ALBERT

Description: Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)–CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4’s ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3S433-P) via protein kinase C, resulting in increased WNK4 levels and increased NCC activity. Mechanisms mediating KLHL3S433-P dephosphorylation have heretofore been unknown. We now demonstrate that calcineurin expressed in DCT is a potent KLHL3S433-P phosphatase. In mammalian cells, the calcium ionophore ionomycin, a calcineurin activator, reduces KLHL3S433-P levels, and this effect is reversed by the calcineurin inhibitor tacrolimus and by siRNA-mediated knockdown of calcineurin. In vivo, tacrolimus increases levels of KLHL3S433-P, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC. Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution. Additionally, increased extracellular K+ induced calcineurin-dependent dephosphorylation of KLHL3S433-P. These findings demonstrate that KLHL3S433-P is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.

Description: Key Points Conditional Gata2-deficient mice have profoundly reduced DC populations. Gata2 deficiency in DC progenitors reduced the expression of myeloid-related genes and increased that of T-lymphocyte–related genes.

Description: Background: Bosutinib, a Src/Abl tyrosine kinase inhibitor, is approved at a starting dose of 500 mg once daily (QD) in many countries, including Japan, for patients with Philadelphia chromosome-positive (Ph+) chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) after prior therapy. The indication for bosutinib was expanded to patients with newly diagnosed CP CML, at a starting dose of 400 mg QD, in 2017 by the US Food and Drug Administration and in 2018 by the European Medicines Agency. Approval of first-line bosutinib for CP CML was based on data from the global phase 3 BFORE trial, which demonstrated a significantly higher major molecular response (MMR) rate at Month 12 with bosutinib vs imatinib in patients with Ph+ CP CML and e13a2/e14a2 transcripts (primary endpoint; 47.2% vs 36.9%; 2-sided P=0.02). We conducted a phase 2 study to evaluate the efficacy, safety, and pharmacokinetics (PK) of bosutinib in Japanese patients with newly diagnosed CP CML. Methods: In this open-label, single-arm study (NCT03128411), Japanese patients ≥20 years of age with a molecular diagnosis of CP CML within 6 months, Eastern Cooperative Oncology Group performance status 0 or 1, adequate renal and hepatic function, and no prior treatment for CML (hydroxyurea within 6 months permitted) received bosutinib at a starting dose of 400 mg QD. The primary endpoint was MMR at Month 12 in the modified as-treated population, which included patients who were Ph+ and had e13a2/e14a2 transcripts. A total of 60 patients was required in the modified as-treated population for the study to have 〉82% power to reject the null hypothesis (25% MMR rate at Month 12) and accept the alternative hypothesis (40% MMR rate at Month 12) with a 1-sided ∝-level of 5%. Secondary endpoints included MMR and complete cytogenetic response (CCyR) by Month 12, event-free survival (EFS), overall survival, safety, and PK. Results: In all, 60 Japanese patients with CP CML were treated with bosutinib; all patients were Ph+ and had e13a2/e14a2 transcripts and were included in the modified as-treated population analyzed for efficacy. Median age was 55 years (range 20-83), 60.0% of patients were male, and 45.0%, 43.3%, and 11.7% had low-, intermediate-, and high-risk Sokal scores, respectively. Median duration of follow-up was 16.6 months (range 11.1-21.9), and median duration of bosutinib treatment was 15.3 months (range 0.3-21.9). After 12 months of follow-up, 42 (70.0%) patients remained on bosutinib; 17 (28.3%) discontinued due to adverse events (AEs) and 1 (1.7%) due to physician decision. Median dose intensity was 354.7 mg/day (range 95.3-494.1). The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval [CI] 44.4-65.6); the test of the null hypothesis was rejected (1-sided P

