78) was 33.6% at 2 years. Multivariate analysis on OS revealed MK, TP53 mutation, de novo AML (no prior history of MDS), ECOG performance status score 2 or more, C reactive protein 1.0 mg/dL or more, peripheral blood blast frequency of 1% or more at the initiation of conditioning regimen were independent prognostic factors for poor OS. Among them, to determine the prognostic factors critical for deciding the indication of allo-HSCT, we chose pre-transplant factors which were available around one months before transplant. From this point of view, multivariate analysis revealed independent prognostic factors for poor OS after allo-HSCT including MK (Hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.30 - 3.25, p=0.00217), TP53 mutation (HR 1.72; 95% CI 1.04 - 2.86, p=0.035), and de novo AML (HR 1.67; 95% CI 1.04 - 2.86, p=0.036). Because the HR of these three factors were comparable, a score of 1 was assigned to each factor. OS at 2 years was 49.7%, 26.5% and 13.1% for patients with low (score 0, n=23), intermediate (score 1, n=63) and high (score 2 or 3, n=34) risk, respectively (p

Description: Introduction: Bortezomib (Bor) is widely used as a frontline therapy and improves outcome in treatment of multiple myeloma (MM). Although Bor was initially approved for intravenous (IV) administration, subcutaneous (SC) administration is currently standard practice, based on the randomized trial showing that SC exhibited similar overall response rate (ORR) and lower incidence of peripheral neuropathy (PN) compared with IV among relapsed MM. On the other hand, the other groups revealed that IV achieved better response than SC after 3 cycles of therapy, and overcame SC resistance in some patients. In this study, to clarify whether SC actually improves the outcome of MM patients, we compared the efficacy and side-effects between IV and SC Bor administration. Patients and methods: We retrospectively analyzed 46 MM patients including newly-diagnosed (n=37) and relapsed (n=9) cases treated with at least two cycles of Bor-containing regimens at The University of Tokyo Hospital from August 2007 until June 2016. Bor-containing regimens consisted of Bor only (Bor 1.3 mg/m2, days 1, 4, 8, and 11, repeated every 21 days), Bor/dexamethasone (Dex) (BD, Bor 1.3 mg/m2, days 1, 4, 8, and 11; Dex 40 mg/body, days 1-4, 9-12, repeated every 21 days), Bor/cyclophosphamide (Cy)/Dex (CyBorD, Bor 1.3 mg/m2, Cy 300 mg/m2, Dex 40 mg/body, days 1, 8, 15, and 22, repeated every 35 days), Bor/lenalidomide (Len)/Dex (VRD, Bor 1.3 mg/m2 days 1, 4, 8, and 11; Len 25 mg/day days 1-14; Dex 40 mg/body, days 1, 8, and 15, repeated every 21 days), and Bor/melphalan (Mel)/prednisolone (PSL) (VMP, Bor 1.3 mg/m2, days 1, 8, 15, and 22, Mel 6 mg/m2, PSL 40 mg/m2, days 1-4, repeated every 35 days). Response categories were in accordance with International Myeloma Working Group uniform response criteria. Bor responders were defined as those who achieved more than 5% of monoclonal protein reduction within the first two courses of treatment. To measure the initial response among Bor responders, we calculated per-cycle reduction rate of monoclonal protein until achieving maximal response. For statistics, t-test, Fisher exact test and Log-rank test were utilized. Results: Of 46 patients, 24 (52.2%) and 21 (45.7%) patients received IV- and SC-Bor, respectively. One case in which administration route was switched from IV to SC due to vasculitis was excluded from further analysis. Thirteen patients (54.1%) in IV received BD, while 18 patients (85.7%) in SC received triple combination therapy (CyBorD, VRD, or VMP). Between IV and SC, there was no significant difference in age, laboratory data, disease status (newly diagnosed or relapsed) and clinical staging (ISS and Durie/Salmon) (Table 1). Grade 3 PN was more frequently observed in IV (n=5, 20.8%) than in SC (n=0, 0%) (p=0.05). ORR (partial response (PR) or better) was 70.8% in IV and 85.7% in SC (p=0.30). Very good PR (VGPR) or better response was achieved in 29.1% and 47.6% for IV and SC, respectively (p=0.23). Three-year survival rate was 78.3% in IV and 85.6% in SC (p=0.52). Among Bor responders (n=40), no significant difference was observed between IV and SC in per-cycle monoclonal protein reduction rate (25.4% vs 36.8%, p=0.08), median number of courses (3.1 vs 2.8, p=0.50) and median number of Bor administration (11.2 vs 10.7, p=0.75) until achieving maximal response. Subgroup analysis among newly-diagnosed MM patients treated with IV-BD (n=10) and SC-triple (n=16; 9 with CyBorD, 5 with VMP, 2 with CyBorD followed by VRD) showed that there was no significant difference in patient characteristics, ORR (70% for IV-BD and 87% for SC-triple (p=0.34)), and VGPR or better response rate (40% for IV-BD and 37% for SC-triple (p=1.0)). Three-year survival rate was 77.8% and 78.6% for IV-BD and SC-triple, respectively (p=0.70). Additionally, among Bor-responders, no significant difference was observed between IV-BD and SC-triple regarding per-cycle reduction rate of monoclonal protein (26.6% vs 31.0%, p=0.52), median number of courses (2.6 vs 2.8, p=0.59), and median number of Bor administration (9.6 vs 11.0, p=0.42) until achieving maximal response. Conclusions: In this retrospective study, IV-BD exhibits similar initial and maximal response compared with SC-triple among newly-diagnosed MM patients, while SC reduces the incidence of severe PN. Taking into account the therapeutic superiority of Bor-based triple drug regimen, our findings suggest the stronger therapeutic potency of IV-Bor administration. Figure 1 Figure 1. Disclosures Nakamura: Janssen Pharmaceutical K.K.: Speakers Bureau.