ALBERT

Description: Background: Second generation tyrosine kinase inhibitors (2G-TKIs) are more potent than imatinib against chronic myeloid leukemia in chronic phase (CML-CP) as a first-line therapy, and the majority of patients (pts) on 2G-TKIs could achieve favorable molecular responces over MR3.0 by 24 M (Saglio G, et al. Blood 2011, Kantarjian HM, et al. Blood 2012). It is also likey that molecular response at 3 M will predict outcome for CML-CP pts on imatinib. Furthermore, Mustjoki S, et al. showed that Ph+ stem cell burden at diagnosis is a prognostic marker of molecular responses at 3-9 M on dasatinib or imatinib (Leukemia 2013). Thus, early prognostic marker of outcome is feasible for CML-CP on TKIs. Methods: We are conducting a phase II study (N-road) for newly diagnosed CML-CP pts, in which nilotinib 300mg BID is given for 24 M and is to be escalated to 400mg BID if no optimal response at any check points. The primary endpoint is CMR rate by 24 M, and secondary endpoints include MR3.0/MR4.0 by 12 M and exploring prognostic factors. In this setting, the impact of initial Ph+ stem cell burden on clinical findings and therapeutic responses has been investigated in a sub-study. By July 2014, 48 pts were enrolled and BM CD34+ cell fractions could be evaluated by FACS-FISH analysis at diagnosis in 43 pts, among those 35 pts passed 3 M, 34 pts 6 M and 15 pts 12 M, respectively. Results: MR3.0 rate was 8/35 at 3M, 23/34 at 6M and 10/15 at 12M. When 43 pts were classified into two groups (higher: H, lower: L) according to the mean CD34+ cell counts at diagnosis (5995/mL of BM aspirates), there were significant differences (p

Description: Background; The number of non-Hodgkin's lymphoma (NHL) patients in the elderly has been increasing due to the long-lived society. It is not rare to treat elderly NHL patients aged over 85 years old. Individualizing the doses of cancer chemotherapy agents and progress in supportive therapy has improved the prognosis for elderly patients with NHL. Prolonged hospitalization elderly patients have adverse effects, which include dementia, difficulty in walking, and depression. Optimal treatment for these patients is unknown. Patients and Methods; In our hospital between April 2012 and December 2014, we treated 19 elderly patients (85 and over 85 years) with NHL as outpatients with VDS 3mg (day 1) and Dexa. (day 1-4) which repeated every 3 weeks for as long as possible. Results; Complete remission was achieved in 5 patients and partial remission in 6; the median duration of survival was 14 months. Adverse effects included leukopenia in 1 patient (

Description: Background: Cytogenetic abnormalities at diagnosis are recognized as a potent prognostic factor for acute leukemia patients. Among acute myeloid leukemia patients, the prognostic implications of cytogenetic abnormalities have been established for those treated with chemotherapy as well as those undergoing allo-SCT. In the context of Ph-negative ALLpatients, cytogenetic abnormalities at diagnosis clearly stratify the prognosis, whereas it has not been elucidated whether similar prognostic stratification is applicable to allo-SCT recipients. Objective: The aim of this retrospective study was to assess the prognostic impact of cytogenetic abnormalities in adult Ph-negative ALL patients who underwent allo-SCT. Patients and Methods: The study cohort included 373 adult Ph-negative ALL patients aged over 15 years who underwent allo-SCT for the first time between January 2001 and December 2012 at the 23 institutions participating in the Kanto Study Group for Cell Therapy (KSGCT). Patients' clinical data were collected from the KSGCT database. The Institutional Review Board of Gunma University approved the protocol of this study. Karyotypes considered high risk (HR) included t(4;11), t(8;14), low hypodiploidy, and complex (equal or more than five abnormalities), and all other karyotypes were designated standard risk (SR). On this basis, 308 patients (82.6%) were categorized as SR and 65 patients (17.4%) were categorized as HR at diagnosis. Of the 373 patients, 267 underwent allo-SCT in complete remission (CR) (224 in the SR group and 43 in HR group), and 106 in non-CR (84 in the SR group and 22 in HR group). For analysis, the study population was stratified based on disease status at the time of transplant. Almost all patients were