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: Development of prophylactic cranial irradiation (CRT) has greatly contributed to the improvement of outcome of childhood ALL. However, late complications, including secondary malignant neoplasms, arising from CRT are becoming big problems. Furthermore, the prognosis of the patients with relapse in central nervous system (CNS) after CRT is extremely poor. To eliminate CRT in the treatment for majority of the patients with B-cell precursor (BCP) ALL, we had attempted to reduce the indication of CRT by conducting randomizations in 3 studies. We present here the long-term results of 4 consecutive clinical trials, to assess the effect of reducing the proportion of patients who received CRT on the treatment outcome. Of the 2,116 children with newly diagnosed ALL with 1–18 years of age who were enrolled to the 4 consecutive TCCSG ALL studies between 1989 and 2003, 1845 BCP ALL patients were evaluable: 354 Pts in L89-12 protocol (1989–1992), 291 Pts in L-92-13 (1992–1995), 536 Pts in L95-14 (1995–1999) and 664 Pts in L99-15 (1999–2003). The probability of event-free survival (EFS) and overall survival (OS) were constructed using the Kaplan-Meier method. Events in the analysis of EFS included induction failure, death, relapse and secondary malignant neoplasm. The initial status of CNS disease was examined after 7 or 10 days of pre-phase treatment consisted of steroid and/or other drugs. The definition of the CNS status was as follows: CNS positive = CNS-1 with symptomatic CNS disease, CNS-2, CNS -3 and traumatic lumbar puncture (TLP) with leukemic blasts; CNS negative = CNS-1 and TLP without leukemic blasts. In L89-12 study, all but a half of the standard risk group (SR) patients had received CRT. After this study, no CRT was given for the patients in SR. Patients in the intermediate risk group (IR) were randomly assigned into either high-dose methotrexate (HD-MTX) arm or CRT arm in L92-13 study. In L95-14 study, patients with initial leukocyte count exceeding 50,000/ul received CRT, whereas the others were treated with HD-MTX in IR. A part of patients in the high risk group (HR) in L95-14 study proceeded to stem cell transplantation during the first remission. In L99-15 study, only patients with high WBC, more than 100,000/ul, at diagnosis received CRT. Overall, no increase in CNS relapse was observed. The EFS rate and the OS rate at 8 years in L99-15 study were significantly improved compared to those in L89-12 study. Details of the results are shown in the table. By intensifying systemic chemotherapy and intrathecal injections, the proportion of the patients who received CRT in L99-15, which was the last study, was reduced to as small as 4% without increase in CNS relapse. These remaining 4% of the patients who had received CRT included those with CNS-3 disease (= 0.3 %), and they are the ultimate target who needs innovative treatment. In conclusion, we have succeeded to reduce the proportion of the patients with BCP ALL receiving CRT from 79% to 4% in the past 20 years, without compromising the treatment outcome. Table. Treatment and outcome in each study L89-12 L92-13 L95-14 L99-15 LP: lumbar puncture, IT: intrathecal injection, *randomization, **Pts with WBC higher than 50,000/ul at diagnosis received CRT. ***Pts with WBC higher than 100,000/ul at diagnosis received CRT. Rate of CNS positive 2.0% 3.4% 1.3% 2.1% Date of 1st LP/IT Day8 Day8 Day11 Day8 Rate of Pts receiving CRT 79% 36% 23% 4% Dose of CRT 18Gy 1y:12Gy, 2-18y: 18Gy 1y:12Gy, 2–18y: 18Gy 1–6y:12Gy, 7–18y: 18Gy CNS directed therapy SR*: A; HD-MTX 9g B; CRT IR: CRT HR: CRT SR: HD-MTX 6g IR*: A; HDMTX 6g B; CRT HR: CRT SR: HD-MTX 9g IR**:A;MTX9g B;CRT HR: CRT SR: HD-MTX 9g IR***: HD-MTX 9g (*HD-or LD-Ara-C) HR***: HD-MTX 6g Rate of Pts receiving SCT 0% 0% 15% 8% 8y-EFS 65+/−3% 55+/−3% 76+/−2% 74+/−2% 8y-OS 76+/−2% 79+/−2% 84+/−2% 86+/−2% Rate of BM relapse 25.6% 31.1% 17.6% 18.7% Rate of Isolated CNS relapse 2.6% 0.72% 1.2% 1.5% Rate of all CNS relapse 3.2% 1.4% 1.7% 3.2%

