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The cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen, containing doxorubicin (DXR), which is a key drug for aggressive non-Hodgkin lymphoma (NHL), is a standard chemotherapeutic regimen; however, its administration in elderly patients is often intolerable. Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracycline developed in Japan. We have conducted a phase II trial of a full-dose THP-COP (modified CHOP regimen with DXR replaced by THP) regimen for elderly patients with newly diagnosed, advanced-stage, aggressive NHL. Patients aged 70-79 years old with previously untreated NHL according to the Working Formulation (D through H and J), disease stage I with a bulky mass or stage II-IV, and performance status of 0-1 were eligible. The THP-COP regimen, which consisted of 750-mg/m

The optimal combined chemotherapy regimen with rituximab has yet to be established for elderly patients with advanced-stage indolent B-cell lymphoma (B-NHL). A multicenter study was performed to evaluate the efficacy and toxicity of R-THP-COP therapy in elderly patients (aged 70–79 years) with newly diagnosed advanced-stage indolent B-NHL using the complete response rate (%CR) as the primary endpoint. Patients with newly diagnosed, clinical stage III/IV, indolent B-NHL, aged 70–79 years, with a performance status of 0–2 were eligible for this study. R-THP-COP consists of 375 mg/m2 of rituximab, 50 mg/m2 of pirarubicin, 750 mg/m2 of cyclophosphamide, 1.4 mg/m2 of vincristine, and 100 mg/day of oral prednisolone for 5 days. This study was discontinued due to poor accrual after the enrollment of 18 patients, although the planned sample size was 40 patients. The numbers of patients with follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and mantle cell lymphoma were 16, 1, and 1, respectively. The median age was 73 (range, 70 to 79) years. The %CR including unconfirmed CR was 45% (95% confidence interval: 25-66%) and the overall response rate was 72%. The estimated 5-year overall survival and progression-free survival rates were 55% and 28%, respectively. The major toxicity observed was grade 4 neutropenia (94%). Grade 4 non-hematological toxicities were not observed and no patients developed grade 3/4 cardiac toxicities. This phase II study provides useful information regarding the efficacy and toxicity of R-THP-COP therapy for patients aged 70 years or older with newly diagnosed, advanced-stage, indolent B-NHL, although the sample size was small.

We report the results of a multicenter observational study using the New TARGET system, in which the effectiveness and safety of tyrosine kinase inhibitors (TKIs) were evaluated in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. A total of 506 patients were enrolled between April 2010 and March 2013. Median age was 56 (range 18–92) years; 35% of patients were females. As the first-line therapy, 139 (27.9%), 169 (33.9%) and 144 (28.9%) patients were treated with imatinib, nilotinib, and dasatinib, respectively. Five-year progression-free survival (PFS) and overall survival (OS) were 93.8% and 94.5%, respectively. The OS curve was significantly superior for patients treated with second-generation TKIs than imatinib (P = 0.0068), and an early molecular response (EMR) at 3 months (BCR-ABL1

Given the poor prognosis of patients with relapsed/refractory acute myeloid leukemia (AML), better therapy is needed. Fludarabine enhances the efficacy of Ara-C (cytarabine) by increasing intracellular Ara-C-triphosphate. The FLAG (fludarabine, high-dose Ara-C, supported with granulocyte colony-stimulating factor) regimen has been tested for use in AML patients by other investigators. In the phase II study reported here, we evaluated the efficacy and toxicity of FLAGM therapy (FLAG with mitoxantrone), further intensified by adding mitoxantrone, based on the results of a phase I study by our group. The major endpoints were complete remission (CR) rate and early death. From June 2004 to February 2008, 41 patients (median age 52 years; range 18-64 years) were enrolled. Thirty (73% 95% CI 58-84%) patients achieved CR, which met the primary endpoint; there was a single case of early death from pneumonia. Two-year overall survival was 39.4% (95% CI 25.2-55.6%). Of those who achieved CR, 27 underwent allogeneic stem cell transplantation (SCT), and 12 SCT recipients showed long-term survival. Grade 3/4 non-hematological adverse events included infection (59%), nausea/vomiting (15%), diarrhea (7%), and elevated liver enzymes (7%). In conclusion, FLAGM is an effective and safe salvage therapy for patients with relapsed/refractory AML, and facilitated SCT for a large proportion of patients.

Comorbidities at diagnosis among patients with chronic myeloid leukemia in chronic phase (CML‐CP) may affect their overall survival (OS) rate even in the tyrosine kinase inhibitor (TKI) era. However, the prognostic impact of comorbidities in patients with CML‐CP treated with a second‐generation TKI (2GTKI) has not been elucidated. We evaluated the effect of comorbidities on survival using the Charlson Comorbidity Index (CCI) in patients with CML‐CP treated with imatinib or a 2GTKI (nilotinib and dasatinib). From April 2010 to March 2013, 506 patients with CML‐CP were registered for the population‐based cohort study, and 452 with a median age of 56 y were assessable. Treatment groups included 139 patients receiving imatinib, 169 receiving nilotinib, and 144 receiving dasatinib. Comorbidities were diagnosed in 99 patients. CCI scores were stratified as follows: 2, 353 patients; 3, 72 patients; and ≥4, 27 patients. Treatment response did not vary relative to CCI scores. However, across the entire cohort, the OS rate was significantly lower among patients with higher CCI scores than in those with a CCI score of 2 (94.4% in score 2, 89.0% in score 3, and 72.8% in score ≥4; P, The prognostic impact of comorbidities in chronic myeloid leukemia in patients with chronic phase CML (CML‐CP) treated with a second‐generation tyrosine kinase inhibitor (TKI) remains to be elucidated. This study demonstrated that comorbidities at diagnosis were the most important predictive factor for successful treatment, regardless of the TKI type used in CML‐CP.

We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54 years (range 22–88 years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1–99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4–94.8%) and 87.2% (95% CI 78.1–93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.