conditioned with total body irradiation (TBI)-containing myeloablative conditioning (MAC) regimens prior to transplantation. Overall survival (OS) was defined as the interval from the date of transplantation to the date of death. Non-relapse mortality (NRM) was defined as any death in continuous complete remission (CR). The Fisher's exact test was used for comparison of binary variables. OS and RFS were estimated by the Kaplan-Meier method, and compared using the log-rank test. Cumulative incidences (CI) of relapse and NRM were compared using the stratified Gray test. P 〈 0.05 was considered as statistically significant. Results: [Patients in CR] No significant difference in patient characteristics and transplant procedures was observed between the SR and HR groups. The 5-year OS rates were similar between the SR and HR groups (60.5% vs. 74.1%, respectively; p = 0.225) (Figure 1). Similarly, there were no significant differences in the 5-year CI of relapse and NRM rates between the two groups (relapse: 26.3% vs. 24.8%, respectively; p = 0.498, NRM: 19.6% vs. 10.0%, respectively; p = 0.232). Multivariate analysis for OS identified MAC and TBI-containing regimens, not cytogenetic risk, as significant positive prognostic factors. [Patients in non-CR] No significant difference was observed between the SR and HR groups in terms of patient characteristics or transplant procedures, although there was a female predominance in the HR group. Patients in the SR group had a significantly superior 5-year OS rate compared to the HR group (15.4% vs. 4.5%, respectively; p = 0.022). There was no significant difference in the 5-year CI of relapse between the SR and HR groups (60.3% vs. 50.0%, respectively; p = 0.411), whereas the 5-year CI of NRM in the SR group was significantly lower than that in the HR group (24.8% vs. 45.5%, respectively; p = 0.024). Multivariate analysis revealed cytogenetic risk group as an independent prognostic factor. Conclusion: These findings suggest that adult Ph-negative ALL patients in remission with HR cytogenetic abnormalities have similar transplant outcomes to those in the SR group. Considering the reported equality of the CR rates between the two groups, allo-SCT at an early clinical phase is recommended for HR group patients, reminiscent of Ph-positive ALL patients in the pre-imatinib era. Current transplant procedures do not improve outcomes for patients who are not in remission, especially those with HR cytogenetic abnormalities. Disclosures Usuki: MSD: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Shionogi: Other: personal fees; Fujimoto Pharmaceutical: Research Funding; Bristol-Myers Squibb: Other; Takeda Pharmaceutical: Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Sanofi: Other: personal fees, Research Funding; Shire: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Novartis: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Chugai Pharmaceutical: Other: personal fees; Fuji Film RI Pharma: Other: personal fees; Taiho Pharmaceutical: Other: personal fees, Research Funding; Astellas: Research Funding. Nakaseko:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Otsuka: Honoraria, Research Funding.

Description: Purpose It has been proposed that imatinib can be discontinued without molecular relapse at least in some CML patients. But little is known about whether the assumption could be exploitable for the second-generation ABL-tyrosine kinase inhibitors. Here we conducted a prospective, multicenter clinical trial to assess whether dasatinib can be discontinued without occurrence of molecular relapse in CML patients in complete molecular response (CMR). Methods In our Dasatinib Discontinuation (DADI) trial (Japan Primary Registries Network #UMIN000005130, http://rctportal.niph.go.jp/), main eligibility criteria for pre-registration were; CML patients in chronic phase, 15 years and older, undergoing dasatinib treatment used as a second-line therapy after confirmation of resistance or intolerance to imatinib treatment. Previous treatments with interferon-α (IFN-α) or nilotinib were allowed. In this trial, CMR was defined as “No detectable BCR-ABL transcript determined by international scale (IS)-based RQ-PCR at a single central laboratory (BML Inc., Tokyo, Japan, which obtains conversion factor (CF) 0.87).” Patients in CMR status confirmed by RQ-PCR at the central laboratory were