ALBERT

Description: Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Description: Introduction: Pomalidomide plus low-dose dexamethasone (POM + LoDEX) is approved for the treatment of patients with relapsed and refractory multiple myeloma (RRMM). In RRMM, POM + LoDEX significantly prolonged progression-free survival (PFS) compared with POM alone (MM-002; Richardson et al Blood, 2014) and significantly improved PFS and overall survival (OS) compared with high-dose DEX alone (MM-003; San Miguel et al Lancet Oncol, 2013), while demonstrating an acceptable safety profile. In Japanese patients with RRMM, a phase 1 study identified POM 4 mg/day as the tolerated dose (MM-004; Iida ASH 2014), consistent with observations in Caucasian patients. The study presented here, MM-011, was conducted to evaluate the efficacy and safety of POM + LoDEX in Japanese patients with RRMM. Methods: MM-011 was a multicenter, single-arm, open-label phase 2 study in patients with RRMM. Eligible patients had received ≥ 2 prior therapies, including ≥ 2 cycles of lenalidomide and ≥ 2 cycles of bortezomib (either separately or in combination) and had developed progressive disease on or within 60 days of the last prior therapy. Patients received POM 4 mg orally on days 1-21, and LoDEX orally on days 1, 8, 15, and 22 of each 28-day cycle. LoDEX was given at 40 or 20 mg in patients aged ≤ 75 or 〉 75 years, respectively. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was overall response rate (ORR; partial response rate [PR] or better) of POM + LoDEX according to the International Myeloma Working Group criteria. The required sample size was calculated using the expected response rate of 25%, the threshold response rate of 10% on 1-sided alpha of 0.05, and the statistical power of 80% based on the test for 1 sample proportion. Thirty-three pts were needed as a result of this calculation. Results: A total of 36 patients were enrolled. Median age was 64.5 years (range, 43-78 years), and 11% were aged 〉 75 years. Patients had a high tumor burden (81% had Durie-Salmon stage II or III disease) and were heavily pretreated (median of 6.5 prior anti-myeloma regimens; range, 2-15 regimens). All but 1 patient (97%) were refractory to lenalidomide and 58% were refractory to both lenalidomide and bortezomib. At the data cutoff (February 3, 2015), 16 patients (44%) remained on treatment. Disease progression was the most common reason for discontinuation (n = 14; 39%). All 36 patients enrolled were evaluable for efficacy. The ORR was 42% (n = 15 [95% CI, 26%-58%]), including complete response in 3% (n = 1) and PR in 39% (n = 14). Median PFS was 10.2 months (median follow-up, 4.6 months), and median OS was not reached (median follow-up, 7.7 months). In the 15 responders, median time to response was 1.9 months and median duration of response was not reached. The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (n = 23; 64%), anemia (n = 15; 42%), and thrombocytopenia (n = 11; 31%), and the most common grade 3/4 non-hematologic AEs were pneumonia (n = 3; 8%) and decreased appetite (n = 3; 8%). Peripheral neuropathy (any grade) occurred in 8% (n = 3). No deep vein thrombosis or pulmonary embolism was reported. Overall, AEs were similar to those in other POM studies, and no new significant AEs were reported in Japanese RRMM patients. Three patients (8%) had an AE that led to discontinuation. Three patients died on study (or within 28 days of the last dose of study drug). Two of these patients died due to multiple myeloma and 1 due to AE (asthma and pneumonia, suspected to be related to study drug). Conclusions: POM + LoDEX is an effective regimen in heavily pretreated Japanese patients with RRMM with acceptable safety profiles that are comparable with those of POM studies in RRMM in other regions. Disclosures Hagiwara: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Matsue:Celgene Corporation: Honoraria. Iida:Celgene Corporation: Honoraria, Research Funding; Janssen Pharmaceuticals Inc: Honoraria; Kyowa Hakko Kirin Inc: Research Funding; Ono Pharmaceutical Inc: Research Funding; Chugai Pharmaceutical Co: Research Funding; Eli Lilly Inc: Research Funding. Sunami:Ono Pharmaceutical Company, Limited: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding. Ando:Kyowa Hakko Kirin Co., Ltd: Research Funding. Tobinai:Gilead Sciences: Research Funding. Chou:Celgene Corporation: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ono Pharmaceutical CO., LTD.: Consultancy, Honoraria. Kaneko:Celgene Corporation: Research Funding. Uemura:Celgene Corporation: Employment. Tamakoshi:Celgene Corporation: Employment. Zaki:Celgene Corporation: Employment, Equity Ownership. Doerr:Celgene Corporation: Employment.