Recent studies have described various impacts of obesity and being overweight on acute myeloid leukemia (AML) outcomes in adult patients, but little is known about the impact of being underweight. We compared the outcomes of underweight patients to those of normal weight and overweight patients. Adult patients with AML who registered in the JALSG AML201 study (n = 1057) were classified into three groups: underweight (body mass index [BMI]

Background: Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequisite condition to discontinue a tyrosine kinase inhbitor (TKI). In ENESTnd and DASISION trials, both nilotinib and dasatinib achieved DMR more effectively than imatinib. However, there is no direct comparative study to determine which TKI is better to achieve DMR for de novo CML-CP. So, we conducted a randomized phase 3 JALSG CML212 study to compare the achievement of MR4.5 (BCR-ABL IS≤0.0032%) between nilotinib and dasatinib. Methods: The JALSG CML212 study is a multicentral open-labeled prospective randomized controlled phase 3 study for de novo CML-CP. This study was reviewed and approved by the institutional review board of each institute and registered in the UMIN Clinical Trials Registry (#UMIN000007909). All patients provided written informed consent before enrollment. Diagnosis of CML was done by a cytogenetic study (G-banding or FISH) and/or detection of BCR-ABL by RT-PCR. The primary endpoint is a rate of cumulative achievement of MR4.5 by 18 mon. Major secondary endpoints were safety, continuity, progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and cytogenetic and molecular responses. A total of 461 patients were registered from 82 institutes and 454 patients were randomly assigned to the nilotinib arm or dasatinib arm (both, n=227) with Sokal risk scores as a stratification factor. Treatment doses were 300 mg, bid for nilotinib and 100 mg, qd for dasatinib. Treatment responses were evaluated by ELN2009. Patients were allowed to stop study treatment if judged as failure by ELN2009 or showed intolerance (repetitive ≥Grade 3 or continuous Grade 2 side effects) to the allocated TKI. BCR-ABL mRNA levels were monitored every three months with international scales using a MolecularMD, ODK-1201, or M135R kit with ≥MR4.5 sensitivities. Adverse events were evaluated by the CTCAE ver 4.0. Results: The median age of the patients was 53 years old in both arms. The proportions of Sokal low, intermediate, and high risk groups were 44.1%, 37.0%, and 18.9% in the nilotinib arm and 44.5%, 37.0%, and 18.5% in the dasatinib arm, respectively, without a significant difference. Also, there was no significant difference in ECOG PS, EUTOS risk groups, complications, or frequencies of additional chromosomal abnormalities in both arms. In the ITT population, the cumulative achievement rates of MR4.5 by 18 mon were 33.0% (75/227) (95% CI:27.0-39.6%) in the nilotinib arm and 30.8% (70/227) (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference with a CMH test (p=0.62). This finding was also confirmed in the per-protocol (PP) population (33.5% in the nilotinib arm and 31.8% in the dasatinib arm, p=0.72). At 18 mon, 75.9% and 79.6% of the patients continued the allocated TKI in the nilotinib and dasatinib arms, respectively (p=0.36) (in the PP population).There was no significant difference in PFS, EFS, or OS between two arms by log-rank tests (the estimated rates at 36 mon: 98.8%, 67.2%, and 98.8% in the nilotinib arm; 99.0%, 65.4%, and 99.0% in the dasatinib arm). In addition, PFS, EFS and OS didn't differ between both arms regardless of Sokal and EUTOS risk groups. The cumulative CCyR rates by 12, 18, 24, and 36 mon were 77.1%, 78.0%, 78.4%, and 78.4% in the nilotinib arm and 78.4%, 78.9%, 78.9%, and 78.9% in the dasatinib arm, respectively without no significant difference. The MMR rates by 12, 18, 24, and 36 mon were 62.6%, 67.0%, 72.3%, and 73.1% in the nilotinib arm and 68.7%, 73.1%, 75.3%, and 77.1% in the dasatinib arm, respectively, without no significant difference. The MR4.5 rates by 12, 24, and 36 mon were 25.6%, 37.4%, and 40.5% in the nilotinib arm and 23.4%, 36.6%, and 44.5% in the dasatinib arm, respectively, with no significant difference. In the safety population, Grade 3/4 adverse events observed with ≥10% frequencies were lipase elevation (11.5%) in the nilotinib arm and neutropenia (12.8%) and thrombocytopenia (16.8%) in the dasatinib arm. Any new safety issue was observed in neither of the arms. Conclusions: Based on these results, we consider that nilotinib and dasatinib are equally effective for de novo CML-CP patients in achieving MR4.5 as well as in achieving CCyR and MMR in terms of both frequencies and times to achievement with similar continuity. Figure Disclosures Matsumura: Kyowa Kirin Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K: Speakers Bureau; Amgen K.K.: Speakers Bureau; DAIICHI SANKYO COMPANY, LIMITED.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb Company: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau. Minami:Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Takeda: Honoraria. Takahashi:Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria, Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Iriyama:Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau. ONO:Mundipharma K.K.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria. Fujisawa:Janssen Pharmaceutical K.K: Speakers Bureau; Celgene: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Kobayashi:Pfizer Japan Inc.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; SymBio Pharmaceuticals Limited.: Consultancy. Asou:Fuji Pharma Co.,Ltd.: Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria, Speakers Bureau; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma KK: Honoraria; Asahi Kasei Pharma.: Speakers Bureau. Kiyoi:Celgene Corporation: Research Funding; Bristol-Myers Squibb Company: Speakers Bureau; Astellas Pharma Inc.: Consultancy, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma KK: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; NIPPON SHINYAKU CO.,LTD.: Research Funding; Amgen Astellas BioPharma K.K.: Consultancy; Kyowa Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Perseus Proteomics Inc.: Research Funding. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Naoe:Sysmex co.: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau.

High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd-MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd-MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL.

This long-term follow-up of a completed phase 1/2 study assessed the safety and efficacy of bosutinib in Japanese Philadelphia chromosome-positive, chronic phase (CP) or advanced phase (ADV) chronic myeloid leukemia patients who were resistant/refractory or intolerant to prior tyrosine kinase inhibitor treatment. This analysis included 63 patients with a median bosutinib follow-up of 132 weeks (range 3‒372). In the CP second-line (2L) cohort, the cumulative major cytogenetic response (MCyR) and major molecular response (MMR) rates throughout the study were 73 and 53%, respectively. In the CP third-line (3L) cohort, the cumulative MCyR and MMR rates throughout the study were 70 and 40%, respectively. Of the eight ADV patients, MCyR was attained or maintained by 50% of patients, and complete hematologic response was attained or maintained by 25% of patients. Progression-free survival rate and overall survival rate at 96 weeks were, respectively, 91 and 98% in CP2L, 88 and 100% in CP3L, and 33 and 50% in ADV patients. The most common adverse events (50%) reported were diarrhea (95%), nasopharyngitis (57%), and rash (57%). Bosutinib demonstrated durable efficacy and a manageable tolerability profile over long-term use in Japanese patients.ClinicalTrials.gov: NCT00811070.

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib-combined chemotherapy for newly diagnosed BCR-ABL-positive ALL in adults. Sixty-eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients55 years of age. Sixty-five patients achieved CR (95.6%). The estimated 2-year event-free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo-SCT) at initial CR was performed in 43 patients. Thirty-five of 39 patients55 years and 8 of 26 patients55 years underwent allo-SCT at first CR. The 3-year OS in patients55 years receiving allo-SCT at first CR, patients55 years receiving allo-SCT at first CR, patients55 years not receiving allo-SCT at first CR, and patients55 years not receiving allo-SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three-year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib-based chemotherapy allowing allo-SCT in a high proportion of patients, particularly those55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo-SCT. This trial was registered with the UMIN (000001226).