pre-registered before the full enrollment for the discontinuation. The pre-registration period was between April 1, 2011, and March 31, 2012. The levels of BCR-ABL transcripts were monitored every 3 months throughout the pre-registration period during the dasatinib treatment. Patients with sustained CMR for one-year duration were then enrolled for the dasatinib-discontinuation stage. In order to detect molecular relapse after the dasatinib-discontinuation, RQ-PCR was performed monthly for the first 12 months, and then every 3 months for the subsequent follow-up. Molecular relapse was defined as positivity of BCR-ABL transcript by RQ-PCR even at one analysis point. Dasatinib was immediately reintroduced in patients who showed molecular relapse during the discontinuation period. After the relapse, RQ-PCR monitoring was performed 1 month, 3 months, 6 months, and 12 months after the reintroduction of dasatinib. Primary endpoint of this study was “Molecular relapse-free survival (MoRFS) rate at 6 months after discontinuation of dasatinib.” Total follow-up duration was set to be 36 months after the discontinuation. In addition to the molecular assessment of the BCR-ABL transcript level, increase of large granular lymphocytes (LGL) in the peripheral blood, in combination with flow cytometry analysis, was also investigated. Results In total, 88 patients were pre-registered at 41 participating institutions in Japan. Among them, a total of 63 patients who maintained stable CMR for one year after pre-registration were enrolled for the dasatinib-discontinuation stage. All of these 63 patients (42 male, 21 female) had been treated with imatinib before the start of the dasatinib treatments. Among these 63, 14 were imatinib-resistant, and 35 were imatinib-intolerant. Other previous treatments were; IFN-α (n=12), nilotinib (n=4), IFN-α and nilotinib (n=1). Median age was 59.5 years (range 24-84). Sokal scores were; low 70%, intermediate 15%, and high 15%. In this interim analysis with a data cut-off date of 31 July 2013, 27 patients out of 88 pre-registered patients were over the observation period of 6 months after the dasatinib-discontinuation. Among 27, 12 patients achieved 6 months-sustained CMR after dasatinib-discontinuation. The estimated MoRFS at 6 months determined by Kaplan-Meier method was 44 % (95%CI 26-62). Reintroduction of dasatinib to the relapsed patients showed rapid molecular responses in all of them. Among the 15 patients who lost CMR after dasatinib-discontinuation, 13 patients were available for the evaluation of reintroduction to CMR. 12 out of 13 patients (92%) returned to CMR again within 3 months (7 patients at 1 month, and 5 patients at 3 months) after the reintroduction, and all these patients have sustained CMR up to now. The remaining one patient out of 13 also showed a marked reduction of the BCR-ABL transcript level at 3 months. Conclusion Dasatinib could be safely discontinued in a proportion of CML patients with stable CMR for at least one year, provided that frequent molecular monitoring is performed. Patients who lost CMR after dasatinib-discontinuation still maintained good sensitivity to the reintroduction of dasatinib. Disclosures: Nakamae: Novartis: Honoraria, Speakers Bureau, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; BMS.: Consultancy, Honoraria, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Hino:Chugai Pharma: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other. Kimura:Bristol-Myers: Honoraria, Research Funding.

Description: Introduction Tyrosine kinase inhibitors (TKIs) markedly enhance the prognosis of chronic myelogenous leukemia (CML), potentially enabling the attainment of deep molecular response (DMR). Subsequently, the discontinuation of TKI became imperative to evade adverse events and financial burden of TKI therapy. In several studies, beginning with the STIM1 (Lancet Oncol 2010;11:1029), nearly 40%-60% of patients with chronic CML who sustained long DMR could discontinue TKI and attain long-term treatment-free remission (TFR). Remarkably, initial dasatinib specifically induces the elevation in lymphocytes, including large granular lymphocytes (LGL), NK cells, and cytotoxic T cells, as well as the decline in regulatory T cells (Tregs) in the early phase of treatment, related to early clinical responses.