Description: Introduction A significant progress in the management of multiple myeloma (MM) has been made in recent years by the introduction of novel treatment modalities including high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) and novel drugs such as proteasome inhibitors and immunomodulatory drugs (IMiDs). Nevertheless, MM is still an incurable disease with various complications, and it is not clear whether these approaches contribute to the improvement of patient outcomes in routine practice. Previously, the Japanese Society of Myeloma surveyed the clinical features of 1383 patients with MM diagnosed and treated between January 1990 and December 2000. In the present study, we conducted a multicenter retrospective study to evaluate the treatment outcome and prognostic factors in the era of novel agents in Japan involving 2593 new patients diagnosed and treated after December 2000. Patients and Methods We analyzed 2593 patients with symptomatic MM newly diagnosed in the period between January 2001 and December 2012 at the affiliated hospitals of the Japanese Society of Myeloma. This study was conducted in accordance with the institutional guidelines with approval of the local institutional review board. There were 1342 males and 1251 females. The median age was 66 (range 26-96) years; 21% were older than 75 years. The type of monoclonal immunoglobulin was IgG in 1547 patients, IgA in 488, light chain only in 399, IgD in 72, and others in 87, respectively. Performance status (PS) of 0, 1, ≥2, and unknown were 340, 657, 756, and 840 patients, respectively. Durie & Salmon stage was as follows: 8.4% had Stage I, 25.5% Stage II, and 66.1% Stage III, respectively. As for the International Staging System (ISS) stages, 28.0% had stage I, 38.0% stage II, and 34.0% stage III, respectively. Cytogenetic abnormalities were detected in 24.9% of the patients. Initial therapy was composed of conventional chemotherapy in 45.6%, novel agents such as bortezomib-based or IMiDs-based regimens in 20.6%, conventional chemotherapy + ASCT in 20.4%, and novel agents (mainly bortezomib) + ASCT in 12.8% of the patients, respectively. Results The median overall survival (OS) was 63.8 and 62.5 months in the 2001-2005 cohort and in the 2006-2012 cohort, respectively, which was significantly improved compared with our previous results of 38.9 months in the 1990-2000 cohort. The median OS tended to be shorter according to the patient age (97.3, 79.7, 56.9, and 44.6 months in the patients aged

Description: Background Clinical impact of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is not well studied in a large series of patients with lymphoma undergoing autologous stem cell transplantation (ASCT). Retrospective analysis was performed to evaluate clinical outcomes of patients with lymphoma receiving ASCT with or without HBV and HCV infections. Patients and Methods Among 13218 adult patients registered in the Adult Lymphoma Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) database, we selected patients who had the information on HBV and HCV infection status and received ASCT from 1989 to 2010. Patients diagnosed as Hodgkin lymphoma, mature or precursor T- and B-cell lymphoma were included. Histological diagnosis of natural killer (NK)-cell lymphoma and adult T-cell leukemia/lymphoma were excluded in this analysis. Patients who had human immunodeficiency virus (HIV) infection and history of previous transplantation were also excluded. Survival analysis was performed to compare patients positive for HBV and HCV with those negative for both. Prognostic indicator for survival was also investigated in patients positive for HBV and HCV. Results A total of 4641 patients with 2819 male were analyzed. The median age of all patients was 54 years (range: 16-81 