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Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment-refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP-2033), a potent cyclin-dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open-label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30-min intravenous (i.v.) bolus (30 mg/m

Azacitidine is a mainstay of therapy for MDS-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their post-treatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pre- (n=449) and post- (n=289) treatment bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their post-treatment clone size on treatment outcomes. In Cox proportional hazard modeling, multi-hit TP53 mutation (HR, 2.03; 95% CI, 1.42-2.91; P

Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.

The concurrent onset of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) is rare, and no autopsy case has been reported. We report herein the first case of concurrent-onset CLL and AML with an atypical phenotype revealed by autopsy. Notably, the diagnosis of AML was quite difficult during the patient’s lifetime because of the atypical phenotype. However, autopsy revealed that the patient’s bone marrow, liver, and spleen were filled with myeloblasts. In addition, p53 stain and PCR of IgH rearrangement using the autopsy specimen suggested that CLL and AML might be different clones. In conclusion, our case highlights the importance of considering synchronous complications of AML in CLL patients, particularly in those with an atypical clinical course.

The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high-risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose-limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut-off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment-related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%-54.9%) and 54.5% (95% CI: 36.4%-71.9%), respectively. The median progression-free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM.

Objective For patients with Gaucher disease (GD), a rare, inherited lysosomal storage disease, obtaining a definitive diagnosis is currently time-consuming and costly. A simplified screening method to measure the glucocerebrosidase (GBA) activity using dried blood spots (DBS) on filter paper has recently been developed. Using this newly developed screening method, we evaluated real-world GD screening in patients suspected of having GD. Methods This multicenter, cross-sectional, observational study with a diagnostic intervention component evaluated real-world screening in patients suspected of having GD based on their clinical symptoms and a platelet count

Long-term survival in patients with acute myeloid leukemia (AML) remains low, and current treatment modalities are inadequate. Milademetan (DS-3032, RAIN-32), a small-molecule specific murine double minute 2 inhibitor, has shown a p53 status-dependent antitumor effect in vitro studies. This is the first phase I study report of milademetan monotherapy in relapsed/refractory (R/R) AML patients evaluating the safety, tolerability, pharmacokinetics, and preliminary tumor response for further clinical development. Fourteen patients received 90 (starting dose, n = 4), 120 (n = 6), or 160 mg (n = 4) of oral milademetan once daily in a 14/28 treatment cycle. The median total treatment duration was 1.5 cycles. Dose-limiting toxicity did not occur, and the maximum tolerated dose was not reached. Thus, the recommended dose was defined as 160 mg. The most common adverse events (AEs) were decreased appetite (64.3%), febrile neutropenia (50%), nausea (42.9%), and anemia (35.7%). No deaths or AEs leading to treatment discontinuation occurred. Five serious treatment-emergent AEs occurred in 4 patients. Plasma concentration increased linearly with milademetan dose. However, trends in the safety and efficacy of oral milademetan in patients with R/R AML warrant further clinical investigation. This study can inform future milademetan studies in hematologic malignancies.

Isatuximab, an anti‐CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open‐label, single‐arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose‐limiting toxicities occurred; the recommended dose for the single‐arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high‐risk cytogenetic abnormalities had comparable results. In phase 2, the median progression‐free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high‐risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706., This open‐label, single‐arm, multicenter phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). The results demonstrated that isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM, including high‐risk cytogenetic patients.

Patients with indolent non-Hodgkin lymphoma (iNHL) typically respond to first-line immunochemotherapy, but relapse is common. Treatment options for relapsed iNHL include chemotherapy ± rituximab and rituximab monotherapy. Lenalidomide plus rituximab (R2) is an immunomodulatory regimen that enhances rituximab-mediated cytotoxicity and improves clinical activity in iNHL. AUGMENT was a double-blind phase III randomized trial of R2 vs. rituximab + placebo (R-placebo) in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma who were not refractory to rituximab. The primary endpoint was progression-free survival (PFS). Data reported here focus on Japanese patients from AUGMENT and reflect 36 patients (n = 18, each group). PFS was superior in the R2 group, HR = 0.32 (95% CI 0.11–0.96). Median PFS was not reached (95% CI 19.7–NE) in the R2 group vs. 16.5 months (95% CI 11.3–30.6) in the R-placebo group. Grade 3/4 adverse events were more frequent in patients treated with R2 (67%) than with R-placebo (22%), primarily attributable to increased neutropenia (50% vs 17%). R2 resulted in significantly longer median PFS than R-placebo in Japanese patients with R/R iNHL, and the efficacy and the safety profile of R2 were similar to those reported in the global population.

The hypomethylating agent azacitidine (AZA) significantly extends overall survival (OS) in patients with higher risk myelodysplastic syndromes (MDS), when compared with other conventional care regimens, including supportive care and low-dose and intensive chemotherapy. However, the effects of 5- and 7-day treatment schedules of AZA (AZA-5 and AZA-7, respectively) on the OS of MDS patients had not been compared prospectively. We started a phase 3 trial comparing the effects of AZA-7 and AZA-5 on MDS patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T). However, this trial was prematurely terminated because of poor recruitment. Using all data, there was no significant difference in the OS of patients between AZA-7 (92 patients) and AZA-5 (95 patients), with the 2-year OS rates of AZA-7 and AZA-5 at 36.4% and 25.8%, respectively (P = 0.293). Adverse event profiles were similar between the two groups. Interestingly, data of the centrally diagnosed RAEB and RAEB-T cases showed that AZA-7 significantly prolonged the time to leukemia transformation compared with AZA-5 (P = 0.022), confirmed by multivariate analysis. Although this trial could not provide definite evidence, the results support the use of AZA-7 for RAEB and RAEB-T. (UMIN Clinical Trials Registry UMIN000009633).

A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients.