(Int J Hematol 2014;99:41) Nevertheless, lymphocyte variations by dasatinib during sustained DMR before cessation is an area of growing interest. In the Japanese multicenter prospective D-STOP trial (NCT01627132), we discontinued dasatinib following 2-year consolidation to sustain DMR in chronic CML to assess the TFR rate. We here present the final results of the D-STOP trial, including the peripheral NK/T cell change during dasatinib consolidation associated with successful TFR. Methods: Chronic phase CML patients treated with TKIs who had undetectable BCR-ABL1 mRNA were enrolled. After confirmation of undetectable BCR-ABL1 mRNA (International Scale 12-months), these subsets elevated transiently after 12 months but returned to basal levels after 24-month consolidation. (Figure 2)There were no differences in CD8-CD4+ helper T and Treg. cell numbers during consolidation between 2 groups. Therefore, smaller changes in the NK/T sebsets, particularly NK subset throughout consolidation, exhibited higher TFR rates. TFR rates of those exhibiting elevation in CD3-CD56+NK 〉 376 cells/mL, CD16+CD56+NK 〉 241 cells/mL,CD57+CD56+NK-LGL 〉 242 cells/mL or CD8+CD4- cytotoxic T cells 〉 212 cells/mL during consolidation compared with others were 26.7% (8.3%-49.6%) versus 78.3% (55.4%-90.3%), HR 0.032 (0.0027-0.38; P = 0.0064) (Figure 3), 31.2% (11.4%-53.6%) versus 85.0% (60.4%-94.9%), HR 0.039 (0.0031-0.48; P = 0.011), 36.8% (16.5%-57.5%) versus 77.3% (53.7%-89.8%), HR 0.21 (0.065-0.69; P = 0.010), or 41.2% (18.6%-62.6%) versus 76.5% (48.8%-84.9%), HR 0.18 (0.019-1.77; P = 0.14), respectively. Conclusion Silent responses of the T/NK subsets to dasatinib throughout consolidation was significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, could be immature cells with little immunosurveillance; their decline subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR might be immunologically significant. Disclosures Kumagai: Pfizer: Honoraria; Otsuka pharmacology: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Nakaseko:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria. Nishiwaki:Novartis: Research Funding. Yoshida:Otsuka: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Matsue:Janssen Pharmaceutical K.K.: Honoraria; Novartis Pharma K.K: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria. Morita:Bristol-Myers Squibb: Honoraria. Sakamoto,:Yakult Honsha Co. Ltd: Other: remuneration. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

Description: Abstract 691 Background: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for patients with chronic phase chronic myelogenous leukemia (CML-CP). Compared with imatinib, dasatinib is known to induce a faster and better response as a first- and second-line treatment. A unique effect of dasatinib treatment is the induction of clonal lymphocytosis with large granular lymphocyte (LGL) morphology, presumed to be the effect of off-target kinase inhibition. These LGLs are known to possess either cytotoxic T-cell (CTL) or natural-killer (NK) cell phenotype. Several reports have shown that this clonal LGL expansion is associated with a better response to dasatinib treatment. Purpose: To prospectively analyze the immunoprofile of Japanese patients treated with dasatinib, and to correlate the increase of lymphocytes and their subsets (LGL, CTL and NK cells) with the clinical efficacy of dasatinib. Method and Patients: Japanese patients with CML-CP who were resistant or intolerant to first-line imatinib therapy participated in the prospective phase II study assessing the efficacy and safety of dasatinib. Peripheral blood LGL, CTL and NK cell counts before and 2 weeks, 1 month (M), 3M, and 6M after the initiation of treatment were analyzed at the central laboratory (BML Inc.) by flow cytometry. LGL, CTL and NK cells were defined as CD57+/CD14-, CD8+/CD4- and CD56+/CD3- cells, respectively. Lymphocytosis was defined as a lymphocyte count of 〉3.0×109/L. The clinical efficacy of dasatinib was evaluated at 12M as complete molecular response (CMR) or less than CMR by peripheral blood quantitative RT-PCR (BML Inc.). The full data set was available for 50 out of 65 patients and was included in this analysis. Results: The median age of the patients enrolled was 57 years (range: 16 – 87 years). There were 37 male and 13 female patients. Twenty patients were switched to dasatinib due to intolerance to imatinib and 30 due to resistance. Lymphocytosis