Description: Abstract 1712 Poster Board I-738 [Background and Purpose] Everolimus (RAD001), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR) serine-threonine kinase, which plays a key role in regulating cell growth and proliferation. Although anti-lymphoma effects of RAD001 have been shown in preclinical studies and one phase II clinical study in NHL, there is no PK data in NHL patients (pts). A phase I (P1) study was conducted to evaluate safety, PK profile, and efficacy of RAD001 in Japanese pts with relapsed and/or refractory NHL. [Patients and Methods] Pts with relapsed or refractory NHL, age ≥20, and PS 0-2 (ECOG) were enrolled and treated with RAD001, administered orally once daily at either 5 or 10 mg. Dose escalation was based on the clinical assessment of safety, incidence of dose-limiting toxicity (DLT), and probability of incidence of DLT. The latter probability distribution was estimated by a Bayesian logistic model, using prior information from other P1 trials with this agent in solid tumors. DLTs were evaluated in 6 pts at each dose level during the initial 28 days of study treatment (cycle 1). PK parameters were evaluated on days 1 and 15 of cycle 1. Response was assessed according to the International Workshop Criteria for NHL (1999). [Results] A total of 13 pts were enrolled into 2 cohorts as follows; 5 mg (7 pts, DLBCL: 2; MCL: 1; FL: 1; PTCL: 1; CTCL: 1; ALCL: 1) and 10 mg (6 pts, FL: 4; MCL: 1; ALCL: 1). 12 pts were evaluable for DLTs. 1 pt in the 5 mg cohort was inevaluable for DLTs due to early disease progression. No DLTs were observed at either dose level. Frequently encountered potentially drug-related adverse events (AEs) (≥40%) include leukopenia (8/13, 62%), thrombocytopenia (8/13, 62%), elevated AST (9/13, 69%), stomatitis (7/13, 54%), anemia (6/13, 46%), nasopharyngitis (6/13, 46%), and elevated ALT (6/13, 46%). Potentially drug-related Gr 3 or 4 toxicities include anemia (Gr 4 : 1), thrombocytopenia (Gr 4 : 1; Gr 3: 1), lymphopenia (Gr 4 : 1; Gr 3: 3), elevated LDH (Gr 3: 1), anorexia (Gr 3: 1), hyperglycemia (Gr 3: 1), fatigue (Gr 3: 1), hepatic function abnormal (Gr 3: 1), P. jiroveci pneumonia (Gr 3: 1), hyperkalemia (Gr 3: 1), and hypokalemia (Gr 3: 1). All toxicities cited above were transient and reversible. Non-infectious pneumonitis (Gr 1) was observed in 1 pt but resolved following discontinuation of RAD001 without additional therapy. Tmax was achieved within 4 hours, and Cmax and AUCtau both showed dose-proportional increases. The accumulation ratio after daily administration was approximately 2-fold. These data are consistent with those from a previous P1 study in solid tumors. A total of 4 objective responses (OR) were observed (summarized below): [Conclusions] RAD001 is well tolerated in this pt population at doses up to 10 mg/day and shows preliminary evidence of activity in relapsed or refractory NHL. The PK profile in pts with NHL is similar to that in pts with solid tumors. A global randomized phase III study to determine efficacy of RAD001 as adjuvant therapy following front-line R-CHOP induction in poor-risk DLBCL is currently ongoing. The data from this P1 study led directly to Japan's decision to participate in the global phase III study. Disclosures Shimada: Novartis Pharma K.K. Japan: Employment. Kobayashi:Novartis Pharma K.K. Japan: Employment.