years). The patient characteristics were summarized in Table 1. HBV and HCV infections were present in 162 (3.5%) and 104 (2.2%) patients, respectively. Ten patients (0.2%) had both HBV and HCV infections. Detailed data on anti-HBV antigen or antibody and genetic data were not available in the analysis. Patients with HBV and HCV infections were older and more diagnosed with advanced stage than those without infections. With a median follow-up of 2.8 years, the 2-year overall survival (OS) rate of all patients was 75% (95%CI: 73 to 76). Cumulative incidence of treatment-related mortality (TRM) at one year after ASCT was 5.8% (95%CI: 5.2 to 6.6). According to HBV and HCV positivity, the estimated 2-year overall survival (OS) rates were 74% (95%CI: 65 to 81), 77% (95%CI: 66 to 84), 60% (95%CI: 25 to 83) and 75% (95%CI: 73 to 76) in patients with HBV-positive, HCV-positive, both virus positive and negative patients, respectively. Cumulative incidence of TRM at one year was 11% (95%CI: 6.2 to 16) 6.6% (95%CI: 2.7 to 13) and 5.7 (95%CI: 5.0 to 6.4) in patients with HBV-positive, HCV-positive and both virus negative patients, respectively. In patients with or without HBV and HCV infections, there was no statistically significant difference in rates of OS (p=0.82, Figure 1) and TRM (p=0.63). In multivariate analysis of patients infected with HBV, factors associated with shorter OS were male sex (HR: 3.1, 95%CI: 1.2 to 7.6), non-remission/relapse status at ASCT (HR: 2.7, 95%CI: 1.2 to 5.9) and ASCT before 2005 years (HR: 3.6, 95%CI: 1.6 to 8.4). ASCT before 2005 years was associated with higher TRM in patients with HBV infection (HR: 4.4, 95%CI: 1.5 to 13). In patients with HCV infection, multivariate analysis revealed that partial remission (HR: 3.5, 95%CI: 1.2 to 10.6), non-remission/relapse (HR: 5.3, 95%CI: 1.9 to 14.6) status at ASCT and age≥ 50 years at ASCT (HR: 7.0, 95%CI: 1.5 to 31.9) were significantly associated with shorter OS. Non-remission/relapse status at ASCT was associated with higher TRM in patients infected with HCV (HR: 4.4, 95%CI: 1.1 to 18.3). Difference in histology was an adverse factor for outcomes in the HBV- and HCV-negative groups, however, the factor could not be identified as adverse indicator in the HBV- and HCV-positive groups. Conclusions Prognosis of patients with HBV and HCV infections would be comparable to patients without those infections. Disease status at ASCT could be one of useful landmarks to predict outcomes in patients positive for HBV and HCV undergoing ASCT. After careful consideration, ASCT might be a feasible option for patients with HBV and HCV infections. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Patients (pts) with refractory or relapsed and refractory multiple myeloma (RRMM) who have exhausted treatment (Tx) with lenalidomide (LEN) or thalidomide (THAL) and bortezomib (BORT) have shortened overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a novel oral IMiDs® immunomodulatory agent with direct antimyeloma and stromal cell inhibitory effects (Quach, Leukemia, 2010; Mark, Leuk Res, 2014). POM 4 mg (± dexamethasone) is approved in some countries for Tx of pts with RRMM based on phase 3 results showing significant improvement vs high-dose dexamethasone in response, progression-free survival (PFS), and OS and phase 1/2 results showing high and durable overall response rates (ORRs; Richardson, Blood, 2013; Richardson, Blood, 2014; San Miguel, Lancet Oncol, 2013). MM-004 is a phase 1, open-label, dose-escalation study designed to assess the tolerated dose (TD), safety, efficacy, and pharmacokinetics (PK) of POM alone or POM + low-dose dexamethasone (LoDEX) in Japanese pts with RRMM. Methods: Pts must have been ≥ 20 yrs old with a documented diagnosis of MM, have had ≥ 2 prior lines of