Abstract: Introduction:Central nervous system invasion in multiple myeloma (CNS-MM) is extremely rare (approximately 1% of MM). Prognosis of patients with CNS-MM is generally poor, and the median overall survival (OS) time from its diagnosis (Dx) has been reported to be 2 to 7 months. However, because of its rareness, most available data concerning CNS-MM are based on anecdotal reports on small case series. In this study, we retrospectively collected clinical data of Japanese patients with CNS-MM and analyzed them to reveal clinical features and prognosis of this disease entity. Methods:We conducted a nationwide multicenter retrospective study involving 107 centers that consist of educational facilities authorized by Japanese Society of Hematology and its related hospitals. CNS-MM was defined based on the previously reported criteria (Br J Haematol 2013;162:483-48). Univariate and multivariate analyses were performed to explore prognostic factors and the suitable treatment of CNS-MM. Results:From December 1978 to February 2016, 75 patients with CNS-MM were identified. The median age was 58 (range: 32-77 years). CNS invasion was detected at initial Dx of MM in 4% and at relapse in 96%. The median time from Dx of MM to that of the secondary CNS-MM was 1.8 years. Concomitant plasma cell leukemia (18%), skull plasmacytoma (12%), and myeloma cells in the cerebrospinal fluid (63%) were observed at the Dx of CNS-MM. Common symptoms of CNS-MM included consciousness disturbance (37%), cranial nerve palsy (25%), diplopia (18%), headache (16%), spinal nerve disorder (13%), and nausea/vomiting (12%). Intrathecal chemotherapy (IT) was used in 37%, cranial and/or spinal irradiation therapies (RTx) in 45% in addition to various systemic therapies, which included immunomodulatory drugs (IMiDs) (21%), bortezomib (19%), alkylators (21%), dexamethasone alone (6%), autologous stem cell transplant (auto-SCT, 4%), and allogeneic stem cell transplant (allo-SCT, 3%). With a median follow-up of 3.4 months from Dx of CNS-MM and of 31.5 months from that of MM, the median OS time from Dx of CNS-MM was only 3.7 months. The median OS times for the 12 untreated and 61 treated patients were 0.2 and 5.1 months, respectively (P 〈 0.01), suggesting that the patients who did not receive any treatments (Txs) were in a severe condition and their prognoses were extremely poor. In univariate analyses for the entire group, absence of both atypical lymphocytes and plasma cells in the peripheral blood at Dx of MM and no Tx for MM before Dx of CNS-MM were significantly favorable prognostic factors (P = 0.008 and P 〈 0.0001, respectively). Regarding Tx for CNS-MM patients who received any Txs (conventional chemotherapies, bortezomib, IMiDs, IT, and RTx), only RTx was correlated with longer OS time (P = 0.047). In multivariate analyses, RTx and IT had a significant impact on longer OS time ( 〉 6 months, OR = 3.80, 3.97, P = 0.002, 0.01, respectively). Although the prognosis of CNS-MM in this study cohort was very poor, seven patients could survive for 〉 1 year from Dx of CNS-MM. Among them, RTx, IMiDs, IT, bortezomib, auto-SCT, and allo-SCT were given to 5, 4, 5, 3, 1, and 1 patients, respectively. Conclusions:Prognosis of CNS-MM is extremely poor in general. Although there must be a selection bias that patients who received various salvage Txs for CNS-MM were in a better condition, the results of our study suggest that multi-modality Txs with RTx, IT, and IMiDs/bortezomib may prolong the survival time in some cases. Prospective studies are needed to confirm our preliminary observations. Disclosures Takamatsu: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria. Sunami:Janssen Pharmaceutical: Research Funding; Sanofi: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb K.K.: Research Funding; Novartis: Research Funding; Celgene: Honoraria, Research Funding; Takeda: Research Funding; Ono Pharmaceutical: Research Funding. Hagiwara:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kuroda:Janssen: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria, Research Funding. Murakami:Bristol Meyers Squibb: Honoraria; Astellas: Honoraria; Mochida: Honoraria; Eisai: Honoraria; Takeda: Honoraria; MSD: Honoraria; Chugai: Honoraria; Celgene: Honoraria. Nakao:Alexion Pharmaceuticals: Honoraria, Research Funding. Tobinai:Celgene: Research Funding; Mundipharma KK: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Kyowa Hakko Kirin: Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Abbvie: Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Janssen Pharmaceuticals: Honoraria, Research Funding. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.