Background: In the New TARGET observational study, 452 newly diagnosed chronic myeloid leukemia chronic phase (CML-CP) patients were analyzed and the results reported recently in International Journal of Hematology (IJH). The median follow-up period was 5.4 years, and eight patients progressed to AP/BC and six had a CML-related death. Herein, we evaluated the impact of additional chromosomal abnormalities (ACAs) on the clinical outcomes of participants in this study. Methods: Cytogenetic analyses of bone marrow aspiration were performed at enrollment and every 6 months until complete cytogenetic response (CCyR) was achieved. If physicians switched to TKI because of resistance or intolerance to the first TKI, cytogenetic analyses of bone marrow aspiration were performed at baseline of the second-line treatment. Chromosome banding analysis was performed on bone marrow cells after short-term culture (24 hours). At least 20 metaphases were analyzed by the G-banding method according to the International System for Human Cytogenetic Nomenclature. This sub-analysis in the New TARGET observational study 1 was approved by the ethics committee of Akita university school of medicine (No. 2178). Results: For cytogenetic analyses, 1,732 samples were collected over the entire observation period from 452 patients. Chromosomal abnormalities, besides standard Ph translocation, were identified in 164 samples from 61 patients. Constitutional alterations (n=7) and single abnormality with -Y at the onset of CML (n=11), clonal chromosomal abnormalities in Ph negative metaphases during TKI treatment (n=10) and t(v;22) including three-way Ph translocation at the onset of CML (n=9) were excluded from patients with ACAs. ACAs were detected in 24 patients either at the onset of CML (n=19) or over the duration of TKI treatment (n=5). Among them, i(17q), monosomy7/7q-, chromosome3q26, and complex karyotype composed of these 3 abnormalities, which were proposed as a high-risk ACAs in a previous study were identified in three patients. Among 24 patients with ACAs, 8 patients received imatinib(IM) and 16 patients 2G-TKI. There were no statistically significant differences in the clinical background between the group with and without ACAs.Six patients with TKI resistance could hardly achieve MMR, and 4 patients died after progression to AP/BC. In a multivariate analysis of prognostic factors for predicting the clinical outcomes, including age, 2G-TKI, Charlson Comorbidity Index (CCI) score, performance status (PS), EUTOS long-term survival score (ELTS), and the presence of ACAs (Table), ACAs was one of the independent adverse prognostic factors for OS (HR 3.701 [95%CI: 1.175−11.660] P= 0.025), EFS (HR 3.920 [95%CI: 1.563−9.833] P= 0.036), PD (HR 39.02 [95%CI: 7.103−214.30] P< 0.0001), and loss of response (HR 8.346 [95%CI: 3.221−21.630] P The Kaplan-Meier curve for PFS, and OS were significantly lower for the group with ACAs than without (Figure A, D: Log-rank test P= 0.00842, 0.00408, respectively); the 5-year PFS and OS rates of the group with ACAs were 81.3% (95%CI: 56.6−92.7), and 77.6% (95%CI: 49.8−91.2), respectively. Although there were statistically significant differences in PFS, and OS between the group with and without ACAs in imatinib arm (Figure B, E: Log-rank test P= 0.00007, 0.00007, respectively), there were no differences in 2G-TKI arm (Figure C, F: Log-rank test P= 0.478, 0.515, respectively). Conclusions: In the present cytogenetic analysis of the New TARGET observational study 1, ACAs had a negative impact on clinical outcomes. However, we discovered that 2G-TKI might be able to overcome the poor prognosis of CML patients with ACAs in 2G-TKI era. Therefore, cytogenetic analysis at CML diagnosis and during TKI treatment is very important for the prediction of outcome and the selection of TKI. Acknowledgments: This study was supported by research fundingfrom Novartis Pharmaceuticals and Bristol-Myers Squibb to Japanese Society of Hematology. Disclosures Takahashi: Pfizer: Research Funding, Speakers Bureau; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Chug Pharmaceuticals: Research Funding; Asahi Kasei Pharma: Research Funding; Novartis Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau. Kizaki:Daiichi Sankyo: Research Funding; Janssen Pharm: Speakers Bureau; Takeda Pharm: Research Funding, Speakers Bureau; Ono Pharm: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Kyowa Kirin: Research Funding; Chugai Pharm: Research Funding; Celgene: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Sumitomo Dainippon Pharm: Consultancy. Kawaguchi:Pfizer: Honoraria; Novartis: Honoraria; Alexion: Honoraria. Suzuki:AbbVie: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Janssen: Honoraria; Meiji Seika: Honoraria; Bristol-Myers Squibb: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; Eisai: Honoraria. Yamamoto:Meiji Seika Pharma: Consultancy, Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Bayer: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ARIAD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; SymBio: Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Gilead Sciences: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; MSD: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

Background: Pretreatment status assessment at diagnosis in patients with chronic myeloid leukemia in chronic phase (CML-CP) is more important for successful treatment in the tyrosine kinase inhibitors (TKIs) era. For instance, the Charlson comorbidity index (CCI) score is considered the useful tool for predicting overall survival (OS) in patients with CML treated with imatinib (IM) (Saussele S et al., 2015). However, the effect of CCI in patients with CML treated with second-generation TKI (2nd TKI) and clinical practice setting was unknown. This study aimed to evaluate the effect of pretreatment statuses, including CCI, on OS of participants of the New TARGET observational study 1 conducted by the Japanese Society of Hematology (JSH). Methods: Patients newly diagnosed with CML-CP were registered to the New TARGET observational study 1 from April 2010 to March 2013. They were treated with TKIs (IM, nilotinib [NIL], or dasatinib [DAS]) after registration. Exclusion criteria were defined as follows: (1) accelerated phase/blast crisis (AP/BC) CML and (2) pretreatment with interferon-alfa, any TKIs, or hydroxyurea for more than 3 months, or allogeneic hematopoietic stem cell transplantation before registration. Other details of the protocol were previously reported (Kizaki et al., 2019). Patients were classified into CCI risk groups of 2, 3, and ≥4 for analysis. The New TARGET observational study 1 was supported by research fundings from Novartis Pharmaceuticals and Bristol-Myers Squibb to JSH. This subgroup analysis was approved by the institutional review board of the Hamamatsu University School of Medicine. The chi-square test was used to compare clinical characteristics for categoricaldata and the Wilcoxon rank-sum test for continuous data. OS was calculated using the Kaplan-Meier method and compared by the log-rank test. Gray's test was used to compare cumulative incidence curves. Cox proportional hazard analyses were performed to determine prognostic indicators of OS. The Wald test was used to assess the prognostic significance of a candidate variable. Statistical analyses were performed using EZR, a graphical user interface for R (Kanda Y, 2013). Results: Among 506 enrolled patients, 475 with a median age of 56 years were assessable. The median follow-up period was 5.4 years. In total, 103 patients (21.7%) had various types of comorbidities, with diabetes mellitus, mild liver disease, peripheral vascular disease, myocardial infarction, renal disease, and peptic ulcer disease (7.3%, 4.1%, 3.2%, 2.6%, 2.2%, and 2.2%, respectively) as the most common. The lowest CCI score was 2 owing to CML. CCI scores were stratified as follows: 2, 372 patients (78%); 3, 74 patients (16%); and ≥4, 29 patients (6%). Higher CCI scores were significantly associated with older age (P Conclusion: Our results demonstrated that comorbidities and poor PS at diagnosis were important predictive factors for OS, regardless of the type of TKI in patients with CML-CP. The risk-adopted management based on comorbidities and PS may be important to further improve the clinical outcomes of CML-CP. Disclosures ONO: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Kyowa Hakko Kirin: Research Funding; ONO Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Takahashi:Novartis Pharmaceuticals: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Eisai Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Asahi Kasei Pharma: Research Funding; Chug Pharmaceuticals: Research Funding. Kizaki:Kyowa Kirin: Research Funding; Chugai Pharm: Research Funding; Novartis: Speakers Bureau; Ono Pharm: Research Funding, Speakers Bureau; Takeda Pharm: Research Funding, Speakers Bureau; Janssen Pharm: Speakers Bureau; Sumitomo Dainippon Pharm: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Research Funding. Kawaguchi:Alexion: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Suzuki:Merck Sharp & Dohme: Honoraria; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Eisai: Honoraria; Janssen: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Meiji Seika: Honoraria; Kyowa Hakko Kirin: Honoraria; AbbVie: Honoraria; Novartis: Honoraria. Yamamoto:Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Gilead Sciences: Research Funding; Otsuka: Honoraria; Novartis: Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Solasia Pharma: Research Funding; SymBio: Research Funding; MSD: Consultancy, Honoraria; Janssen: Honoraria; Sumitomo Dainippon: Honoraria; ARIAD: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Incyte: Research Funding; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