Description: Abstract 3443 Background: Developmental control mechanisms often utilize multimeric complexes containing transcription factors, coregulators, and additional non-DNA binding components. It is challenging to ascertain how such components contribute to complex function at endogenous loci. LMO2 (LIM-only protein 2) is a non-DNA binding transcriptional coregulator, and is an important regulator of hematopoietic stem cell development and erythropoiesis, as mice lacking this gene show defects in blood formation as well as fetal erythropoiesis (Warren et al. Cell. 1994). In the context of erythropoiesis, LMO2 has been demonstrated to be a part of multimetric complex, including master regulators of hematopoiesis (GATA-1 and SCL/TAL1), chromatin looping factor LDB1 and hematopoietic corepressor ETO2 (referred as GATA-SCL/TAL1 complex). As LMO2 controls hematopoiesis, its dysregulation is leukemogenic, and its influence on GATA factor function is still not evident, we investigated here the transcriptional regulatory mechanism via LMO2 in erythroid cells. Methods: For LMO2 knockdown, anti-LMO2 siRNA (Thermo Scientific Dharmacon) and pGIPZ lentiviral shRNAmir system (Open Biosystems) were used. Western blotting and Quantitative ChIP analysis were performed using antibodies for GATA-1, LMO2 (abcam), GATA-2, TAL1 and LDB1 (Santa Cruz). To obtain human primary erythroblasts, CD34-positive cells isolated from cord blood were induced in liquid suspension culture. For transcription profiling, human whole expression array was used (Agilent), and the data was analyzed with GeneSpring GX software. To induce erythroid differentiation of K562 cells, hemin was treated at a concentration of 30 uM for 24h. Results: siRNA-mediated LMO2 knockdown in hemin-treated K562 cells results in significantly decreased ratio of benzidine-staining positive cells, suggesting that LMO2 has an important role in the erythroid differentiation of K562 cells. Next, we conducted microarray analysis to characterize LMO2 target gene ensemble in K562 cells. In contrast to the predominantly repressive role of LMO2 in murine G1E-ER-GATA-1 cells (Fujiwara et al. PNAS. 2010), the analyses (n = 2) demonstrated that 177 and 78 genes were upregulated and downregulated (〉1.5-fold), respectively, in the LMO2-knockdowned K562 cells. Downregulated gene ensemble contained prototypical erythroid genes such as HBB and SLC4A1 (encodes erythrocyte membrane protein band 3). To test what percentages of LMO2-regulated genes could be direct target genes of GATA-1 in K562 cells, we merged the microarray results with ChIP-seq profile (n= 5,749, Fujiwara et al. Mol Cell. 2009), and demonstrated that 26.4% and 23.1% of upregulated and downregulated genes, respectively, contained significant GATA-1 peaks in their loci. Furthermore, whereas LMO2 knockdown in K562 cells did not affect the expression of GATA-1, GATA-2 and SCL/TAL1 based on quantitative RT-PCR as well as Western blotting, the knockdown resulted in the significantly decreased chromatin occupancy of GATA-1, GATA-2, SCL/TAL1 and LDB1 at beta-globin locus control region and SLC4A1 locus. We subsequently analyzed the consequences of LMO2 knockdown in primary erythroblasts. Endogeneous LMO2 expression was upregulated along with the differentiation of cord blood cell-derived primary erythroblasts. shRNA-mediated knockdown of LMO2 in primary erythroblasts resulted in significant downregulation of HBB, HBA and SLC4A1. Conclusion: Our results suggest that LMO2 contributes to the expression of GATA-1 target genes in a context-dependent manner, through modulating the assembly of the components of GATA-SCL/TAL1 complex at endogeneous loci. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4884 Background: Bendamustine is an alkylating agent with a unique mechanism of action and has demonstrated efficacy as a single agent for the treatment of relapsed or refractory indolent B-NHL or MCL. We conducted a multicenter, phase II study of bendamustine in Japanese patients with indolent B-cell NHL or MCL, reporting an overall response rate of 91% (90% in indolent B-NHL and 100% in MCL) according to International Workshop Response Criteria after a median follow-up of 12.6 months (Ohmachi et al. Cancer Sci 2010 [Epub ahead of print]). Here we report the updated progression-free survival (PFS) data, including median PFS, which had not been reached at the time of previous reports. Patients and Methods: Eligible patients (aged 20–75 years; Eastern Cooperative Oncology Group performance status of 0 or 1) with measurable, pathologically confirmed indolent B-NHL or MCL that failed to respond to, or relapsed after, prior therapy were enrolled. Bendamustine 120 mg/m2 was administered intravenously over 60 minutes on days 1 and 2 every 21 days for up to 6 cycles. PFS was assessed 3 months after completion of the last cycle, and then at 3-month intervals. Results: A total of 69 patients, aged 33–75 years, were enrolled: 58 with indolent B-NHL, mainly follicular lymphoma (n = 52), and 11 with MCL. Patients had primarily stage III or IV disease. The median number of prior regimens was 2 (range, 1–9) for patients with indolent B-NHL and 4 (range, 1–16) for those with MCL. A median of 5 (range, 1–6) bendamustine cycles were administered, with 72% of patients completing 3 or more cycles. The median follow-up time for all patients is 20.6 months (range, 2.5–27.2 months). The median PFS was 21.1 months (95% CI, 15.8-NA; NA = not available due to short period of observation): 20.0 months (95% CI, 12.3-NA) in indolent B-NHL, and 21.7 months (95% CI, 16.5-NA) in MCL. Estimated 2-year PFS rates were 45.2% and 34.1% in indolent B-NHL and MCL, respectively. Conclusions: Bendamustine monotherapy is highly effective in patients with relapsed or refractory indolent B-NHL and MCL. The durable responses observed in this study strongly support the use of bendamustine in these patients and are particularly encouraging in the relapsed or refractory MCL population. Disclosures: Off Label Use: Bendamustine is a novel alkylator that has shown efficacy and safety in patients with indolent lymphomas, and particularly encouraging is the activity in patients with mantle cell lymphoma, which is difficult to treat. Although bendamustine is currently investigational in Japan, approval for relapsed/refractory indolent NHL and mantle cell lymphoma is anticipated in October 2010.