Abstract: Background: Autologous stem cell transplantation (ASCT) combined with novel therapeutic drugs, including proteasome inhibitors (PIs)/immunomodulatory agents (IMiDs), can substantially improve the prognosis of patients with multiple myeloma (MM). Because MM patients survive longer, the incidence of secondary primary malignancies (SPMs) in long-term survivors is increasing. To date, only few studies have evaluated SPMs in real-world patients, particularly in those with MM in Asia. Aims: To analyze the risk factors of SPMs in MM patients after ASCT before and after the introduction of PIs/IMiDs. Methods: In this retrospective observational study, data from the Registry of the Japan Society for Hematopoietic Cell Transplantation were collected and analyzed. A total of 2340 newly diagnosed MM patients who underwent ASCT between 1993 and 2016 were enrolled in this study. Median age 58 at ASCT (range 22-72); males 1329 (56.8%), females 1011 (43.2%); IgG 1340 (57.3%), IgA 452 (19.3%), IgD 63 (2.7%), IgE 3 (0.1%), IgM 6 (0.3%), BJP 416 (17.8%), non-secreting 38 (1.6%), unknown 22 (0.9%); ISS1 774 (33.1%), ISS2 825 (35.3%), ISS3 455 (19.4%), not assessed 286 (12.2%). 1908 (81.5%) and 432 (18.5%) patients received single melphalan 200 mg/sqm (Mel200) and double Mel200, respectively as conditioning regimen before ASCT. Moreover, 771 (32.9%) and 1569 (67.1%) patients underwent ASCT from 1993 to 2006 and from 2007 to 2016, respectively. 659 (28.2%) patients received PIs, 73 (3.1%) IMiDs and 903 (38.6%) both PIs and IMiDs. Meanwhile, 38 (1.6%) patients received radiation treatment. The disease status at ASCT was as follows: 690 (29.5%), sCR/CR; 580 (24.8%), VGPR; 831 (35.5%), PR; 144 (6.2%), SD; 50 (2.1%), PD; and 45 (1.9%), unknown. Results: The median follow-up from ASCT was 24 (range: 0-218) months. A total of 38 patients in this cohort developed SPMs, with a cumulative incidence of 0.8% [95% confidence interval (CI): 0.4%-1.2%] and 2.4% (95% CI: 1.6%-3.5%) at 24 and 60 months, respec tively. Twenty-four solid (4, stomach; 3, breast; 5, lung; 2, liver; 2, pancreas; 2, colon; 1, uterus; 1, thyroid gland; 1, bladder; 2, sarcoma; and 1, basal cell carcinoma), 11 hematologic (7, myelodysplastic syndrome; 1, acute leukemia; 2, lymphoma; and 1, unknown), and 3 unknown tumors were observed. The cumulative incidence of hematologic and solid SPMs at 60 months was 0.8% and 1.7%, respectively. OS at 60 months after ASCT was 62.9%, and OS after the diagnosis of SPMs at 24 months was 70.7% for hematologic and 64.6% for solid SPMs (median follow-up of 23 months). Next, the risk factors affecting the incidence of SPMs were analyzed, which included age at ASCT (≤65 or 〉 65 years), sex, PI/IMiD treatment, use of radiation, single/double ASCT, and period of ASCT (1993-2006 or 2007-2016). Because bortezomib, thalidomide, and lenalidomide were released for relapse/refractory MM treatment in Japan in December 2006, February 2009, and July 2010, respectively, we categorized the patients into two treatment cohorts: pre-novel agent era (1993-2006) and novel agent era (2007-2016). Univariate analysis showed that the novel agent era (1.7% vs 4.3% at 60 months; P = 0.013; Fig. 1) and use of radiation (2.3% vs 9.5% at 60 months; P = 0.027) were significant independent risk factors for SPMs. Multivariate analysis revealed that the use of radiation [hazard ratio (HR): 3.895; 95% CI: 1.163-13.050; P = 0.027] was a significant, independent risk factor for SPMs. The novel agent era (HR: 1.716; 95% CI: 0.857-3.438; P = 0.13) and IMiD without PI treatment (HR: 2.206; 95% CI: 0.787-6.189; P = 0.13) were likely high-risk factors for SPMs. In contrast, PI without IMiD treatment (P = 0.79) was not a risk factor for SPMs. The probabilities of developing SPMs and death due to other causes (mainly MM) at 60 months were 2.4% and 36.5% (Fig. 1), respectively, indicating that the risk for SPMs was lower than that for death from MM. Furthermore, OS between the