was observed in 19 patients (38%) at 3M. Of those 19 patients, 14 (73.7%) had lymphocytosis persisting at 6M. In total, 21 patients (42%) achieved CMR at 12M. The absolute count of lymphocytes, LGL, CTL or NK cells, did not differ significantly between patients who achieved CMR at 12M and those who did not (p〉0.05). However, there were significant differences between these two groups in the relative increase of these cell counts. Relative increase of lymphocytes compared to baseline as early as 2 weeks after initiation of treatment was identified by univariate analysis as a significant factor associated with CMR at 12M (p=0.0348). This increase persisted at each time point observed until 6M. As for the different subsets of lymphocytes, the relative increase of CTL at 3 and 6M and LGL at 1, 3 and 6M were also significantly associated with a higher rate of CMR at 12M. When adjusted for possible confounding factors (age, sex, performance status, whether 1st or 2nd CP, resistance or intolerance to imatinib), the relative increase of lymphocytes at 1, 3 and 6M, CTL and LGL at 3 and 6M remained significant (Fig a-c). Patients who showed an increase of lymphocytes of over 1.5-fold at 1M showed a significantly higher rate of CMR at 12M (66.7% vs 25.8%, p=0.0007). Similar differences were seen in patients with increases of over 2-fold in CTL, LGL and NK cells (70.6% vs 22.6%, p=0.0011; 74% vs 21%, p=0.0003; and 57.9% vs 28.6%, p=0.0444). Detailed analysis at 3M showed a further significant difference in the treatment effect. An increase of over 2-fold in lymphocytes (81.3% vs 21.2%, p

Description: [Background] Bendamustine has demonstrated high response rates in non-Hodgkin lymphomas (NHL). However, standard administration schedule frequently shows delayed hematological recovery resulting in the discontinuation of treatment. Here we designed a novel treatment schedule that could be more tolerable and conducted randomized phase II study (UMIN000008702). [Methods] Patients (pts) with relapsed/refractory(R/R) indolent B-cell NHL and mantle cell lymphoma were randomly assigned to standard arm (120mg/m2 on day1 and 2, every 3 weeks) or Benda-14 arm (120 mg/m2 on day1 and 15, every 4 weeks) of bendamustine monotherapy. Each arm was repeated to 6 cycles and the accomplishment rate (AR) of all scheduled treatment was analyzed as primary end point. [Results] A total of 46 pts were enrolled into the study. Baseline characteristics were: median age 64 years (range 46-78); 48% male; 76% follicular lymphoma; 33% ECOG PS ≥1; 50% having one previous regimen. 65% stage III/IV. 24% bone marrow positive. 33% with bulky mass (〉6cm). Using random allocation, twenty two and 24 pts were assigned to standard and Benda-14 arm and the AR of 6 cycles in each arm was 41 and 38%, respectively. The median number of cycles was 4.5 in both arms. Eleven (50%) in standard and 10 (42%) in Benda-14 arm withdrew from protocol due to mainly prolonged hematological toxicities. Three withdrew due to disease progression. Two withdrew due to adverse events (AE). Grade 4 non-hematological AE was observed in one. Overall response rate (ORR) in the standard arm was 77% (95% confidence interval [CI], 59 to 95), including a 50% complete response (CR) compared with 83% (95% CI, 68-99), including a 46% CR in Benda-14 arm.　After a median follow-up time of 16 months, the median event-free survival (EFS) in the standard arm and Benda-14 arm was 14.6 months (95% CI, 8-26) and 15 months (95% CI, 11 - not reached), respectively. There was no significant difference between two arms in AR and in EFS (p=0.431). The overall survival (OS) in both arms was the same of 89% at 15 months. [Conclusions] Although this study did not confirm the superiority of Benda-14 to complete 6 cycles of treatment, Benda-14 arm appears to be equally tolerable and active as the present standard therapy. Benda-14 could be a study arm of next trial that determines better practical strategy for this disease population. Disclosures Igarashi: Zenyaku-Kogyo Inc.: Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