Recurrence in acute myeloid leukemia (AML) is a major barrier in patients who achieve complete remission after induction of remission and consolidation therapy and desire long-term survival. Allogeneic hematopoietic stem cell transplantation lowers recurrence risk in patients; however, recurrence is common even after transplantation. Many maintenance therapies for AML aim to lower recurrence risk; therefore, research has focused on identifying drugs with a tolerable adverse-effect profile. Thus far, many trials of cytotoxic anticancer drugs used in maintenance therapy have showed no improvement in survival rates. In contrast, recent studies on immunomodulation, epigenetics, molecular-targeted drugs, etc. have demonstrated promising results. Therefore, we plan to review various maintenance therapies, such as immunotherapy, demethylating agents, and targeted therapies (including fms-like tyrosine kinase 3 inhibitors in particular) based on the current evidence. Moreover, we describe a new strategy that incorporates the assessment of measurable minimal residual disease.

Summary Background BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase. Methods DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0–2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period. Findings Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5–83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48–71), with a median follow-up of 366 days (IQR 353–372). Grade 3–4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3–4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed. Interpretation Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population. Funding Bristol-Myers Squibb.

Azacitidine is a mainstay of therapy for high-risk MDS and other myeloid neoplasms. A significant correlation between azacitidine response and clinical outcome suggests a potential role of mutational profiling based on next-generation sequencing (NGS) before and after therapy in evaluating response and predicting overall survival (OS), which however has not fully elucidated. Here through NGS-based mutational profiling of large cohorts (n=451) of azacitidine-treated patients with high-risk MDS and other myeloid neoplasms, we show significant roles of multi-hit TP53 and germline DDX41 mutations in pre-treatment samples and post-treatment clone size in the evaluation/prediction of azacitidine response and OS after azacitidine therapy, which outperformed the prediction based only on clinical response and IPSS-R score. Post-treatment clone size strongly correlated with clinical response with exception of large persistent mutations frequently affecting TET2 after achieving complete remission and those with DDX41 mutations, which poorly correlated with clinical response. Our results highlight the importance of evaluating mutations in both pre- and post-treatment samples in the assessment of response and the prediction of OS after azacitidine therapy.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response. Clinical sequencing across a large prospective cohort of patients with myelodysplasic syndrome uncovers distinct associations between the mono- and biallelic states of TP53 and clinical presentation

Negative immunofixation electrophoresis (IFE) of serum and/or urine is a diagnostic marker for determining a complete response (CR) after immunotherapy for multiple myeloma (MM). However, residual therapeutic antibodies such as elotuzumab (IgG-κ), can compromise IFE evaluation when the affected immunoglobulins belong to the same IgG-κ subclass. We thus sought to develop a simple and rapid method to treat patient serum before IFE to distinguish the residual elotuzumab. Serum samples from patients receiving elotuzumab were treated with a predetermined amount of soluble signaling lymphocyte activation molecule F7 (SLAMF7) protein and then subjected to conventional IFE testing. We tested our method in samples from 12 patients. The IgG-κ band in IFE disappeared or shifted after elotuzumab treatment in four patients with no bone marrow minimal residual disease and normalized free light chain, whereas seven patients with any sign of residual MM showed a remaining IgG-κ band after treatment. One-hour incubation of samples with 6-9 molar excess soluble SLAMF7 before IFE was sufficient to distinguish residual elotuzumab in 11 of 12 samples. This simple method does not require special reagents, can be performed in most clinical laboratories, and enables differentiation between patients with a CR and those requiring further treatment.