anti-MM Tx including ≥ 2 cycles of LEN and BORT (alone or in combination), and have RRMM defined as progressive disease (PD) during or within 60 days of completing their last anti-MM Tx. Tx consisted of POM 2 mg (Cohort 1) or 4 mg (Cohort 2) day (D) 1-21 of a 28-D cycle and DEX 40 mg (20 mg for pts 〉 75 yrs) D1, 8, 15, and 22 (starting on cycle 2). Tx was continued until PD, unacceptable adverse event (AE), or voluntary withdrawal. Pts enrolled in Cohort 1 received a single dose of POM 0.5 mg at D7 for PK evaluation. The primary endpoint was TD; secondary endpoints included ORR based on International Myeloma Working Group criteria, objective response, duration of response (DOR), PFS, PK, and safety. Results: Twelve pts were enrolled (6 in each cohort); 2 pts remain on Tx as of June 27, 2014 (Cohort 2, n= 2). Median age was 68 yrs (range, 52-76 yrs); 75% of pts were aged 〉 65 yrs. Median number of prior anti-MM Tx was 6 (range, 4-10) and baseline creatinine clearance (CrCl) was ≥ 60 mL/min for all pts except one. Six pts received prior THAL-based Tx (Cohort 1, n= 3; Cohort 2, n= 3). TD was determined to be POM 4 mg D1-21 of a 28-D cycle (a dose-limiting toxicity of grade 4 neutropenia for ≥ 7 days was observed in 1 pt in cohort 1). This result showed that the TD of POM in Japanese pts with MM was the same as that in Caucasian pts with MM. Median duration of treatment was 6.5 cycles in all pts. The best ORR (≥ partial response [PR]) was 25% (3/12 pts) across both cohorts; ORR was 17% (1/6) in Cohort 1 and 33% (2/6) in Cohort 2. Overall median PFS was 5.5 months (5.1 months in Cohort 1; not reached in Cohort 2). Maximum POM plasma concentration (Cmax) was 9.1, 35.6, and 70.2 ng/mL after single dose of POM 0.5, 2, and 4 mg, respectively, and was reached at times ranging from 0.9 to 6 h. Cmax was 37.6 and 71.2 ng/mL after multiple doses of POM 2 and 4 mg. Systemic POM exposure as measured by geometric means of area under the plasma concentration time curve (AUC) was 84.9, 364.4, and 685.7 ng•h /mL after a single doses of POM 0.5, 2, and 4 mg, respectively. AUC was 411.5 and 713.8 ng•h /mL after multiple doses of POM 2 mg and 4 mg. Both Cmax and AUC exposures increased in a dose-proportional manner from 0.5 to 4 mg, as assessed by both visual inspection and statistical analysis. Clearance and volume of distribution were similar across dose levels. The mean half-life (t1/2) of POM was comparable across dose levels, with t1/2 of approximately 6.4, 6.9, and 6 h after single doses of POM 0.5, 2, and 4 mg, respectively. After multiple doses of POM 2 mg and 4 mg, t1/2was approximately 7.3 and 5.5 h. Grade ≥ 3 AEs occurred in 11 pts (92%), and the most frequently reported AE was neutropenia (8 pts, 67%). Other frequently reported AEs (all grades) were thrombocytopenia, anemia, leukopenia, and peripheral edema. Conclusions: POM 4 mg was identified as the TD in Japanese pts with RRMM, which is consistent with previous findings in Caucasian pts with MM. However, pts should be monitored for the known AE profile of POM and managed appropriately. The combination of POM with LoDEX was also found to be tolerable in Japanese pts with RRMM. Systemic exposure to POM increased dose proportionally, and limited drug accumulation was observed following multiple doses. Responses (≥ PR) were observed in 25% of pts. Further investigation of the efficacy and safety of POM + LoDEX in Japanese pts with RRMM in a phase 2 trial is warranted. Disclosures Iida: Celgene Corp: Honoraria, Research Funding. Tobonai:Ono: Research Funding; Lilly: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding. Sunami:Celgene Corp: Honoraria. Kurihara:Celgene Corporation: Employment. Midorikawa:Celgene: Employment. Zaki:Celgene : Employment, Equity Ownership. Doerr:Celgene Corp: Employment.