Description: Background Nilotinib (NIL) is a second-generation tyrosine kinase inhibitor (TKI) that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). Superior rates of deeper molecular responses (DMR) were achieved with NIL vs. imatinib (IM) in patients newly diagnosed with CML in chronic phase (CML-CP) in the ENESTnd trial. In addition, the ENESTcmr study demonstrated that switching to NIL after a minimum of 2 years on IM led to increased rates of DMR vs. remaining on IM. Switching to NIL treatment for 2 years safely led to MR4,5 (BCR-ABLIS…0.0032%) in 47.5% of patients with major molecular response (MMR) on long-term IM therapy in our STAT1 trial. Recently, treatment free remission (TFR) was proposed as one of the goals in CML treatment. Indeed, prospective trials suggest that IM therapy may be safely and successfully discontinued in 40% of CML patients with MR4.5. STAT2 is the first study to evaluate the efficacy of two-year consolidation by NIL for successful TFR in patients with CML-CP who had achieved MR4.5. Before enrolling in STAT2, some patients were treated by not only IM but also NIL because of MMR but no MR4.5 after IM therapy, and some patients changed over from STAT1 to STAT2. Here, we present the results of the subgroup analysis from STAT2 based on the prior treatments at the time of entry into the study. Methods In the STAT2 trial, patients who achieved MR4.5 on IM front line therapy (subgroup 1; SG1) or NIL second line therapy after IM therapy (subgroup 2; SG2) were eligible and NIL was given twice daily at the dose of 600 mg/day for 2 years in consolidation phase. The primary endpoint of STAT2 was the proportion of patients with successful TFR, defined as no confirmed loss of MR4.5 (2 consecutive IS RQ-PCR tests), within the first 12 months of TFR phase. Thirty-five institutions in STAT study group participated. The study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was signed by all patients according to institutional guidelines. The study was approved by all institutional review boards and registered with UMIN-CTR (000005904). Results Between July 2011 and December 2012, 96 patients were enrolled in STAT2. Among 96 patients, 50 patients were treated by IM first line only as prior therapy (SG1). On the other hand, 40 patients were treated by IM first line and NIL second line including 21 patients who changed over from STAT1 to STAT2 because they achieved MR4.5 (SG2). Six patients were excluded in this analysis because second generation TKIs were taken as a first line therapy. Among patients treated by NIL for 2 years in this study, 40/50 (80%; 95% CI, 68.4%-88.7%) in SG1 and 33/40 (82.5%; 95% CI, 69.6%-91.5%) in SG2 entered the TFR phase, respectively. The median age was 54.5 years in SG1 and 56.0 years in SG2. The ratio of men to women was 26:14 in SG1 and 18:15 in SG2. The total duration of TKI treatment was 110 months for the SG1 with a median of 86 months of IM, and 24 months of NIL, and 93 months in SG2 with a median of 62 months of IM, and 31 months of NIL,, respectively. All patients achieved MR4.5 at the time of entry into the study and the median time to MR4.5 was 47 months in SG1 and 60 months in SG2.The proportion of patients who maintained TFR at 12 months after stopping NIL was similar across the 2 subgroups: 25/40 (62.5%; 95% CI, 48.3%-77.3%) in SG1, and 23/33 (69.7%; 95% CI, 54.0%-82.5%) in SG2. The Kaplan-Meier (KM) analysis of TFR survival showed that in the 2 subgroups, the majority of events occurred within the first 6 months after stopping NIL (Figure 1). There were no significant differences between these 2 subgroups. Conclusion After two-year consolidation by NIL of CML-CP patients who achieved MR4.5, the TFR rate was 67.9% (90%CI: 58.2% to 76.6%) at 12 months in the STAT2 trial. In the present analysis looking at the prior TKI exposure, the TFR rate was similar in patients treated with IM first line only or who switched from IM to NIL before entering the study, despite the fact that the treatment duration of switched patients was slightly shorter. These findings suggest that two-year consolidation by NIL is associated with successful TFR in CML with MR4.5 that was achieved with IM alone or after switching to NIL. Figure Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Figure. Kaplan-Meiercurve of TFR survival in the 2 subgroups based onthe prior treatmentsbefore two-year consolidation by NIL, IM first line only as prior therapy (subgroup1) and IM first line and NIL second line (subgroup2). Disclosures Takahashi: PFIZER: Honoraria, Research Funding; BMS: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Nishiwaki:Novartis PHARMA: Research Funding.