Introduction: Tyrosine kinase inhibitors (TKIs) dramatically improved the prognosis of chronic myelogenous leukemia (CML), as nearly half of CML patients presenting with a deep molecular response (DMR) over several years could achieve treatment-free remission. DASISION study reported dasatinib (DAS), a second-generation TKI was superior to imatinib to achieve faster and deeper response in treating newly-diagnosed chronic CML. However, standard initial dosage of 100 mg DAS/day might be too potent for patients aged >70 years with CML, possibly owing to the presence of other health conditions that threaten the life spans (e.g., lung and cardiovascular disease), thereby preventing TKI continuation. In this open-label, multicenter, single-arm, phase 2 study (DAVLEC), we evaluated the efficacy and safety of a reduced initial dose of DAS (20 mg/day) in the elderly with chronic CML. Patients and Methods: We included CML patients aged >70 years with an ECOG performance status of 0-2 and adequate organ function. After diagnosis, they began orally taking 20 mg of DAS per day. BCR-ABL mRNA values were measured and aligned to an international scale at a central laboratory to evaluate the drug's efficacy at 3, 6, 9, and 12 mo of therapy, per recommendations by European LeukemiaNet. The dosage was maintained in case of the optimal, increased by 20 mg/day when the warning appeared and could be decreased when an adverse event (AE) > grade 3 appeared. Patients were excluded if the respond was the failure or disease progression was detected. Primary endpoint was the cumulative major molecular response (MMR) rate at 12 mo. Secondary endpoints included the rates of the cumulative DMR, treatment discontinuation due to AEs, and failure to DAS treatment or disease progression. The non-inferiority of primary endpoint MMR (non-inferiority limit of 38%) was evaluated by binomial test with normal approximation. Other differences were investigated by Mann-Whitney tests, with p < 0.05 indicating significance. Results: Among the 56 patients enrolled from 25 centers, 4 declined participation, and so 52 (median age, 77.5 years) began taking 20 mg/day of DAS. In total, 73.1% of the patients had comorbidities. Median BCR-ABL values at 3, 6, and 12 mo were 1.47%, 0.23%, and 0.03%, respectively; cumulative MMR rate at 3, 6, 9, and 12 mo were 11.5%, 36.5%, 40.4%, and 59.6%, respectively. Calculated MMR at 12 mo was higher than 38%, a value selected based upon findings from the DASISION trial, accounting for a non-inferiority margin of 10% (p=0.047). At 12 mo, among the 31 patients achieving MMR, 23 were only given 20 mg DAS/day, and 14 and 7 respectively achieved MR4.0 and 4.5. Patients discontinued the study due to treatment failure (n=3), content withdrawal (n=2), drug-related AEs (Long QT Syndrome; n=1), or others (n=2). No patient discontinued it due to disease progression. Treatment-related AEs of all grades were noted in 96.2%and that of grade 3 or 4 events in 23.1% of the patients. Median dose interruptions for a median of 7 days (range: 5-36) were respectively noted in 3 and 2 patients due to hematological and non-hematological AEs. Furthermore, 4 patients experienced pleural effusion < grade 2, and 1 had lymphocytosis. Patients who achieved MMR at 12 mo (n=31) had a significantly lower BCR-ABL value at 3 mo (0.41% vs. 4.26%, p=0.0020) and a lower halving time from diagnosis to 3 mo (11.35 vs. 18.34 days, p=0.0050) than those who did not (n=21). Patients who achieved MMR by 12 mo with only 20 mg/day of DAS (n=23) had lower BCR-ABL values at 1 and 3 mo (25.51 vs. 63.63 %, p=0.00028; 0.33 vs. 5.89%, p Patients who achieved MMR at 12 mo (n=31) had higher plasma DAS concentration (23.5 vs. 8.0 ng/mL, p Conclusion: This study discovered that prescribing a starting very-low dose DAS (20 mg/day) while monitoring IS and AEs was a successful initial therapeutic strategy for the elderly with chronic CML comparable to previous studies using standard-dose. Notably, rapid BCR-ABL downregulation, early molecular responses at 1 and 3 mo, a shortened halving time from diagnosis to 3 mo, and sufficient increase in plasma DAS concentrations 2 h post-intake after 12 mo of treatment were key indicators for successful low-dose therapy. Disclosures Kumagai: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria, Speakers Bureau. Murai: Bristol Myers Squibb: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria; CHUGAI Pharmaceutical Co., Ltd.: Honoraria; TAKEDA Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation.: Honoraria. Tanaka: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Otsuka Pharmaceuticals: Honoraria. Nishiwaki: Kyowa-Kirin: Research Funding; Alexion: Honoraria. Inokuchi: Bristol-Myers Squibb: Research Funding. Yoshida: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis KK,: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria; AbbVie GK: Honoraria; Janssen Pharmaceutical KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Uoshima: Janssen: Honoraria; Eisai: Honoraria. Usuki: MSD K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Amgen-Astellas Biopharma K.K.: Research Funding; Mundipharma K.K.: Research Funding; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Ono: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding. Fujimaki: CSL Behring K.K.: Honoraria; Mundipharma K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Meiji Seika Pharma Co., Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; AbbVie GK: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Shibayama: Chugai: Research Funding; Eizai: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Kyowa Kirin: Speakers Bureau; AbbVie: Research Funding; Celgene: Research Funding; Novartis: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Mundi Pharma: Speakers Bureau; Otsuka: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; AstraZeneca: Research Funding, Speakers Bureau; Takeda: Speakers Bureau. Kondo: Abbvie: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding. Kimura: Eisai: Speakers Bureau; Kyowa-Kirin: Research Funding, Speakers Bureau; PharmaEssentia: Speakers Bureau; Astellas: Speakers Bureau; Sanifi: Speakers Bureau; Gilead: Research Funding; Nippon-Boehringer-Ingelheim: Research Funding; Celgene: Research Funding, Speakers Bureau; Sumitomo-Dainippon: Research Funding; Chugai: Research Funding, Speakers Bureau; Mundi: Research Funding; Yakult: Research Funding, Speakers Bureau; MSD: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; SymBio: Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding, Speakers Bureau; Janssen: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Takeda: Research Funding, Speakers Bureau; Nippon-Shinyaku: Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion: Research Funding, Speakers Bureau; Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ohara Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; AbbVie: Research Funding, Speakers Bureau; Apellis: Research Funding.

This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039.