Description: Abstract 5035 Background: The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However the difference of clinical characteristics between ethnic groups is not well-defined. In Asian countries the incidence of MM has been lower compared with Western countries. However, there are growing evidences that MM is increasing very rapidly in this region. Until now, only few data of Asian patients has been reported. Asian myeloma network (AMN) decided to analyze the first multinational project to explore clinical characteristics of Asian MM patients and clinical practice performed in Asian countries. Methods: Data were collected from 22 centers from 7 countries and regions were collected retrospectively. Clinical characteristics of 3377 symptomatic MM patients at diagnosis were described. Overall survival (OS) and prognostic factors were analyzed for 3324 patients who have survival data. Results: Clinical and genetic characteristics were summarized at table 1. Median OS was 47 months (95% CI 48. 0–60. 0). Patients who were diagnosed before 2000 were shorter survival. Transplantation was performed to 607 patients with better survival (84 vs 40 months, p

Description: Abstract 5030 With the emergence of novel agents, the treatment paradigm of multiple myeloma (MM) has changed dramatically in the last decade. Although there have been many attempts to improve the outcome by using novel agents as first-line and/or salvage therapies, it is not clear whether the combined use of novel agents with autologous stem cell transplantation (SCT) has translated into better outcome for elderly patients with MM. To clarify this issue, we retrospectively analyzed the clinical features and treatment outcome of patients with ages 65–70 (median 67) years. From January 2004 to December 2009, a total of 318 patients (167 male and 151 female) were treated in 38 centers in Japan and Italy. The monoclonal immunoglobulin (Ig) was IgG in 169 patients, IgA in 80, light chain in 56, IgD in 7, and others in 6, respectively. Twenty-two patients were classified as Durie & Salmon stage I, 77 were stage II, and 212 were stage III, respectively. As for the International Staging System (ISS), 86 patients were in ISS stage I, 107 were in ISS stage II, and 102 were in ISS stage III, respectively. Treatment for each patient was determined by a physician-in-charge. As initial therapy, 192 patients were treated with conventional chemotherapy; melphalan and prednisone (MP) in 78, vincristine, adriamycin, and dexamethasone (VAD) in 56, and other regimens in 58, respectively. Eighty-eight patients were treated with novel agent-containing regimens composed of bortezomib in 62, lenalidomide in 17, and thalidomide in 9, respectively. Twenty-one patients were treated with conventional chemotherapy (VAD) plus SCT, and 17 were with novel agents (bortezomib and dexamethasone) plus SCT. The median progression-free survivals (PFS) of the 4 different treatment groups were 19. 1 months, 24. 5 months, 26. 8 months, and 35. 2 months, respectively, and there was a significant improvement in the groups with novel agents (p=0. 006) and novel agents plus SCT (p=0. 032) compared with the conventional chemotherapy group. The median overall survival (OS) of the conventional chemotherapy group was 46. 0 months, while those of other groups were not reached. When compared with the outcome of the conventional chemotherapy group, there was a significant improvement in OS in the groups with novel agents (p=0. 001), chemotherapy plus SCT (p=0. 02), and novel agents plus SCT (p=0. 02), and novel agents plus SCT resulted in the best OS (88% at 6 years). Best responses to treatment of 318 patients were as follows: complete response (CR) in 26 patients (8. 2%), very good partial response (VGPR) in 56 (17. 6%), partial response (PR) in 127 (39. 9%), stable disease (SD) in 92 (28. 9%), and disease progression (PD) in 17 (5. 3%), respectively. Significant differences in OS were found between CR and PR groups (p=0. 002) and between VGPR and PR groups (p=0. 045). In 168 relapsed patients after initial treatment, 148 patients were treated with novel agent-containing regimens and the median OS from the time of relapse was 45. 5 months compared with 15. 0 months for 20 patients treated with conventional chemotherapy alone (p=0. 03). In a multivariate analysis using stepwise selection, IgG or IgA type (p=0. 013), normal serum albumin (p