Description: Abstract Introduction The introduction of the tyrosine kinase inhibitor (TKI) imatinib has dramatically improved outcomes in chronic myeloid leukemia (CML) patients. A previous report from the DASISION study demonstrated remarkable improvement in treatment responses with dasatinib compared with imatinib. Regarding outcomes in chronic-phase CML (CML-CP) patients, the significance of an early treatment response was emphasized; the treatment goal primarily focused on molecular responses, i.e., major molecular response (MMR) and complete molecular response (CMR). However, although molecular response criteria seemed promising, the clinical entities such as the BCR-ABL transcript level at diagnosis varied in each patient. Recently, tumor reduction velocity was proposed as a useful predictor of patient outcomes. We therefore hypothesize that the halving time may sensibly predict molecular responses in dasatinib-treated patients. We conducted an open-label, multicenter, prospective "D-First" study (ClinicalTrials.gov; NCT01464411) and observed molecular responses of newly diagnosed CML-CP patients treated with dasatinib (100 mg QD). Methods Fifty-two newly diagnosed CML-CP patients were enrolled between June 2011 and June 2012. The primary endpoint of our study was the CMR rate by 18 months; therefore, all patients were followed-up for at least 18 months. To assess molecular responses, BCR-ABL transcripts were quantified using RQ-PCR. BCR-ABL transcripts were analyzed at diagnosis and 1, 3, 6, 9, 12, 15, and 18 months after initiating dasatinib treatment. BCR-ABL transcripts were measured as described previously (Yoshida C et al. Int J Clin Oncol. 2012;17:584). MMR was defined as

Description: Introduction Achievement of deep molecular response (DMR) has become an important treatment goal for patients with chronic phase chronic myeloid leukemia (CP-CML) since it is considered to be necessary for the challenge of stopping tyrosine kinase inhibitor (TKI) treatment. However, prognostic marker for prediction of DMR has not been established. We have previously reported the results of D-First study that shorter having time of BCR-ABL1 transcripts and early cytotoxic lymphocyte expansion were associated with achievement of DMR in newly diagnosed CP-CML patients treated with dasatinib. Here, the long-term follow-up results of the study were analyzed after a minimum 36 months follow-up. In this analysis, we mainly focus on dynamics of regulatory T cells (Treg) influencing patients' clinical course, as well as immunoprofiles during dasatinib treatment. Methods: A total of 52 patients with newly diagnosed CP-CML who were enrolled between June 2011 and June 2012 and treated with dasatinib 100 mg once daily on an open-label, multicenter, prospective phase II clinical trial (NCT01464411). All patients were followed-up for minimum of 36 months. Patients were assessed for molecular response before and 1, 3, 6, 9, 12, 15, 18, 24, and 36 months after starting dasatinib by real-time quantitative polymerase chain reaction analysis of BCR-ABL1 transcripts standardized on an international scale (BCR-ABL1 IS). A DMR was defined as less than 0.01% BCR-ABL1IS (MR4). The analysis of immunophenotyping of lymphocyte fractions in the peripheral blood samples was performed by flow cytometry before and 1, 2, 3, 6, 9, 12, 15, 18, 24, and 36 months after starting dasatinib treatment at a centralized laboratory (BML). Results: Patients' characteristic at diagnosis has been reported previously. Briefly, the median age was 52 years. High Sokal risk score was seen in 12% patients. With a minimum follow-up of 36 months, 12 (23%) patients have discontinued therapy. Reasons for treatment discontinuation includes: pleural effusion (N=3), pericardial effusion (1), proteinurea and systemic edema (1), pulmonary hypertension (1), malaise (1), elevation of intraocular pressure (1), interstitial pneumonia (1), and patient's requests (3). A cumulative rate of MMR was 75% by 12 months, 80% by 18 months, 86% by 24 months and 88% by 36 months. A cumulative rate of DMR was 49% by 12 months, 59% by 18 months, 59% by 24 months, and 65% by 36 months. Two patients died because of reasons unrelated to CML. No patients progressed to accelerated or blastic phase. Three-year overall survival was 96%. Flow cytometric analysis of peripheral blood revealed that average number of CD4+ T lymphocytes did not change over the course of 36 months. In contrast, ratio of CD4+CD25+CD127low Treg among CD4+ T cells decreased in a time-dependent manner during the follow-up. The ratio of Treg at 12 months of dasatinib treatment was associated with achievement of DMR, which was especially significant at 18 months (p