Background: Alvocidib is a potent cyclin-dependent kinase 9 inhibitor, which has previously been shown to downregulate the B-cell lymphoma-2 family member MCL-1 (myeloid cell leukemia-1) which, in turn, sensitizes tumor cells to apoptotic signals. Alvocidib has been studied globally in relapsed/refractory (R/R) AML in combination with cytarabine/mitoxantrone, as well as in newly diagnosed AML in combination with cytarabine/daunorubicin, and has demonstrated acceptable clinical activity. However, safety and tolerability in Japanese AML pts are unknown. Aims: To evaluate the safety and tolerability of alvocidib administered as ACM or A+7+3. Methods: This multicenter, open-label, uncontrolled phase 1 study (NCT03563560) included 2 regimens: ACM (in pts R/R to cytarabine/anthracycline based intensive chemotherapy and without a cumulative total exposure of anthracycline [daunorubicin-equivalent dose] exceeding 360 mg/m2 at entry) and A+7+3 (in newly diagnosed, treatment naive pts). Key eligibility criteria for both regimens were age 20-64 years, Eastern Cooperative Oncology Group performance status ≤ 2, a left ventricular ejection fraction ≥ 50%, and no major organ dysfunction. The ACM regimen (cohorts R1 and R2) comprised a fixed dose hybrid regimen of alvocidib (30 mg/m2/day as a 30-minute intravenous [IV] bolus followed by 60 mg/m2/day over 4 hours as a continuous IV infusion on days 1-3), and escalating doses of cytarabine (300 or 667 mg/m2/day by continuous IV infusion on days 6-8) and mitoxantrone (14 or 40 mg/m2/day IV infusion on day 9 or 10 starting 12 hours after completing cytarabine) in a standard 3+3 design. In the A+7+3 regimen (cohort F1) the dose of each component was fixed according to the recommended dose from the ongoing phase 1 study in the US (NCT03298984). Treatment consisted of the alvocidib hybrid regimen on days 1-3, cytarabine 100 mg/m2/day by continuous IV infusion on days 5-11, and daunorubicin 60 mg/m2/day IV on days 5-7. The primary study objective was to determine the safety and tolerability of alvocidib in combination with each type of chemotherapy, via the assessment of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs; graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03). Secondary objectives were to evaluate the pharmacokinetics (including maximum plasma concentration [Cmax] and area under the concentration-time curve up to the last measurable concentration [AUC0-last]) and clinical activities of these regimens. Results: Between April 2018 to October 2019, 10 pts were enrolled, with a median (range) age of 45.0 (25-64) years. Of these, 6 pts (2 with relapsed disease and 4 with refractory disease) received ACM and 4 pts received A+7+3 (Table). Alvocidib was tolerated and DLTs were not observed in either of the two regimens. The most common TEAEs were hematologic events. The most common Grade ≥ 3 non-hematologic TEAEs occurring in ≥ 2 pts in the ACM regimen were diarrhea (50%), hepatic function abnormal (33%), sepsis (33%), cardiac failure (33%) and hypokalemia (33%). The most common Grade ≥ 3 non-hematologic TEAEs noted in ≥ 2 pts in the A+7+3 regimen were diarrhea (100%), tumor lysis syndrome (50%), and vomiting (50%). In the ACM regimen in R/R AML, all 6 pts were evaluable, of whom 5 (83%) achieved an objective response, including 4 complete remissions (CRs) and 1 morphologic leukemia-free state. The mean duration of CR was 13.6 months. In the A+7+3 regimen in newly diagnosed AML, 3 out of 4 pts were evaluable. All 3 evaluable pts achieved CR. One pt did not complete the A+7+3 regimen due to tumor lysis syndrome and was discontinued from the study prior to disease assessment. Overall, the mean Cmax of alvocidib in plasma was 1241 ng/mL on day 1 and 1217 ng/mL on day 3. The mean AUC0-last was 6555 h*ng/mL on day 1 and 7998 h*ng/mL on day 3. WSummary: Alvocidib in combination with cytarabine 667 mg/m2/day and mitoxantrone 40 mg/m2/day IV infusion in Japanese pts with R/R AML or cytarabine/daunorubicin (7+3) induction in Japanese pts with newly diagnosed AML showed an acceptable safety profile similar to previously investigated regimens in other studies. These data suggest that future studies of alvocidib in hematological malignancies are warranted, and planned directions for alvocidib development include phase 1/2 efficacy and safety studies in combination with other agents. Disclosures Ando: Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Kiguchi:SymBio Pharmaceuticals., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria; Taiho Pharmaceutical Co., Ltd.: Research Funding; Teijin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Co., Ltd.: Honoraria, Research Funding; Celltrion, Inc.: Research Funding; Bristol-Myers Squibb Co., Ltd.: Honoraria, Research Funding; MSD Co., Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Honoraria, Research Funding; Astellas Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Kasai:Sumitomo Dainippon Pharma Co., Ltd.: Current Employment. Sugimoto:Sumitomo Dainippon Pharma Co., Ltd.: Current Employment. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria.

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6–36.7) and the median OS was 55.3 months (95% CI 51.6–NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.

Patients with indolent non-Hodgkin lymphoma (iNHL) typically respond to first-line immunochemotherapy, but relapse is common. Treatment options for relapsed iNHL include chemotherapy ± rituximab and rituximab monotherapy. Lenalidomide plus rituximab (R

Background: Although acute myeloid leukaemia (AML) with RUNX1-RUNX1T1 and CBFB-MYH11 is categorized into a favorable cytogenetic risk group, several prognostic factors are suggested. However, those clinical significance remains controversial. We aimed to evaluate the prognostic relevance of gene mutations and minimal residual disease (MRD) in AML with RUNX1-RUNX1T1 and CBFB-MYH11. Methods: In this phase 4 trial, we enrolled AML with RUNX1-RUNX1T1 or CBFB-MYH11 patients aged 16 to 64 years old who achieved complete remission. Patients received three courses of high-dose cytarabine therapy, but no further treatment until haematological relapse. We analyzed mutations in exons 8, 10-11, and 17 of the KIT gene, and 55 genes that are frequently identified in myeloid malignancies, and also evaluated MRD. The primary endpoint was relapse-free survival (RFS) according to KIT mutation. This study is registered with UMIN Clinical Trials Registry, number UMIN000003434. Findings: Between May 25, 2010, and September 10, 2014, 203 patients were enrolled, and 199 patients were eligible. Median follow-up was 52·2 months (IQR 39·2-62·2). The primary endpoint RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio [HR] 1·92; 95% CI 1·23-3·00; p=0·003). Subgroup analysis showed a prognostic impact of KIT mutation in patients with RUNX1-RUNX1T1 (HR 3·27; 95% CI 1·90-5·64; p

The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance. Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year. Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group. The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.

In the version of this article initially published, the affiliation provided for author Matteo Giovanni Della Porta (37Cancer Center, Humanitas Research Hospital & Humanitas University, Milan, Italy) was incorrect, and a second affiliation was missing. The correct affiliations are as follows (with subsequent affiliations renumbered accordingly): 37Humanitas Clinical and Research Center–IRCCS, Humanitas Cancer Center, Milan, Italy. 38Department of Biomedical Sciences, Humanitas University, Milan, Italy. The errors have been corrected in the HTML and PDF versions of the article.

Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan.An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period.Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups.Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy.http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.

A prospective, multicenter, phase II study was performed to assess the efficacy and safety of thalidomide maintenance therapy at different doses in Japanese multiple myeloma (MM) patients. This study included 34 patients (median age, 74 years) who were previously treated with not more than three prior therapies and whose response status was evaluated as at least stable disease. They were randomized into Group A (no maintenance; 12 patients), Group B (50 mg thalidomide maintenance; 12 patients), and Group C (100 mg thalidomide maintenance; 10 patients), respectively. Thalidomide maintenance therapy resulted in improved depth of response in three cases (13.6%) and sustained response after induction therapy in eight cases (36.4%). Two-year progression-free survival (PFS) was 25.0%, 33.3%, and 77.8% in Groups A, B, and C, respectively, and was significantly higher in Group C than in Group A (p = 0.005). There was no difference in the incidence of hematological or non-hematological adverse events between Groups B and C. The current study demonstrates that maintenance with daily thalidomide at 100 mg, but not 50 mg, improved depth of response and prolonged PFS, and that this treatment was feasible for use in Japanese MM patients.

Acute promyelocytic leukemia (APL) with PML-RARA is an acute myeloid leukemia (AML) with a predominance of abnormal promyelocytes. Both hypergranular (typical) and microgranular (hypogranular) types exist. Previously, APL was associated with an extremely high mortality rate due to hemorrhage. However, since the advent of anthracycline, all-trans retinoic acid (ATRA) has been introduced into therapy, resulting in the transformation of APL into AML with a higher probability of cure. Furthermore, for the last 30 years, molecular-targeted drugs, such as arsenic acid (ATO), tamibarotene (Am80), and gemtuzumab ozogamicin (GO), have been developed in succession in addition to ATRA. In recent years, molecular-targeted drugs with different mechanisms of action are being combined, and the APL treatment outcome is revolutionary. In this review, we introduce previously used APL therapies and those at the forefront of APL treatment.

The affiliation of the last author, Kenshi Suzuki has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.

We report a unique case of a B-cell lymphoma patient in whom IgM monoclonal gammopathy resulted in a prolonged activated partial thromboplastin time (APTT) and false-positive results for fibrinogen and fibrin degradation products (FDPs). An 86-year-old man was referred to our hospital for further examination of abnormal cells in his peripheral blood. Laboratory data upon admission revealed an elevation of monoclonal IgM, presence of FDPs and marked prolongation of APTT (180 s). Bone marrow examination revealed a predominant involvement of B lymphoma cells.

The authors would like to correct the errors in the publication of the original article. The correction details are given below.

The present study (ClinicalTrials.gov Identifier: NCT02221492) was conducted to assess the efficacy and safety of plerixafor for the mobilization and collection of haematopoietic stem cells (HSCs) for autologous transplantation in Japanese non-Hodgkin lymphoma (NHL) patients. In this randomized phase 2 study, patients received granulocyte-colony stimulating factor (G-CSF, filgrastim) 400 µg/m²/day for up to 8 days. Starting on the evening of day 4, patients received, for up to 4 days, either plerixafor (240 µg/kg/day) in the G-CSF+ plerixafor arm (GP arm) or G-CSF alone arm (G arm). On day 5, daily apheresis started and was continued for up to 4 days, or until ≥ 5 × 106 CD34+ cells/kg was collected. A total of 32 patients were randomized to either the GP or G arm. In the GP arm, 9/16 patients (56.3%) achieved collection of ≥ 5 × 106 CD34+ cells/kg in ≤ 4 days of apheresis, while 1/16 patient (6.3%) achieved this target in the G arm. The most common treatment-emergent adverse events in the GP arm were back pain (56.3%), platelet count decreased (25.0%), headache, diarrhoea, and nausea (18.8% each). We found that plerixafor was well tolerated and effective for the mobilization and collection of peripheral HSCs for autologous transplantation in Japanese NHL patients.

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan–Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

Introduction: Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation between chromosomes 15 and 17 yielding the PML-RARA fusion gene, which deregulates cell proliferation...

To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

Background Copy-number alterations (CNAs) and gene mutations are hallmarks of cancer genomes, and they are implicated in the development of myeloid neoplasm. However, their relationships have not been fully examined. To address this issue, we have recently developed a novel, next-generation sequencing-based platform for copy-number analysis, which enabled us to detect mutations and CNAs simultaneously. We applied this platform to around 2,000 cases with myeloid neoplasms. Aims We aimed at delineating the landscape of CNAs and their relationships with gene mutations in myeloid neoplasms. Methods We examined 2,101 cases with myeloid neoplasms by whole-exome sequencing (WES) or targeted deep sequencing. Excluding 116 samples showing low qualities of copy-number signals, we performed subsequent analysis on the remaining 1,985 cases with myelodysplastic syndromes (MDS, n = 1,102), myelodysplastic/myeloproliferative neoplasms (MDS/MPN, n = 140), de novo acute myeloid leukemia (de novo AML, n = 448), and secondary AML (sAML, n = 295). In copy-number analysis, total copy numbers and allele-specific copy numbers (ASCNs) were quantified based on sequencing depths and allelic ratios on genome-wide probes. Copy-number signals were corrected for multiple biases (e.g. GC content, ASCN, and fragment length). We also validated the performance of this platform through comparison with SNP-array karyotyping data in 115 de novo AML cases. CNAs longer than 5 Mb were regarded as arm-level CNAs, and those shorter than 5 Mb were regarded as focal CNAs. Results In total, we identified 4,141 CNAs (52.9 % of cases with at least one CNA), and 3,863 mutations (73.9 % of cases with at least one mutation). Most frequent alterations included -7/del(7q) (13.2 %), del(5q) (11.4 %), trisomy 8 (7.2 %), and del(20q) (5.2 %), and mutations of TET2 (12 .3 %), TP53 (11.3 %), ASXL1 (10.1%), and DNMT3A (9.9 %). To evaluate the difference of copy-number landscapes between de novo AML and myelodysplasia (MDS, MDS/MPN, and sAML), we compared the frequencies of CNAs between them. Uni-parental disomy (UPD) of 13q (FLT3) and 11p (WT1), and amplifications of 11q, 13q, and 21q (ERG) were more enriched in de novo AML, while der(1;7), UPD of 11q (CBL), and del(20q) were enriched in myelodysplasia, suggesting differential involvements of CNAs. We next analyzed the correlations between CNA profiles and prognosis in cases with myelodysplasia. Since TP53 status implies a large impact on both patients' prognosis and CNA profiles, we separately analyzed TP53-positive (n = 53) and negative (n = 686) cases with available survival data. In TP53-negative cases, -7/7qLOH (Hazard ratio(HR): 2.28, q < 0.001), and UPD of 11q (CBL) (HR: 2.60, q = 0.0034) significantly correlated with shorter overall survivals (OS), while, in TP53-positive cases, amp(11q), +19, and amp(21q) were marginally associated with shorter OS. To delineate the relationships between CNAs and mutations, we interrogated correlations between both lesions among MDS cases without TP53 alterations (n = 937). A number of significant correlations were detected, such as those between trisomy 8 and del(20q) with U2AF1 mutations (q < 0.05, for each), and monosomy 7 and amp(21q) with mutations of RUNX1 and NRAS (q < 0.01, for each). These correlations were also revealed in clustering analysis based on CNA and mutation profiles, which identified 5 unique clusters: Cluster 1 (n = 171) with trisomy 8, del(20q), and mutations of U2AF1 and ETV6, Cluster 2 (n = 43) with monosomy 7, amp(21q), and mutations of NRAS, SETBP1, and RUNX1, Cluster 3 (n = 19) with amp(1q) and amp(3q), Cluster 4 (n = 127) with those of SF3B1, TET2, and DNMT3A, and Cluster 5 (n = 50) with those of SRSF2, STAG2, ASXL1, and RUNX1. The remaining 527 cases were not assigned into any cluster due to lack of significantly correlated alterations. Finally, the temporal relationships of coexisting alterations were estimated based on their cell fractions; monosomy 7 had significantly greater cell fractions (P = 0.031) and is predicted to precede NRAS mutations, while the cell fractions of U2AF1 mutations tended to be greater than those of trisomy 8 (P = 0.063), suggesting their implications in different stages of disease progression. Conclusion An integrated analysis of CNAs and mutations in >2,000 cases revealed the impacts of CNAs on disease characteristics and provided novel insight into the interplay between CNAs and mutations in the pathogenesis of MDS. Figure Disclosures Atsuta: CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Kanda:Celgene: Consultancy, Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Taiho: Research Funding; Asahi-Kasei: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Taisho-Toyama: Research Funding; Tanabe Mitsubishi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Asahi-Kasei: Research Funding; Alexion: Consultancy, Honoraria; CSL Behring: Research Funding; Takara-bio: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Taiho: Research Funding; Celgene: Consultancy, Research Funding; Tanabe Mitsubishi: Research Funding; Taisho-Toyama: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Otsuka: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Usuki:Boehringer-Ingelheim Japan: Other: Received Research ; Daiichi Sankyo: Other: Received Research ; SymBio Pharmaceuticals Limited.,: Other: Received Research ; Novartis: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Takeda Pharmaceutica: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau; Celgene Corporation: Other: Received Research , Speakers Bureau; Sumitomo Dainippon Pharma: Other: Received Research , Speakers Bureau; Pfizer Japan: Other: Received Research ; Stellas Pharma: Other: Received Research ; Otsuka: Other: Received Research ; Kyowa Kirin: Other: Received Research ; GlaxoSmithKline K.K.: Other: Received Research ; Sanofi K.K.: Other: Received Research ; Shire Japan: Other: Received Research ; Janssen Pharmaceutical K.K: Other: Received Research . Imada:Bristol-Meyer Squibb K.K.: Honoraria; Celgene K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co.,LTD.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria. Takaori-Kondo:Kyowa Kirin: Research Funding; Pfizer: Honoraria; Janssen: Honoraria; Chugai: Research Funding; Takeda: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kiguchi:Celltrion, Inc.: Research Funding; Astellas Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; MSD CO., Ltd.: Research Funding; Novartis Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myeres Squibb Co., Ltd.: Research Funding; Janssen Pharmaceutical Co., Ltd.: Research Funding; Celgene Co., Ltd.: Research Funding; SymBio Pharmaceutical Co., Ltd.: Research Funding; Taiho Pharmaceutical Co., Ltd.: Research Funding; Tejin Co., Ltd.: Research Funding; Sanofi K.K., Ltd.: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Ogawa:Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; RegCell Corporation: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Kan Research Laboratory, Inc.: Consultancy.

Background In patients with Myelodysplastic Syndromes (MDS), TP53 mutations associate with high-risk presentation, complex karyotype, acute myeloid leukemia (AML) progression and poor response to hematopoietic stem cell transplantation. These associations highlight the relevance of TP53 as a prognostic and predictive biomarker. Consistent with its role as a tumor suppressor, bi-allelic targeting of the TP53 locus is a frequent but not an obligatory event. Despite the central role of TP53 in MDS, the clinical implications of TP53 mutations in the context of allelic state have not been extensively studied. Methods Under the auspices of the International Working Group for Prognosis in MDS, we sequenced a representative cohort of 3,324 peri-diagnosis MDS patients on a next generation sequencing (NGS) panel optimized for myeloid disease. Conventional G-banding analysis (CBA) was available for 2,931 patients. Focal (~3MB) gains and deletions and regions of NGS-derived copy-neutral loss of heterozygosity (cnLOH) were assessed using an in-house algorithm CNACS. Putative oncogenic mutations in TP53 were characterized by consideration of normal controls and established population databases. A validation cohort of 1,120 samples with independent but comparable molecular and clinical annotation was sourced from a compendium of Japanese MDS data to include JALSG-MDS212, JMDP registry, and regional registries. Results NGS-derived ploidy alterations and CBA show a high genome-wide concordance. From NGS profiles, 11% of patients (n=360) are subject to cnLOH, of which 80 target the TP53 locus. We characterize 490 TP53 mutations in 380 patients, representing 11% of the cohort. Amongst those patients, 22% (n=85) and 21% (n=78) have a deletion or a cnLOH involving the TP53 locus, respectively. Taken together, these segregate patients into two TP53 states: a mono-allelic state where one wild type allele remains (33% of TP53 mutated patients, n=126); and a multi-hit state where TP53 is altered multiple times by either mutations, deletions or cnLOH (67% of TP53 mutated patients, n=254). We find that TP53 state shapes clinical presentation and outcomes. Mono-allelic TP53 patients present with more favorable disease than multi-hit TP53 patients: they are less cytopenic, have lower bone marrow blasts (median 4 vs. 9%, p Conclusions TP53 is a natural candidate for incorporation in molecularly informed risk stratification schemas (molecular IPSS-R). We show that TP53 state rather than mutation alone is an independent diagnostic and prognostic biomarker in MDS. We propose that ascertainment of TP53 state is critical in prospective clinical sequencing for risk estimation, disease monitoring and future correlative research into predictors of response to established and investigational therapies. Disclosures Bernard: Celgene: Research Funding. Hasserjian:Jazz Pharmaceuticals: Consultancy; Promedior, Inc.: Consultancy. Germing:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Cargo:Celgene: Research Funding. Santini:Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kotsianidis:Celgene: Research Funding. Takaori-Kondo:Pfizer: Honoraria; Chugai: Research Funding; Janssen: Honoraria; Kyowa Kirin: Research Funding; Takeda: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Savona:Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding. Ades:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Stevenson:Celgene: Research Funding. Fenaux:Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Aprea: Research Funding; Celgene Corporation: Honoraria, Research Funding. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Heuser:Synimmune: Research Funding; Bayer Pharma AG, Berlin: Research Funding. Valent:Blueprint: Research Funding; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Deciphera: Honoraria, Research Funding. Miyazaki:Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Otsuka: Honoraria; Chugai: Research Funding; Novartis: Honoraria; Kyowa-Kirin: Honoraria. Finelli:Novartis: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Gattermann:Novartis: Honoraria; Takeda: Research Funding; Alexion: Research Funding. Ebert:Broad Institute: Other: Contributor to a patent filing on this technology that is held by the Broad Institute.; Celgene: Research Funding; Deerfield: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Greenberg:Notable Labs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; H3 Biotech: Research Funding; Aprea: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Ogawa:Qiagen Corporation: Patents & Royalties; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; RegCell Corporation: Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Kan Research Laboratory, Inc.: Consultancy; Asahi Genomics: Equity Ownership. Papaemmanuil:Celgene: Research Funding.

Background Azacitidine (AZA) is one of the hypomethylating agents (HMAs) proven to significantly prolong overall survival (OS) for patients with higher-risk myelodysplastic syndromes (h-MDS) via a prospective phase 3 trial. However, the optimal treatment schedule of AZA for h-MDS has not yet been prospectively determined. As a 7-day treatment schedule includes weekends, a 5-day administration has also been applied with h-MDS, though solid evidence has not been established. Based on this background, we planned to compare AZA treatment on 7-day and 5-day schedules. Patients Patients diagnosed with de novo or treatment-related MDS (FAB-defined RAEB and RAEB-t), aged 16 years or older were eligible for this study, if they showed adequate performance status (ECOG PS 0-2) and no history of HMA treatment or chemotherapy. Candidates for allogeneic stem-cell transplantation were excluded. Study design This was a multicenter, randomized, open-label, phase 3 trial to compare the efficacy of AZA treatment for 7-days (AZA-7) to 5-days (AZA-5). The primary endpoint was 2-year OS rate (2y OS). AZA was given subcutaneously at 75 mg/m² every 28 days. To test the non-inferiority of AZA-5 to AZA-7, 2y OS of AZA-7 was estimated at 30%, and the delta was defined as 11%, for which 410 patients were needed to complete the trial. However, because of the poor recruitment, this study closed prematurely, and the protocol-planned interim analysis (when 200 patients were registered) was performed. This protocol was approved by the IRB at each trial center. All patients provided written informed consent, and the trial was conducted in accordance with the Declaration of Helsinki. The efficacy of AZA was evaluated using IWG2006 criteria, and treatment was continued until study completion, or relapse, unacceptable toxicity, or disease progression was observed. Efficacy was analyzed by intention-to-treat. Secondary endpoints were the hematological response rate, 2-year leukemia-free survival (2y LFS) rate, the cytogenetic response, and occurrence of adverse events. Results Between January 2013 and Jun 2018, 201 patients were randomly assigned to AZA-7 (n=99) or AZA-5 group (n=102). The median age of all patients at the enrollment was 73.5 years old (range, 48 to 91). Between the two groups, there was no significant difference in the baseline characteristics, such as sex, type of MDS (de novo or treatment-related), percent of BM blasts, FAB and WHO classification, and IPSS and IPSS-R risk. After excluding 5 and 6 patients from AZA-7 and AZA-5, respectively (poor data entry, change in diagnosis), at the time of last follow-up, 59 and 67 patients died in AZA-7 and AZA-5, respectively. The Kaplan-Meier estimates of the 2y OS and 2y LFS were 35.1% (95% CI, 23.8 to 46.7) and 27.3% (95% CI, 17.3 to 38.3) for AZA-7, and 22.4% (95% CI, 13.1 to 33.3) and 20.5% (95% CI, 11.6 to 31.2) for AZA-5, respectively. There was no significant difference in the frequency of erythroid, platelet or neutrophil improvement, or hematological response (complete or partial response, or any hematological improvement) between the two groups. The most common non-hematological adverse event of grade 3 to 4 (in ≥20% of the patients in either group) was febrile neutropenia (33.7% for AZA-7, and 30.5% for AZA-5). Conclusion and Discussion Because of the premature termination of this trial, statistical analysis for the primary endpoint (2y OS of 35.1% for AZA-7, and 22.4% for AZA-5) could not provide any solid evidence. However, considering the difference of more than 10% in 2y OS, and no major differences in the safety profiles, we favor AZA-7 to AZA-5 for MDS patients with RAEB and RAEB-t. Figure Disclosures Kiguchi: Tejin Co., Ltd.: Research Funding; Taiho Pharmaceutical Co., Ltd.: Research Funding; SymBio Pharmaceutical Co., Ltd.: Research Funding; Celgene Co., Ltd.: Research Funding; Janssen Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharmaceutical Co., Ltd.: Research Funding; MSD CO., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myeres Squibb Co., Ltd.: Research Funding; Sanofi K.K., Ltd.: Research Funding; Celltrion, Inc.: Research Funding. Usuki:Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc: Research Funding, Speakers Bureau. Suzuki:kyowa Hakko Kirin: Consultancy, Honoraria; MSD k.k.: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; takeda: Research Funding; Incyte and Pfizer: Research Funding; astellas: Research Funding; Celgene: Honoraria; Chugai: Honoraria, Research Funding; daiichi sankyo: Research Funding; eisai: Research Funding. Tomita:Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Taiho Pharma: Research Funding. Handa:Ono: Research Funding. Maeda:Janssen Pharmaceutical K.K..: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria. Iyama:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Factory: Honoraria; Astellas Pharma: Honoraria; Daiichi Sankyo: Honoraria; Allexion Pharma: Honoraria; CSL Behring: Honoraria. Yamauchi:Astellas, AbbVie: Consultancy; Pfizer, Chugai, Teijin, Solasia: Research Funding. Kiyoi:Daiichi Sankyo Co., Ltd: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Japan Inc.: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; FUJIFILM Corporation: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria.

To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD.Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development.Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapy-free patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy.Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.

The present study was intended to examine the efficacy and safety of bendamustine monotherapy in patients with previously untreated chronic lymphocytic leukemia (CLL) for whom treatment with fludarabine (FLU) was not suitable, and in FLU-naive patients with relapsed/refractory CLL. We intravenously administered bendamustine 100 mg/m2/day on days 1 and 2 of each 28-day cycle to 10 patients (eight previously untreated; two relapsed/refractory) up to six cycles. The primary endpoint was overall response rate (ORR: partial remission or better) according to the 2008 International Workshop on the CLL guidelines. The ORR was 60.0% (6/10), with the 95% confidence interval of 26.2-87.8%. Neither disease progression nor mortality occurred during follow-up. Therefore, the medians for progression-free survival, duration of response, and overall survival were estimated to exceed 12.6, 8.7, and 12.6 months, respectively. Adverse events (AEs) occurred in all 10 patients. Grade 3/4 hematologic AEs included lymphopenia (90%), neutropenia (80%), CD4 lymphopenia (80%), and leukopenia (70%). Nonhematologic AEs included constipation (80%), nausea (80%), malaise (50%), and anorexia (50%). There was one case each of grade 3 infection and adenocarcinoma of the stomach. Bendamustine showed high efficacy for Japanese patients with previously untreated or relapsed/refractory CLL, and its safety profile was acceptable.

Introduction: In recent decades, a considerable number of tumor antigens have been characterized, including the leukemia-associated antigen, Wilm's tumor 1 (WT1). WT1 is found to be expressed at low levels in various normal tissues such as gonads, kidney and the hematopoietic system. However, it is highly overexpressed in various hematological malignancies and solid tumors, including in the majority of acute myeloid leukemia (AML) cases. OCV-501 is a human leukocyte antigen (HLA) class II-restricted helper peptide derived from the WT1 protein. This Phase II trial was conducted to evaluate the efficacy and safety of OCV-501 in elderly patients with AML (ClinicalTrials.gov identifier: NCT01961882). Methods: This multicenter, randomized, double-blind, placebo-controlled trial was conducted in Japan, the Republic of Korea and Taiwan between October, 2013 to November, 2017. The key eligibility criteria for this trial were patients with AML, aged 60 years or older, who achieved first complete remission within one or two courses of standard induction therapy, completed more than one course of standard consolidation therapy, and not scheduled for hematopoietic stem cell transplantation. Patients were assigned to receive either OCV-501 monotherapy or placebo. Subcutaneous administration of OCV-501 3mg or placebo was given once weekly up to the eighth administration, and once biweekly from the ninth administration onwards up to a duration of 2 years, followed by post-treatment observation period. The primary endpoint was disease-free survival (DFS) that was defined as the time from randomization to AML relapse or death from any cause, whichever came first, within the observation period. Secondary endpoints were overall survival (OS), quality of life (QOL; The European Organization for Research and Treatment of cancer [EORTC] QLQ-C30), and performance status (Eastern Cooperative Oncology Group performance status [ECOG PS]). Safety, including any occurrence of adverse events (AEs) was evaluated. Results: A total of 133 patients who had achieved first remission after prior induction and consolidation therapies were randomized to receive either OCV-501 (OCV-501 arm, N=68) or placebo (placebo arm, N=65). The median age of the patients was 67 years (range, 60 - 85) and most of them had good performance status (ECOG PS score 0 - 1). The WT1 mRNA level at Day 1 was Conclusion: There was no significant difference in DFS between OCV-501- and placebo-treated patients. OCV-501 was found to be generally safe and well-tolerated in elderly AML patients. Disclosures Yamaguchi: Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; Celgene KK: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria. Kiguchi:Teijin Co., Ltd.: Other: Grant; Sanofi K.K., Ltd.: Other: Grant; Celltrion, Inc.: Other: Grant; Taiho Pharmaceutical Co., Ltd.: Other: Grant; SymBio Pharmaceuticals, Ltd.: Other: Grant; Takeda Pharmaceutical Co., Ltd.: Other: Personal fees; Ono Pharmaceutical Co., Ltd.: Other: Personal fees; Astellas Pharmaceutical Co., Ltd.: Other: Grant; Celgene Co., Ltd.: Other: Grant and personal fees; Janssen Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Novartis Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Nippon Shinyaku Co., Ltd.: Other: Grant and personal fees; Mochida Pharmaceutical Co., Ltd.: Other: Personal fees; Eisai Co., Ltd.: Other: Personal fees; MSD Co., Ltd.: Other: Grant and personal fees; Daiichi Sankyo Pharmaceutical Co., Ltd.: Other: Grant; Chugai Pharmaceutical Co., Ltd: Other: Grant; Bristol Myers Squibb Co., Ltd.: Other: Grant and personal fees; Pfizer Co., Ltd.: Other: Personal fees; Otsuka Pharmaceutical Co., Ltd.: Other: grant and personal fees; Kyowa Hakko Kirin Co., Ltd.: Other: Grant and personal fees. Miyawaki:Novartis Pharma KK: Consultancy; Otsuka Pharmaceutical Co., Ltd.: Consultancy; Astellas Pharma Inc.: Consultancy. Heike:Sumitomo Dainippon Pharma Co., Ltd.: Other: Advisor; Otsuka Pharmaceutical Co., Ltd.: Other: Advisor. Mitsuki:Otsuka Pharmaceutical Co., Ltd.: Employment. Yoshida:Otsuka Pharmaceutical Co., Ltd.: Employment. Liew:Otsuka Pharmaceutical Co., Ltd.: Employment. Naoe:Astellas Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Toyama Chemical Co., Ltd.: Research Funding.