Description: Abstract 3694 Poster Board III-630 [Background and Purpose] Bendamustine hydrochloride is a bifunctional alkylating agent with novel mechanisms of action. Although bendamustine is known to have anti-tumor activity against indolent B-NHL as a single agent, efficacy in MCL with bendamustine monotherapy has not been reported. To assess the efficacy and toxicity of bendamustine in patients with relapsed indolent B-NHL and MCL, we conducted a multicenter phase II study. [Patients and Methods] Patients diagnosed with relapsed or refractory indolent B-NHL or MCL, 75= or 〉age= or 〉20, and PS 0-1 (ECOG) were enrolled in the study. Bendamustine was administered intravenously at a dose of 120 mg/m2 infused over 60 minutes on days 1 and 2 of each 21-day treatment cycle for up to 6 cycles (minimum of 3 cycles). The primary endpoint was the overall response rate (ORR). Tumor response was assessed by a central radiological review committee according to the International Workshop Criteria for NHL (1999). [Results] A total of 69 patients were enrolled and treated, including 52 (75%) cases of follicular lymphoma (FL) and 11 (16%) cases of MCL, ages 33 to 75 years, with predominantly stage III/IV indolent B-NHL (86%) or MCL (64%). The median number of unique prior therapies was two (range, 1 to 16), and sixty-six patients (96%) had received rituximab as a prior therapy. Twenty-nine patients (42%) completed the planned six cycles of chemotherapy, with fifty patients (72%) receiving 3 or more cycles. Dose reduction of bendamustine was required in 11 patients (16%). The ORR was 91% (63 of 69 patients; 95% CI, 82% to 97%) with a complete response (CR) rate of 67% (%CR), including %CRu (46 of 69 patients; 95% CI, 54% to 78%). The ORR in FL and MCL was 90% and 100%, respectively. The %CR in FL and MCL was 66% and 73%, respectively. Median progression-free survival (PFS) for all 69 patients was not reached at the median follow-up duration of 248 days (39-359 days). Median PFS for indolent B-NHL (58) and MCL (11) patients was not reached at the median follow-up duration of 254 days and 226 days, respectively. Hematologic toxicities, including grade 4 lymphopenia (72%) and neutropenia (48%), were the most frequently reported toxicities in patients. Non-hematologic toxicities were mild, with no grade 4 non-hematologic toxicity recorded. The most frequently reported grade 3 non-hematologic toxicities were GI toxicities (9%) including grade 3 vomiting (4%) and anorexia (3%), and infections (7%) which included one case of grade 3 febrile neutropenia, pneumonia, herpes infection, and viral pharyngitis. [Conclusion] Bendamustine monotherapy is a highly effective and less toxic treatment in patients with relapsed or refractory indolent B-NHL and MCL who have been pretreated (96%) with rituximab. It is noteworthy that a very high complete response rate (73%) was achieved in relapsed or refractory MCL patients although the number of patients was relatively small. Disclosures: No relevant conflicts of interest to declare.