Description: (INTRODUCTION) Several clinical studies have revealed that dasatinib demonstrated deep and fast responses. We report a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study). (PATIRNTS AND METHODS) Between July 2011 and June 2013, a total of 79 consecutive patients with CML-CP received 100 mg dasatinib daily as a first-line therapy. Treatment was continued until disease progression or until toxicity became unacceptable. The primary end-point was the rate of major molecular response by 12 months. Secondary end-points included the rate of complete cytogenetic response, rate of molecular responses with a 4.5 log reduction (MR4.5) by 12 months, and adverse events. The median age was 62 years, ranging from 27 to 80 years. Patients older than 65 years comprised 41.7% of all patients. Two-thirds of patients (68.4%) were male. Nearly all patients were ECOG performance status 0. Most patients (83.6%) had low and intermediate Sokal scores. The BCR-ABL1 International Scale (BCR-ABL1 IS) in the peripheral blood was measured by the central laboratory center (BML, Tokyo, Japan). (RESULTS) The median BCR-ABL1 IS before therapy was 54.0% (7.8-230.2). Seventy patients (88.6%) received dasatinib therapy for 12 months. The median BCR-ABL1 ISs were 0.25 % at 3 months (range 0.0002-52.2 %, n =77), 0.03 % at 6 months (range not detected-29.2 %, n = 75) and 0.008 % at 12 months (not detected -0.86 %, n = 70). MMR rate was 77.2% (95% CI, 67.9-86.5 %) by 12 months. The rates of CCyR and MR4.5 by 12 months were 88.6% (95% CI; 81.5-95.7 %) and 35.4% (95% CI; 24.8-46.1 %), respectively (Figure 1). Multivariate analysis of MMR or MR4.5 by 12 months showed that female sex (odds ratio 1.1, P = 0.92, odds ratio 1.7, P = 0.35, respectively), low and intermediate Sokal score (odds ratio 0.9, P = 0.90, odds ratio 3.2, P =0.23, respectively), and BCR-ABL1 IS less than 54% at diagnosis (RR =odds ratio 0.8, P = 0.74, odds ratio 0.7, P = 0.55, respectively) were not significantly correlated with MMR by 12 months nor MR4.5 by 12 months (Table 1). However, patients who were more than 62 years old were significantly correlated with MR4.0 and MR4.5 by 12 months (odds ratio 2.8, P =0.04, odds ratio 3.5, P =0.01). Treatment-related all AEs were reported in 98.7% patients (78 of 79). Grade 3/4 non-hematologic AEs were observed in only a few cases. Lymphocytosis (more than 4x 109/L) was observed in 34.1% of patients, which was within grade 2. Only 9 patients withdrew the study because of adverse events (4 patients), ineffectiveness (3 patients), and others (2 patients). (DISCUSSION AND CONCLUSION) The incidence of lymphocyte predominance may depend on a history of previous cytomegalovirus (CMV) infection in CML-CP patients (Leukemia. 2011 25(10): 1587-97). Although the frequency of CMV-positive patients was unknown in this study, that of blood donors in Japan was almost positive in the ages with 60s or older. The median age of CML-CP patients in this study was 62 years. Therefore, we assumed that some immunological effects induced by dasatinib might have improved the clinical efficacy in Japanese CML-CP patients compared to those worldwide. Our phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed CML-CP in Japan revealed that the first-line dasatinib treatment of CML-CP leads to earlier achievement of MMR and MR4.5 with high safety. Elder age patients (〉62 years) were significantly associated with achievement of MR4.5. Disclosures Shindo: Sysmex Corporation: Research Funding. Sakamoto:Yakult: Other: Remuneration; Takeda Pharmaceutical: Consultancy.

Description: Abstract 3087 Poster Board III-24 Objective To evaluate the efficacy and safety profile of an intensive induction and post-remission Cx for untreated patients (pts) with adult ALL and LBL, focusing on the long-term follow-up results. Feasibility and efficacy of autologous or allogeneic SCT were also assessed. Patients and Methods We enrolled pts with untreated adult ALL or LBL aged 15 to 69 years. The Cx regimen consisted of induction Cx (vincristine [VCR], cyclophosphamide [CPA], prednisone [PSL], doxorubicin [DXR], L-asparaginase plus intrathecal methotrexate [IT-MTX]) followed by two consolidation Cx regimens (Consolidation A, consisting of daunorubicin, cytosine arabinoside [Ara-C], vindesine [VDS], PSL plus IT-MTX; Consolidation B, consisting of CPA, Ara-C, 6-mercaptopurine [6-MP], VCR plus IT-MTX) with the prophylactic use of granulocyte colony-stimulating factor. Thereafter, interim maintenance Cx including 6-MP and MTX concurrent with CNS prophylaxis (IT-MTX), intensification Cx (VCR, DXR, PSL, CPA, Ara-C and 6-MP) and maintenance Cx (VDS, CPM, PSL, DXR, MTX and 6-MP) were sequentially performed for two years. For pts with 50 years or younger who achieved complete remission (CR) after induction Cx, allogeneic SCT for ALL from HLA-matched related donor and autologous SCT for LBL were to be considered. Primary endpoint was 5-year progression-free survival (PFS). Secondary endpoints included CR rate (%CR), overall survival (OS) and adverse events. Results Among 115 pts who were enrolled between 1994 and 1999, 108 eligible pts (median age, 33.5 years [15-69]) including 96 ALL and 12 LBL pts who received induction Cx were assessed. Seven pts were judged ineligible, including four histologically ineligible pts revealed by institutional or central review. Other major characteristics of the 108 eligible pts were as follows: 54 males (50%); T-cell phenotype, 23 pts (21%); Ph, 24 pts (22%); t(4;11), 2 pts (2%); B-symptom+, 38 pts (35%); PS 2/3, 24 pts (22%). Eighty-seven pts achieved CR (%CR 81%; 95% CI, 72-88%), while five patients (5%) died during induction Cx mainly due to infections. The median OS and the median PFS of the 108 eligible pts were 1.8 years (95% CI, 1.5-2.6 years) and 1.2 years (95% CI, 0.8-1.6 years), respectively. Their 5-year OS and 5-year PFS were 29% and 28%, respectively, with the median follow-up of the censored cases of 9.3 years (range, 2.0-12.3 years). The 5-year OS from the date of SCT of 31 pts who underwent allogeneic (n=19) or autologous (n=12) SCT during 1st CR was 51% (95% CI, 32-67%). Major non-hematologic toxicities of grade 3 or greater included infections (n=24, 21%), pulmonary complications (n=7, 6%) and diarrhea (n=7, 6%). As compared with the investigators' previous phase II trials for ALL and LBL, JCOG9402 improved PFS and OS as compared with JCOG8702 (MST, 1.2 years; 7-year OS, 15%; 7-year PFS, 13%) (Jpn J Clin Oncol 1999;29:340), but did not show improvement as compared with JCOG9004 (MST, 2.2 years; 5-year OS, 32%; 5-year PFS, 26%) (Cancer Sci 2007;98:1350). Conclusion Although the intensified induction and post-remission Cx was feasible and 28% of pts achieved long-term PFS, JCOG9402 failed to show improvement in long-term follow-up results as compared with the investigators' latest historical control. To further improve the therapeutic outcomes of adult pts with ALL and LBL, novel strategies are warranted. Disclosures No relevant conflicts of interest to declare.

Description: Allogeneic hematopoietic cell transplantation (HCT) from a matched sibling donor (MSD) may provide a cure for acute myeloid leukemia in first complete remission (AML/CR1), although the procedure is associated with a higher rate of treatment-related mortality (TRM) than autologous HCT, and it remains uncertain which modality is preferable as post-remission treatment. We therefore conducted a retrospective registry-based analysis to compare the outcomes of patients with AML/CR1 receiving autologous peripheral blood (PB) grafts (n=398, median age: 47, range: 17-80) and those receiving allogeneic MSD bone marrow (BM) grafts (n=633, median age: 38, range: 16-73) or allogeneic MSD PB grafts (n=475, median age: 42, range: 16-74) between 1995 and 2011. Consequently, the 5-year overall survival (OS) rates for the autologous PB, allogeneic BM and allogeneic PB recipients were 62% (95% confidence interval [CI], 57-67%), 61% (95% CI, 57-65%; P=0.90) and 54% (95% CI, 49-59%; P=0.07), respectively (Fig. 1-A), and the 5-year leukemia-free survival (LFS) rates were 57% (95% CI, 52-62%), 58% (95% CI, 54-63%; P=0.49) and 51% (95% CI, 46-56%; P=0.12), respectively(Fig. 1-B). Meanwhile, the 5-year cumulative incidence of TRM was 8% (95% CI, 5-11%), 16% (95% CI, 13-19%; P=0.009) and 19% (95% CI, 15-23%; P=0.0001), respectively, while that of relapse was 35% (95% CI, 30-40%), 26% (95% CI, 22-29%; P=0.003) and 30% (95% CI, 26-35%; P=0.08), respectively. A multivariate analysis performed with autologous PB HCT as the reference showed a hazard ratio (HR) for OS of 0.93 (95% CI, 0.73-1.18; P=0.53) for allogeneic BM HCT and 1.08 (95% CI, 0.83-1.39; P=0.57) for allogeneic PB HCT and an HR for LFS of 0.86 (95% CI, 0.69-1.09; P=0.21) and 0.98 (95% CI, 0.77-1.24; P=0.85), respectively. Stratifying the patients according to cytogenetics (favorable, intermediate and poor) and age (