Background Clinical practice guidelines should be user-friendly and confirming their penetration rate and compliance are critical. Methods We conducted a nationwide web-based questionnaire survey among pharmacists regarding the 2013 guidelines for the appropriate use of granulocyte-colony stimulating factors (G-CSFs) (version 2, published by the Japan Society of Clinical Oncology [JSCO]) between August 24 and September 6, 2015. Results A total of 301 pharmacists responded; 96.0% belonged to hospitals and were board-certified pharmacists in oncology pharmacy (n = 133) and palliative pharmacy (n = 78). In addition, 61.5% of respondents (n = 185) worked for designated cancer care hospitals. The observation that 75.7% of respondents knew that the JSCO guidelines are available on the internet indicated that several pharmacists used this guideline. A high degree of usability by pharmacists was also demonstrated, as 98.0% and 51.5% of respondents, respectively, agreed with the statements “it is useful for the work of pharmacists” and “it is referred to in the actual work of pharmacists”. However, more than half of the respondents (58.4%) agreed with the phrase “there are differences from the actual work of pharmacists”. Conclusions Their responses indicated that the respondents used the G-CSF guidelines and viewed them positively; however, the observation that about half of the respondents reported feeling that the guidelines do not match their current practice requires additional follow-up in future studies. The use of these guidelines should be routinely assessed in order to introduce novel cancer chemotherapy regimens and long-acting G-CSF in clinical practice.

Recent studies indicate that lipid metabolic changes affect the survival of multiple myeloma (MM) cells. Time-of-flight secondary ion mass spectrometry (TOF-SIMS), an imaging mass spectrometry technique, is used to visualize the subcellular distribution of biomolecules including lipids. We therefore applied this method to human clinical specimens to analyze the membrane fatty acid composition and determine candidate molecules for MM therapies. We isolated MM cells and normal plasma cells (PCs) from bone marrow aspirates of MM patients and healthy volunteers, respectively, and these separated cells were analyzed by TOF-SIMS. Multiple ions including fatty acids were detected and their ion counts were estimated. In MM cells, the mean intensity of palmitic acid was significantly lower than the mean intensity in PCs. In a cell death assay, palmitic acid reduced U266 cell viability dose-dependently at doses between 50 and 1000 μM. The percentage of apoptotic cells increased from 24 h after palmitic acid administration. In contrast, palmitic acid had no effect on the viability of normal peripheral blood mononuclear cells (PBMCs). The results of this study indicated that palmitic acid is a potential candidate for novel therapeutic agents that specifically attack MM cells.

Lipid metabolic changes under diseased conditions, particularly in solid tumors, are attracting increased attention. However, in non-solid tumors, including most hematopoietic tumors, lipid analyses are scarce. Multiple myeloma (MM) is a plasma cell disorder arising from bone marrow, and the lipid status of MM cells has not been reported yet. In this study, we analyzed flow cytometry-sorted single MM cells and normal plasma cells (NPCs) using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), a two-dimensional label-free mass spectrometry technique for biomolecular analysis, to obtain specific lipid information. We isolated 1.31-5.77% of MM cells and 0.03-0.24% of NPCs using fluorescence-activated cell sorting (FACS). Analysis of purified cells using MALDI-IMS at the single-cell level revealed that the peak intensity and ion signals of phosphatidylcholine [PC (16:0/20:4) + H](+) at m/z 782.5 were significantly decreased in MM cells compared to NPCs. By examining particular cell populations rather than cell mixtures, our method can become a suitable tool for the analysis of rare cell populations at the single-cell level and advance the understanding of MM progression.

Purpose The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL. Patients and Methods Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. Results A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 109/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non–high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated. Conclusion In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study.

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.

Objectives Pharmacokinetic disposition of bortezomib in the blood has not been fully characterized in humans. This study aimed to evaluate the blood distribution of bortezomib and its kinetics in multiple myeloma patients. Design and method Eighteen multiple myeloma patients receiving bortezomib–dexamethasone combination therapy were enrolled. Blood specimens were drawn just before bortezomib administration on days 1 and 8 in the second and third cycles and after discontinuation. The relationships between bortezomib concentration and blood components were evaluated. Results Bortezomib concentration in the blood on day 1 was higher than that on day 8 in the second cycle. No difference was observed in bortezomib blood concentrations between day 8 in the second and third cycles. The bortezomib concentration in the blood and blood cells was 3- and 7-fold higher than that in plasma. Bortezomib concentration in the blood was correlated with the red blood cell count. The half-life of bortezomib in the blood was 23 days. Conclusion Bortezomib was taken up into red blood cells to only a limited extent and eliminated in parallel to the red blood cells' lifespan. The turnover of red blood cells can affect the pharmacokinetic disposition of bortezomib in multiple myeloma patients.