Description: Aplastic anemia (AA) is characterized by reduced hematopoiesis resulting in pancytopenia. It is suggested that a certain immunological attack to hematopoietic stem cells play an important role in developing AA. However, limited information is available for the intrinsic characteristics of stem cells in AA. Previous work in our laboratory showed decreased expression of GATA-2 gene in CD34 positive cells in AA, suggesting that there is an aberrant expression of stem cell-specific genes in stem cells in AA. Recently it is emerged that some genes such as HOXB4 and BMI-1, function for the proliferation and maintenance of stem cells. In this study, we examined expression levels of HOXB4 and BMI-1 in CD34 positive cells by quantitative PCR in 10 patients with AA and 13 with idiopathic thrombocytopenic purpura (ITP). Between these two factors, the expression level of HOXB4 was markedly decreased in AA compared with in ITP, whereas that of BMI-1 was not. Moreover, the expression level of GATA-2 in these populations was significantly correlated to HOXB4 gene expression (Spearman’s rank correlation, r=0.6573 p0.05). As they functions as a transcription factor, these results raise the possibility that GATA-2 and HOXB4 regulate each other. To explore this possibility, first, we cloned HOXB4 5′flanking region by PCR and performed promoter analysis. Since the previous report showed that the region from −164 to −116 was important for promoter activity of HOXB4 gene, we focused on a GATA element located at −160. When this element was deleted, the reporter activity was decreased to 60% of wild-type in K562 cells. Furthermore, co-transfection of GATA-2 expression vector significantly activates the reporter gene in a dose dependent manner. EMSA revealed that GATA-2 binds specifically to this element. On the other hand, the active region both of exon 1S and 1G promoter of GATA-2 gene, which was identified by the promoter analysis, did not contain the consensus sequence recognized by HOXB4. These findings suggest that in stem cells in AA, the decreased expression of GATA-2 gene lead to the reduced HOXB4 gene expression, which may responsible for the development of the disease.

Description: Background: Darinaparsin is a novel organic arsenic compound composed of dimethylated arsenic linked to glutathione, and has similar structure to one of the intermediates of the arsenic detoxification pathway. The mechanism of action includes induction of apoptosis in tumor cells, primarily through disruption of mitochondrial functions and increase in reactive oxygen species production. Two phase I studies of darinaparsin for injection were conducted in patients with relapsed or refractory (r/r) PTCL to evaluate its safety, efficacy and pharmacokinetics in Japan and Korea, respectively. Methods: Patients with histologically confirmed PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK) -positive anaplastic large cell lymphoma (ALCL) or ALK-negative ALCL who failed or were refractory to 1 or more prior systemic therapy were eligible. Darinaparsin was administered for 5 consecutive days at 200 mg/m2/day or 300 mg/m2/day every 4 weeks, or at 300 mg/m2/day every 3 weeks in the Japanese phase I study, and at 300 mg/m2/day every 4 weeks or every 3 weeks in the Korean phase I study. Darinaparsin was given intravenously over 1 hour, and the treatment was continued until disease progression or unacceptable toxicity. As one of the secondary endpoints, tumor response was explanatorily assessed by using the Revised Response Criteria for Malignant Lymphoma (Cheson BD et al, J Clin Oncol 2007) in patients who completed at least 2 cycles of treatment and who had evaluable data of FDG-PET and CT scan. Since use of an inorganic arsenic compound is limited by cardiotoxicity, the potential of darinaparsin to prolong QTcF and any possible relationship between darinaparsin plasma concentration and change in QTcF were assessed. Results: In these 2 studies, 17 Japanese patients and 6 Korean patients; a total of 23 patients, included 16 PTCL-NOS, 6 AITL and 1 ALK-negative ALCL; 14 males and 9 females, with a median age of 63 (range 22-83) years were enrolled. Dose-limiting toxicities occurred in 1 Japanese patient who received 300 mg/m2/day (grade [G] 3 hepatic dysfunction). Drug-related adverse events 〉= G3 were reported in 4 Japanese patients who received 300 mg/m2/day. Occurrence of diffuse large B-cell lymphoma was reported in 1 patient, anemia in 1, leukopenia in 1, neutropenia in 2, febrile neutropenia in 1, lymphopenia in 2, thrombocytopenia in 2, hepatic dysfunction in 1, nausea in 1 and activated partial thromboplastin time (APTT) prolonged in 1. No drug-related adverse event 〉= G3 was reported in Korean patients. No patient showed QTcF 〉500 msec or delta QTcF 〉60 msec throughout the study period. Concentration-dependent