pre-novel and novel agent era groups significantly improved (59.2% vs. 69.5%, P 〈 0.0001) at 60 months after ASCT. Conclusions: The incidence of SPMs in patients with MM in Japan was consistent with that reported recently (Sahebi et al. BBMT, 2018). Although the risk for SPMs increased in the novel agent era group, the mortality rate of SPMs was lower than that of other causes (primarily MM). Considering the increase in the number of long-term survivors with MM, the early occurrence of SPMs should be cautiously monitored. Disclosures Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; CSL Behring: Research Funding; SRL: Consultancy, Research Funding; Daiichi-Sankyo Company: Honoraria; Becton, Dickinson and Company: Honoraria; Sanofi: Consultancy, Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Fujimoto Pharmaceutical: Honoraria; Janssen Pharmaceutical: Consultancy, Honoraria; Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Mizuno:Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb Corporation: Honoraria; Celgene Corporation: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Fuchida:Japan Blood Products Organization: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Daiichi-Sankyo Company: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Ono pharmaceutical: Honoraria; Kyowa Kirin: Honoraria; SEKISUI MEDICAL CO., LTD.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria. Hanamura:Asai Clinic: Research Funding; Yamada Yohojo: Research Funding; AbbVie: Honoraria; Chugai: Research Funding; Eli Lilly: Research Funding; Taiho: Research Funding; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; Eisai: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Fukuyu Hospital: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Nihon Shinyaku: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Fujimoto: Research Funding; MSD: Research Funding; Zenyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mundi: Honoraria. Nakamura:Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited: Research Funding; Eisai Co. Ltd.: Honoraria; Kyowa Kirin: Research Funding. Mori:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria. Tsukada:Chugai Pharmaceutical Co.,Ltd: Honoraria; Kyowa Kirin: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MOCHIDA PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Fujimoto Pharmaceutical: Honoraria. Ichinohe:Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Kanda:Pfizer: Research Funding; Novartis: Research Funding; Mochida: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe Mitsubishi: Research Funding; Novartis: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Tanabe Mitsubishi: Research Funding; Asahi-Kasei: Research Funding; MSD: Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Otsuka: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Sanofi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Sanofi: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Celgene: Consultancy, Research Funding; Taiho: Research Funding. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Sunami:Takeda: Honoraria, Research Funding; GSK: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding; Ono: Honoraria, Research Funding; Alexion-pharma: Research Funding; Daiichi Sankyo: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding.

Abstract: The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPα and interacts with MEK1 to enhance extracellular signal-regulated kinase (ERK) phosphorylation. A close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis, where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. Chromatin immunoprecipitation sequencing analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased messenger RNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPα p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

Abstract: We conducted a phase 2 study of ATO followed by autologous HCT for relapsed APL. This sequential treatment is effective and feasible.