Lipid metabolism has attracted much attention in tumor biology studies. Recently, time-of-flight secondary ion-mass spectrometry (TOF-SIMS) imaging has enabled in situ lipid analysis of biological specimens with a submicrometer spatial resolution for analyses of tumor cells. In clinical settings, sample preservation is important, and specimens are often obtained from patients at different times; these samples must be preserved prior to measurement, and preservation techniques commonly involve chemical fixation with aldehydes. However, the influence of sample preservation on TOF-SIMS analysis of fatty acids has not been reported. Thus, we examined the influence of glutaraldehyde fixation on TOF-SIMS analyses by using the multiple myeloma cell line U266. We prepared two indium-tin-oxide-coated glass slides on which cells were attached. One slide was fixed with 0.25% glutaraldehyde and rinsed in ammonium acetate buffer, whereas the other was left untreated. The specimens were subjected to TOF-SIMS analyses in negative-ion mode, and signals in the mass range of m/z 0–1850 were monitored. Both fixed and unfixed cells exhibited intense ion peaks corresponding to phosphoric acids and five types of fatty acids, putatively derived from membrane phospholipids. These ions were localized at the cell attachment site. We statistically compared the mean intensity of fatty acids between fixed and unfixed cells and found that both showed equivalent signals. Glutaraldehyde fixation was thus shown to be an effective method for preparing samples for single-cell lipid analysis by TOF-SIMS. Copyright © 2014 John Wiley & Sons, Ltd.

Multidrug resistance (MDR) is a serious problem faced in the treatment of malignant tumors. In this study, we characterized the expression of non-homologous DNA end joining (NHEJ) components, a major DNA double strand break (DSB) repair mechanism in mammals, in K562 cell and its daunorubicin (DNR)-resistant subclone (K562/DNR). K562/DNR overexpressed major enzymes of NHEJ, DNA-PKcs and DNA ligase IV, and K562/DNR repaired DSB more rapidly than K562 after DNA damage by neocarzinostatin (MDR1-independent radiation-mimetic). Overexpressed DNA-PKcs and DNA ligase IV were also observed in DNR-resistant HL60 (HL60/DNR) cells as compared with parental HL60 cells. Expression level of DNA-PKcs mRNA paralleled its protein level, and the promoter activity of DNA-PKcs of K562/DNR was higher than that of K562, and the 5'-region between -49bp and the first exon was important for its activity. Because this region is GC-rich, we tried to suppress Sp1 family transcription factor using mithramycin A (MMA), a specific Sp1 family inhibitor, and siRNAs for Sp1 and Sp3. Both MMA and siRNAs suppressed DNA-PKcs expression. Higher serine-phosphorylated Sp1 but not total Sp1 of both K562/DNR and HL60/DNR was observed compared with their parental K562 and HL60 cells. DNA ligase IV expression of K562/DNR was also suppressed significantly with Sp1 family protein inhibition. EMSA and ChIP assay confirmed higher binding of Sp1 and Sp3 with DNA-PKcs 5'-promoter region of DNA-PKcs of K562/DNR than that of K562. Thus, the Sp1 family transcription factor affects important NHEJ component expressions in anti-cancer drug-resistant malignant cells, leading to the more aggressive MDR phenotype.

Background The contributions of DRD2 and OPRM1 genetic variants to clinical responses to prochlorperazine remain to be clarified in opioid-treated patients. We evaluated the clinical responses to prochlorperazine based on non-genetic and genetic factors in oxycodone-treated patients. Methods Seventy Japanese cancer patients starting oral prochlorperazine together with oxycodone were enrolled. Predose plasma prochlorperazine concentrations and serum prolactin concentrations were determined. The incidences of oxycodone-induced nausea and vomiting were monitored for 2 weeks. Results Plasma prochlorperazine concentration and oxycodone daily dose were not associated with the incidences of nausea and vomiting. The incidence of nausea was significantly higher in the DRD2 TaqIA A1A2 + A1A1 group than in the A2A2 group. The incidence of vomiting was significantly higher in females than in males. Before and after the prochlorperazine administration, the serum prolactin concentration was significantly higher in female patients than in male patients. The serum prolactin concentration was weakly correlated with prochlorperazine concentration and was significantly higher in the OPRM1 118AA group than in the AG + GG group. Conclusions DRD2 TaqIA and female gender altered the prophylactic antiemetic efficacy of prochlorperazine. OPRM1 A118G together with plasma exposure of prochlorperazine and gender affected prolactin secretion in oxycodone-treated patients.

A multicenter observational study, conducted by the Japanese Society of Hematology (JSH), evaluated the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in newly diagnosed patients with chronic myeloid leukemia -chronic phase (CML-CP). The clinical data of this study were collected using the New Target system, which is an online database that can be easily accessed by physicians. A total of 506 patients were enrolled from 102 institutions between April 2010 and March 2013; data for 444 patients (median age: 56 [range 18-92] years; 65% male) were analyzed. According to the Sokal score, 201 (45.3%), 178 (40.1%), and 64 patients (14.4%) were classified into the low, intermediate, and high-risk groups. As the first-line therapy, 148 (29.8%) patients received imatinib (IM), 173 (34.8%) received nilotinib (NIL), and 146 (29.4%) received dasatinib (DAS). BCR-ABL1 % was regularly monitored every 3 months in the first year and every 6 months thereafter. TKI plasma trough concentrations were determined with LC-MS/MS at 3, 6, and 12 months. At 60 months of follow up, 5-year progression-free survival (PFS) and overall survival (OS) were 94.5% (95%CI, 91.2-96.5) and 94.8% (95%CI, 91.6-96.9), respectively. The 5-year OS curve was significantly better in patients treated with NIL or DAS than that in patients with IM (IM, 90.9% [95%CI, 83.7-95.0]; NIL, 98.0% [95%CI, 92.2-99.5]; DAS, 96.0% [95%CI, 89.4-98.5]; log-rank test: P =0.0345). An early molecular response (EMR; BCR-ABL1 Testing for BCR-ABL1mutation was performed in 101 patients. Various BCR-ABL1mutations were identified in 23 patients (IM, n=13; NIL, n=8; and DAS, n=2). T315I mutation was not identified. Exon 8/9 35bp insertion was identified in 14 patients (IM, n=8; NIL, n=5; DAS, n=1). Seven out of these 14 patients achieved DMR; and all patients with exon 8/9 35bp insertion did not progress to accelerated or blast phase . The achievement of major molecular response (MMR, BCR-ABL1 No new safety issues occurred. Among 444 analyzed patients in the safety data set, only 2 patients with NIL had peripheral arterial occlusive disease [grade 1] or acute coronary disease [grade 3]. No patients developed pulmonary arterial hypertension in this study. We measured pleural effusion (PE) in patients with DAS and liver/pancreas dysfunction in patients with NIL, which were the common adverse events. In the DAS arm, 28 patients revealed pleural effusion (grade 1, 3 patients; grade2, 22 patients; grade3, 3 patients). It occurred not only in the first year of treatment but also in the second or third year (median 10.5 [range 1-60] months). However, no statistically significant association was found between pleural effusion and trough concentration of DAS in this study (2.71 ng/mL in patients with PE vs. 2.27 ng/mL in patients without, P =0.1339). In the NIL arm, 17 patients revealed severe liver dysfunction (grade 3-4, n=6), increased bilirubin values (grade 3, n=4), or increased lipase values (grade 3-4, n=7). The adverse events occurred in 3 months in these patients with NIL, except for 4 patients. In summary, this 5-year Japanese registry using the New Target system demonstrated that TKI treatments in newly diagnosed patients with CML-CP achieved satisfying and trustworthy outcomes. Figure. Figure. Disclosures Takahashi: Bristol-Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Kawaguchi:Novartis Pharma K.K.: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau. Suzuki:Celgene: Honoraria; Sawai Pharmaceutical: Honoraria; Ohtsuka: Honoraria; MSD: Research Funding; Meiji Seika Pharma: Honoraria; Takeda Pharmaceuticals: Honoraria; Shionogi: Honoraria; Novartis: Honoraria; Mochida Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Jazz Pharmaceuticals: Consultancy. Yamamoto:Chugai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy; Mundipharma: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; ARIAD Pharmaceuticals: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Gilead Sciences: Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Solasia Pharma: Research Funding; SymBio: Research Funding; Takeda: Honoraria, Research Funding; AbbVie: Research Funding; Boehringer Ingelheim: Consultancy; Zenyaku: Research Funding; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; HUYA: Honoraria. Naoe:Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Pfizer Japan Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding. Akashi:MSD: Research Funding; Ono Pharmaceutical: Research Funding; Novartis pharma: Research Funding; Otsuka Pharmaceutical: Research Funding; Chugai Pharma: Research Funding; Astellas Pharma: Research Funding; Eisai: Research Funding; Taiho Pharmaceutical: Research Funding; sanofi: Research Funding; Asahi-kasei: Research Funding; Pfizer: Research Funding; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Eli Lilly Japan: Research Funding; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau.

This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence.

The synthesis and antitumor activity evaluation of new branched phospha sugars, especially deoxybromophospha sugar derivatives or bromophospholanes of 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (DBMPP: 3) and 2,3,4-tribromo-3-methyl-1- phenylphospholane 1-oxide (TBMPP: 4), against various types of leukemia cell lines as well as the results of the mechanistic studies for characterizing and developing the novel multiple type molecular targeted antitumor agents are reported in this paper. DBMPP and TBMPP were prepared from 1-phenyl-3-methyl-2-phospholene 1-oxide (1). The isomer mixture of phospha sugars prepared were evaluated as novel antitumor agents by MTT in vitro method. DBMPP and TBMPP were characterized by flow cytometry and Western blot analysis and were revealed to be potential antitumor agents against leukemia cell lines of K562 (one type of leukemia cell lines of CML) and U937 (one type of leukemia cell lines of AML) as well as against the various types of leukemia cell lines and al...

We conducted a phase 1 study of a combination of gemtuzumab ozogamicin (GO) plus conventional chemotherapy in elderly patients (≥65 years old) with relapsed or refractory CD33-positive acute myeloid leukemia (AML). Patients received a standard dose of enocitabine (200 mg/m² × 8 days) and daunorubicin (30 mg/m² × days 1–3) plus an escalating dose of GO (1.5–5 mg/m² on day 4). The dose escalation of GO was done according to a standard 3 + 3 design following a modified Fibonacci sequence. No dose-limiting toxicities were observed in three patients (median age, 71) at level 1 (1.5 mg/m²) or in three patients (median age, 73) at level 2 (3 mg/m²). Neither veno-occlusive diseases nor sinusoidal obstructive syndromes were noted at either level. However, as GO was withdrawn from the US market in June 2010, based on a randomized study in newly diagnosed AML, we decided not to proceed to the level 3 (5 mg/m²) in order to avoid possibly more severe adverse effects, and also because all six patients experienced grade 4 myelosuppression, with complete remission in three. This study showed that 3 mg/m² of GO in combination with enocitabine and daunorubicin may be a recommendable dose for a phase 2 study in Japanese elderly patients with CD33-positive AML. The study was registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ ) as UMIN000002603.

Purpose Tendinitis and tendon rupture are well-known side effects of fluoroquinolones (FQs) in Western countries. In Japan, some case reports have been reported; however, the incidence of FQ-induced tendon disorders has not been investigated. The aims of this study were to measure the occurrence of tendon disorders associated with FQs in Japanese patients and to compare the observed risk with that of previous reports. Moreover, the observed risk in FQ-prescribed patients was compared with that in cephalosporin-prescribed patients. Methods The Hamamatsu University Hospital database was examined to determine the risk of tendon disorders that occurred in all inpatients and outpatients between the first day of prescription of an oral FQ or cephalosporins to the calculated end date plus 30 days. The risk of tendon disorders, the risk ratio, and their 95% confidence intervals (CIs) were evaluated. Results From April 1996 to December 2009, FQs were prescribed to 17 147 patients, 14 of whom had tendon disorders (risk: 0.082%, 95%CI: 0.049–0.137). The risk of a tendon disorder in FQ-prescribed patients was significantly higher than that in cephalosporin-prescribed patients (five tendon disorders in 38 517 patients, risk: 0.013%, 95%CI: 0.006–0.030, and p

A 60-year-old man with Waldenström's macroglobulinemia (WM) was admitted to our hospital for evaluation of rapid progressive renal deterioration despite 3 cycles of oral melphalan and prednisolone (MP) therapy. Renal biopsy just before introducing hemodialysis revealed cast nephropathy and severe tubulo-interstitial infiltration of B lymphocytes. After 6 cycles of rituximab, cyclophosphamide, vincristine and prednisolone (R-COP) therapy, his renal function improved enough to discontinue hemodialysis. This is a rare case of WM-related renal involvement caused by both monoclonal protein and tumor infiltration and, to our knowledge, the second report on improved renal function by rituximab-based therapy.

Starting materials of phosphasugars, 1-phenyl-2-phospholene 1-oxides, were prepared from dienes and phenylphosphonous dichloride (dichlorophenylphosphine). Several substituted novel phosphasugars (3- or 4-halo-substituted)-1-phenyl-2-phospholene 1-oxides as well as 1-phenyl-2-phospholane 1-oxides were prepared from 2-phospholenes. The synthesized compounds were evaluated for their antitumor activities against the leukemia cell lines (U937 and K562) by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 2,3,4-Tribromo-3-methyl-1-phenylphospholane 1-oxide showed superior antitumor activity against U937 and K562 cell lines in a comparative evaluation with Glivec. The analysis by flow cytometry implied that 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide induced apoptosis to leukemia cell lines.

The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of JHDM1B in AML cells. In AML cell lines and AML-derived ALDH(hi) (high aldehyde dehydrogenase activity)/CD34(+) cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDH(hi) /CD34(+) cells. Reduction of JHDM1B expression in AML cells inhibited cell proliferation compared to control cells, through induction of G1 cell cycle arrest, an increase in the p15(Ink4b) mRNA and protein expression. JHDM1B mRNA was overexpressed in all 133 AML clinical specimens tested (n = 22, 57, 34, and 20 for M1, 2, 4, and 5 subtypes respectively). Compared to normal ALDH(hi) /CD34(+) cells, JHDM1B gene expression was 1.57- to 1.87-fold higher in AML-derived ALDH(hi) /CD34(+) cells. Moreover, the JHDM1B protein was more strongly expressed in AML-derived ALDH(hi) /CD34(+) cells from compared to normal ALDH(hi) /CD34(+) cells. In addition, depletion of JHDM1B reduced colony formation of AML-derived ALDH(hi) /CD34(+) cells due to induction of p15(Ink4b) expression through direct binding to p15(Ink4b) promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML-derived ALDH(hi) /CD34(+) cells, and that aberrant expression of JHDM1B induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of JHDM1B expression represents an attractive target for AML therapy.

Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. BCR-ABL transforming activity is mediated by critical downstream signaling pathways that are aberrantly activated by tyrosine kinases. However, the mechanisms of BCR-ABL anti-apoptotic effects and the signaling pathways by which BCR-ABL influences apoptosis in BCR-ABL-expressing cells are poorly defined. In this study, we found that treatment with ABL kinase inhibitors or depletion of BCR-ABL induced the expression of RAB45 messenger RNA and protein and induced apoptosis via reduction of mitochondrial membrane potential and p38 activation in CML cell lines and BCR-ABL + progenitor cells from CML patients. Overexpressed RAB45 induced the activation of caspases-3 and -9 and reduced the expression of Survivin, XIAP, c-IAP1 and c-IAP2 in CML cells. Moreover, in colony-forming cells derived from CML-aldehyde dehydrogenase hi / CD34 + cells, treatment with ABL kinase inhibitors induced RAB45 expression and reduced mitochondrial membrane potential, resulting in inhibited colony formation of Bcr-Abl + progenitor cells. The overexpression of RAB45 significantly decreased colony numbers and induced apoptosis through the activation of caspases-3 and -9. Furthermore, the overexpression of RAB45 increased the phosphorylation levels of p38, resulting in the induction of apoptosis and inhibition of proliferation of CML progenitor cells. Our results identify a new signaling molecule involved in BCR-ABL modulation of apoptosis and suggest that RAB45 induction strategies may have therapeutic utility in patients with CML.

Bcr-Abl activates various signaling pathways in chronic myelogenous leukemia (CML) cells. The proliferation of Bcr-Abl transformed cells is promoted by c-Myc through the activation of Akt, JAK2 and NF-κB. However, the mechanism by which c-Myc regulates CML cell proliferation is unclear. In our study, we investigated the role of Thanatos-associated protein 11 (THAP11), which inhibits c-Myc transcription, in CML cell lines and in hematopoietic progenitor cells derived from CML patients. The induction of THAP11 expression by Abl kinase inhibitors in CML cell lines and in CML-derived hematopoietic progenitor cells resulted in the suppression of c-Myc. In addition, over-expression of THAP11 inhibited CML cell proliferation. In colony forming cells derived from CML-aldehyde dehydrogenase (ALDH)(hi) /CD34(+) cells, treatment with Abl kinase inhibitors and siRNA depletion of Bcr-Abl induced THAP11 expression and reduced c-Myc expression, resulting in inhibited colony formation. Moreover, overexpression of THAP11 significantly decreased the colony numbers, and also inhibited the expression of c-myc target genes such as Cyclin D1, ODC and induced the expression of p21(Cip1) . The depletion of THAP11 inhibited JAK2 or STAT5 inactivation-mediated c-Myc reduction in ALDH(hi) /CD34(+) CML cells. Thus, the induced THAP11 might be one of transcriptional regulators of c-Myc expression in CML cell. Therefore, the induction of THAP11 has a potential possibility as a target for the inhibition of CML cell proliferation.

BCR-ABL1 kinase domain mutations were evaluated in 60 imatinib-resistant patients with Philadelphia-positive (Ph + ) leukemia using PCR-Invader assay and direct sequencing. In chronic myelogenous leukemia (CML) – chronic phase (CP), 5 had P-loop mutations and 3 had T315I mutations. CML-CP patients with high Sokal score showed significantly higher incidence of mutations. P-loop mutations were associated with higher risk of disease progression. In CML-advanced phase, P-loop mutations and T315I mutation were associated with significantly shorter survival. In Ph + acute lymphoblastic leukemia, overall survival was poor irrespective of mutational status. The PCR-Invader assay is useful for screening of mutations and prediction of prognosis.

We conducted a prospective randomized study to assess the optimal postremission therapy for adult acute myeloid leukemia in patients younger than 65 years in the first complete remission. A total of 781 patients in complete remission were randomly assigned to receive consolidation chemotherapy of either 3 courses of high-dose cytarabine (HiDAC, 2 g/m2 twice daily for 5 days) alone or 4 courses of conventional standard-dose multiagent chemotherapy (CT) established in the previous JALSG AML97 study. Five-year disease-free survival was 43% for the HiDAC group and 39% for the multiagent CT group (P = .724), and 5-year overall survival was 58% and 56%, respectively (P = .954). Among the favorable cytogenetic risk group (n = 218), 5-year disease-free survival was 57% for HiDAC and 39% for multiagent CT (P = .050), and 5-year overall survival was 75% and 66%, respectively (P = .174). In the HiDAC group, the nadir of leukocyte counts was lower, and the duration of leukocyte less than 1.0 × 109/L longer, and the frequency of documented infections higher. The present study demonstrated that the multiagent CT regimen is as effective as our HiDAC regimen for consolidation. Our HiDAC regimen resulted in a beneficial effect on disease-free survival only in the favorable cytogenetic leukemia group. This trial was registered at www.umin.ac.jp/ctr/ as #C000000157.

The Ras/Raf-1/MEK/ERK pathway is constitutively activated in Bcr-Abl transformed cells, and Ras activity enhances the oncogenic ability of Bcr-Abl. On the hand, Raf kinase inhibitor protein (RKIP) inhibits activation of MEK by Raf-1 and its downstream signal transduction, resulting in blocking the MAP kinase pathway. Moreover, Raf-1 has been reported to regulate cell cycle progression. However, the mechanism by which Bcr-Abl promotes the cell cycle progression through Raf-1 is not completely understood. In the present study, we found that the expression of RKIP was suppressed in CML cells, and investigated the interaction between RKIP and Bcr-Abl in CML cells. In aldehyde dehydrogenase (ALDH)hi/CD34+ cells derived from CML patients, the inhibition of Bcr-Abl induced RKIP expression and reduced the phosphorylated-FOXM1 (pFOXM1) status, resulting in inhibited colony formation of Bcr-Abl+ progenitor cells. Moreover, overexpression of RKIP significantly decreased the colony numbers, reduced the pFOXM1 status, and reduced pFOXM-1 target genes such as Skp2, Cdc25B and KIS, and induced the expression of p27Kip1a and p21Cip1. Thus, Bcr-Abl represses the expression of RKIP, and continuously activates FOXM1, resulting in the proliferation of CML progenitor cells through the cell cycle modulation.

We analyzed the incidence and prognosis of bacteremia/fungemia and pneumonia during remission induction therapy of a newly diagnosed acute myelogenous leukemia (AML) in the Japan Adult Leukemia Study Group treated with individual protocols of AML-87/-89 (1987-1991), AML-92 (1992-1995), AML-95 (1995-1997), and AML-97 (1997-2001). Bacteremia/fungemia was present in 251 of 2585 cases (9.7%); the causative microorganism was gram-positive bacteria (GPB) in 122 cases (49%), gram-negative bacteria (GNB) in 90 cases (36%), fungi (F) in 31 cases (12%), and polymicrobes (P) in 8 cases (3%). Particularly prevalent were Pseudomonas aeruginosa in 49 cases (20%), Staphylococcus epidermidis in 29 cases (12%), and Staphylococcus aureus in 25 cases (10%). With AML-87/-89, incidence of bacteremia/fungemia was 11.8% while it was 9.4% with AML-92, 8.7% with AML-95, and 9.2% with AML-97. The proportion of GPB, GNB, F, and P was 40, 41, 16, and 3% in AML-87/-89, 46, 40, 11, and 3% in AML-92, 48, 39, 11, and 2% in AML-95, and 59, 26, 11, and 4% in AML-97. The mortality rate by period was 26.5, 16.4, 14.0, and 6.8%, respectively. Pneumonia was found in 433 cases (16.8%); microbiological research covered 359 cases of AML-87/-89, AML-92, AML-97 and excluded AML-95 as there was no listing for the causative microorganism on questionnaires. Microbiologically documented pneumonia was found in 123 cases (34.3%), with GPB in 33 cases (27%), GNB in 28 cases (23%), F in 44 cases (36%), and P in 18 cases (15%); particularly prevalent were Aspergillus in 23 cases (19%), Staphylococcus aureus in 16 cases (13%), and Pseudomonas aeruginosa in 15 cases (12%). The incidence of pneumonia overall was 24.6% with AML-87/-89, 16.9% with AML-92, 13.9% with AML-95, and 12.9% with AML-97, with a mortality rate of 28.9, 33.3, 16.7, and 16.7%, respectively. Incidence of bacteremia/fungemia and pneumonia complicating AML has tended to decline in recent years, and mortality has also tended to improve.

Although cladribine has been reported to be an active purine analog against indolent B-cell non-Hodgkin lymphoma (B-NHL), there are few reports of combination use of cladribine and rituximab. This multicenter phase II study evaluated the efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy in relapsed or refractory indolent B-NHL. Twenty patients with the median age of 58.5 yrs (range, 42-72) were enrolled and received R-2-CdA therapy from April 2005 to July 2007. The median number of prior regimens was 2 (range, 1-3), and fifteen patients (75%) were previously treated with rituximab-containing regimens. Disease histology included follicular lymphoma in 16 patients, MALT lymphoma in two patients, nodal marginal B-cell lymphoma in one patient, and lymphoplasmacytic lymphoma in one patient. The overall response rate (ORR) was 90%, with a complete response rate (CRR) of 70%. Estimated median progression-free survival (PFS) time was 22.4 months (95%CI, 10.9-32.6 months) at a median follow-up time of 27 months (range, 12-43). Two-year PFS and 2-yr overall survival (OS) were 52.6% (95%CI, 31.0-73.2%) and 89.5% (95%CI, 66.1-97.3%), respectively. Grade 3 or grade 4 toxicities were neutropenia in 74% and thrombocytopenia in 11%. R-2-CdA therapy was demonstrated to have a high activity with durable PFS and acceptable toxicity in relapsed or refractory indolent B-NHL mostly pretreated with rituximab-containing therapy. Although a large-scale trial is needed for confirmation, R-2-CdA therapy could be a good salvage therapy option in relapsed or refractory indolent B-NHL.

We designed a treatment protocol for newly diagnosed adult acute lymphoblastic leukemia (ALL) in the pre-imatinib era, employing intensified consolidation therapy with a total of 330 mg/m² doxorubicin and adopting slightly modified induction and maintenance regimen of the CALGB 8811 study. Of 404 eligible patients (median age 38 years, range 15-64 years), 298 (74%) achieved complete remission (CR). The 5-year overall survival (OS) rate was 32%, and the 5-year disease-free survival (DFS) rate was 33%. Of 256 Philadelphia chromosome (Ph)-negative patients, 208 (81%) achieved CR and the 5-year OS rate was 39%, and 60 of them underwent allogeneic-hematopoietic stem cell transplantation (allo-HSCT) from related or unrelated donors during the first CR, resulting in 63% 5-year OS. Of 116 Ph-positive patients, 65 (56%) achieved CR and the 5-year OS rate was 15%, and 22 of them underwent allo-HSCT from related or unrelated donors during the first CR, resulting in 47% 5-year OS. In Ph-negative patients, multivariate analysis showed that older age, advanced performance status and unfavorable karyotypes were significant poor prognostic factors for OS and higher WBC counts for DFS. The present treatment regimen could not show a better outcome than that of our previous JALSG-ALL93 study for adult ALL.

Although imatinib has become the current standard treatment for chronic myeloid leukemia (CML), there is limited information regarding its efficacy and safety among Japanese patients. We therefore conducted a prospective multi-center open-label study of imatinib for Japanese patients with newly diagnosed chronic-phase CML (CP-CML). A total of 107 patients were enrolled and treated with imatinib at an initial daily dose of 400 mg. Eighty-three patients completed 3 years of study treatment. The cumulative rates of major cytogenetic response and complete cytogenetic response (CCyR) were 90.9 and 90.2% at 3 years, respectively. The safety profile was not very different from that reported in the IRIS study, although gradeor =3 neutropenia occurred relatively frequently (31.8 vs. 14.3%). Only seven patients discontinued the study due to adverse events, as did four patients due to insufficient efficacy. The 3-year probabilities of overall survival and progression-free survival were 93.2 and 91.4%, respectively. Higher average daily doses (i.e.,or =350 mg) were significantly associated not only with higher rates of achieving CCyR, but also with longer duration of CCyR. These findings confirm the clinical utility of imatinib in Japanese patients with newly diagnosed CP-CML, and suggest detrimental effect of low average daily dose on treatment results.