or treatment-duration-independent effect on the QTcF was not identified. There was no significant relationship between the plasma concentration of darinaparsin and a change in QTcF interval (r=0.003). Tumor response was assessed in 14 patients who completed at least 2 cycles of treatment, and objective response was observed in 4 patients (1 complete response and 3 partial responses). Five of 6 patients with stable disease showed tumor shrinkage to some extent. In Japanese and Korean patients who received 300 mg/m2/day, the mean (± SD) values of Cmax were 838 ± 181 and 708 ± 81 ng/mL, AUC0-24 were 12759 ± 3419 and 11282 ± 905 ng•h/mL, and t1/2 were 20 ± 6.3 and 20.6 ± 2.8 h, respectively. The systemic arsenic exposures were similar between Japanese and Korean patients. There was no apparent difference in the mean plasma concentration-time profiles between Japanese and Korean patients at the doses studied. Conclusion: The results from integrated data analysis of these 2 phase I studies revealed that darinaparsin was well tolerated at all doses and dosing schedules studied, and demonstrated its potential efficacy against r/r PTCL. Furthermore, it was suggested that 300 mg/m2/day for 5-consecutive days every 3 weeks would be the recommendable dosing schedule of darinaparsin for subsequent studies. Based on the promising results of these phase I studies, we are planning to conduct an Asian multicenter phase II study for r/r PTCL. Disclosures Kim: Kyowa-Kirin: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Roche: Research Funding; Donga: Research Funding; Merck: Research Funding. Ogura:Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; GlaxoSmithKline K.K.: Research Funding; MSD K.K.: Research Funding; AstraZeneca K.K.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Symbio Pharmaceuticals Limited: Research Funding; Solasia Phama K.K.: Research Funding; Mundipharma K.K.: Research Funding; Celgene K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Uchida:Eisai Co., Ltd.: Research Funding. Ishizawa:Takeda: Speakers Bureau; Janssen: Research Funding; Takeda: Research Funding; Kyowa Kirin: Speakers Bureau; GSK: Research Funding; Kyowa Kirin: Research Funding; Celgin: Research Funding; Pfizer: Speakers Bureau; Celgin: Speakers Bureau. Tobinai:Gilead Sciences: Research Funding. Nagahama:Solasia Pharma K.K.: Employment. Sonehara:Solasia Pharma K.K.: Employment. Nagai:Servier: Research Funding; Mundipharma: Research Funding; Otsuka: Research Funding; Takeda: Research Funding; CMIC: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding.

Description: Abstract 4484 Background: Dasatinib is a highly potent BCR-ABL kinase inhibitor. The previous report from the global DASISION trial showed dasatinib 100 mg once daily resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib; both treatment arms were well-tolerated (N Engl J Med. 2010;362:2260-70). The objective of this subset analysis was to assess the efficacy and safety of dasatinib compared with imatinib in the Japanese population. Methods: Forty-nine Japanese patients (total 519 pts) with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg QD or imatinib 400 mg QD. Confirmed CCyR (cCCyR; CCyR on 2 consecutive assessments at least 28 days apart) was the primary efficacy endpoint with MMR as an important secondary endpoint. The safety profiles were also evaluated. Results: Minimum follow-up time and median treatment duration were 12 months and 15 months, respectively. Twenty-six patients with median age 56 (range, 21–70) years were treated with dasatinib and 23 patients with median age 52 (range, 22–77) years were treated with imatinib. Overall 89% of patients receiving dasatinib and 83% of patients receiving imatinib continue to receive treatment. The cCCyR rate by 12 months (primary endpoint), CCyR rate by 12 months and MMR rate at any time in dasatinib arm were higher than those in imatinib for Japanese patients (96% vs 70%, 96% vs 78%, and 73% vs 48%, respectively). Grade 3/4 cytopenias in dasatinib arm and imatinib arm were as follows: anemia (8% vs 4%), neutropenia (27% vs 39%), and thrombocytopenia (8% vs 9%). Non-hematologic and drug-related adverse events occurring in ≥10% of patients are shown as Table. No deaths were reported in either group. Drug-related serious adverse events were rarely reported and all events were not severe (Grade 1–2, including vomiting, hypoxia and cardiomyopathy in dasatinib arm). Conclusion: Dasatinib showed higher rates of cCCyR and MMR compared with imatinib. Both treatments were well tolerated. Given the predictive value of 12 months cCCyR, dasatinib may improve long-term outcomes in Japanese patients with newly diagnosed CML-CP. Disclosures: Ueda: Bristol-Myers K.K.: Employment. Seriu:Bristol-Myers K.K.: Employment. Bradley-Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment.