ALBERT

Description: Key Points Nilotinib induced deeper molecular responses than continued imatinib in patients with minimal residual disease on long-term imatinib. These deeper responses may enable more patients to benefit from treatment-free remission trials.

Description: Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 3422 Poster Board III-310 Autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) and Hodgkin's lymphoma (HL). The absolute lymphocyte count (ALC) in the autograft has been shown to correlate with survival after ASCT for lymphomas, but which lymphocyte subset in the autograft is responsible for this effect remains unknown. The aim of the present study was to retrospectively evaluate the impact of the number of CD4+ and CD8+T-cells in the autograft on the outcomes of ASCT. Patients with a diagnosis of relapsed HL or DLBCL submitted to an ASCT between 1999 and 2006 were included. Patients were excluded if a sample of the autograft was unavailable. No patient had HIV infection. The mobilization scheme consisted of subcutaneous G-CSF in 70% of the patients. The remaining patients were given cyclophosphamide 1.5 g/m2 or 4g/m2 with G-CSF. The conditioning regimen was cyclophosphamide 6 g/m2, BCNU 300 mg/m2 and etoposide 1200 mg/m2 in all but two patients. Growth-factor support was started five days after the infusion. The ALC in the autograft was calculated as the lymphogate in the FACS analysis. T-cell count was calculated as the total number of CD3+ lymphocytes, and T-cell subsets were determined by the number of CD4+ or CD8+ cells in the autograft. The antibodies used in the FACS analysis were: anti- CD45-FITC (BD- PharMingen), anti- CD4-FITC/ CD8-PE/ CD3-PercP (BD- PharMingen) and anti- CD3-FITC (BD- PharMingen). Among the 48 patients (34 with HL and 14 with DLBCL) available for study, the median age was 34 years (12-65), 37 were males (73%), and advanced stage disease (Ann Arbor stage III or IV) was present in 38 patients (75%). The number of previous treatments ranged from one to four, and radiotherapy had been given to 51% of the patients. The median time from diagnosis to the ASCT was 1.8 years (0.4 to 15.3). The median numbers of infused cells were mononuclear cells 5.7×108/kg (1-15), CD34+cells 4.1×106/kg (1.7-19.6) and lymphocytes 261/mm3 (23-978). The median numbers of T-cell subpopulations were CD3+ 164/mm3 (7-706), CD4+ 68/mm3 (3-284), CD8+ 75/mm3 (3-401), CD4-CD8- 9/mm3 (0.3-154) and CD4+CD8+ 1.3/mm3 (0.01-15). Those values were used as cutoffs for the lymphocyte count comparisons. In univariate analysis, the mobilization scheme including chemotherapy was associated with a higher median number of collected CD34+ cells/Kg (8.0 vs 4.17, p= 0.003), with a lower median number of total lymphocytes (203 vs 372, p=0.003), CD3+ T-cells (144 vs 249, p=0.005), CD8+ T-cells (50 vs 114, p

Description: Background: The randomized, phase 3 ENESTcmr study evaluated whether pts with CML-CP with detectable residual disease on long-term IM could achieve deeper molecular responses (MRs) by switching to NIL vs remaining on IM. Achievement of a sustained deep MR is a key prerequisite for successful TFR following frontline tyrosine kinase inhibitor (TKI) therapy; however, limited data are available on TFR following second-line TKI therapy. To estimate the proportion of pts who may be eligible to attempt TFR following second-line NIL, we analyzed 4-y data from ENESTcmr to evaluate the proportion of pts who maintained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale) for 1 y after achieving it after ≥ 2 y on second-line NIL. Methods: In ENESTcmr (NCT00760877), pts with CML-CP with complete cytogenetic response but detectable BCR-ABL1 after ≥ 2 y on IM were randomized to NIL 400 mg twice daily (BID; n = 104) or IM (400 or 600 mg once daily; n = 103). Pts in the IM arm could cross over due to detectable BCR-ABL1 after 2 y on study or treatment failure/confirmed loss of response at any time. In this exploratory analysis of data from ENESTcmr, key criteria for attempting TFR in ENESTop (NCT01698905) were applied a posteriori to estimate the rate of eligibility to attempt TFR with second-line NIL. These criteria included ≥ 3 y of total TKI therapy (≥ 4 weeks of frontline IM and ≥ 2 y of second-line NIL), with MR4.5 achieved on NIL and sustained MR4.5 on NIL for an additional ≥ 1 y. A time-to-event analysis was used to estimate the rate of eligibility for TFR, using these criteria, among pts randomized to the ENESTcmr NIL arm; pts who discontinued early were censored at the data cutoff date, and pts who did not meet the eligibility criteria but were still on treatment at the data cutoff were censored at the date of last dose. Results: Most pts in ENESTcmr had received 〉 3 y of prior IM (NIL 400 mg BID arm, 83%; IM arm, 80%). At the data cutoff (minimum follow-up of 4 y), 59/104 pts in the NIL arm, 36/46 pts who crossed over from IM to NIL, and 41/57 pts in the IM arm who did not cross over remained on study treatment. Median time receiving NIL was 3.9 y among pts in the NIL arm and 1.8 y among pts who crossed over from IM to NIL. By 4 y, rates of MR4.5 in pts without MR4.5 at study entry (NIL, n = 98; IM, n = 96) were 52% and 42% in the NIL and IM arms, respectively; when responses achieved after crossover from IM to NIL were excluded, rates were 52% and 28%, respectively. Among pts who crossed over, 13/46 (28%) achieved a first MR4.5 on NIL after crossover. By 4 y, 44/104 pts in the NIL arm (42.3%) had received ≥ 2 y of NIL and achieved MR4.5 on NIL (Figure). Five of these 44 pts achieved MR4.5 between 3 and 4 y and were therefore not evaluable for sustained MR4.5 for ≥ 1 y by the data cutoff; of the pts who achieved MR4.5 by 3 y, 17/39 (43.6%) had sustained MR4.5 for ≥ 1 y on NIL by 4 y. Overall among pts randomized to NIL (n = 104), an estimated 17.4% (95% CI, 11.1%-26.7%) had both a ≥ 3-y duration of NIL treatment and a ≥ 1-y duration of sustained MR4.5. A similar analysis to estimate the proportion of pts who achieved a sustained deep MR with continued IM therapy was not possible due to the confounding effect of a large proportion of pts crossing over to NIL (46/103) during the study. Similarly, because most of the 46 pts who crossed over to NIL received 〈 2 y of NIL by the 4-y data cutoff, the rate of sustained deep MR on NIL could not be evaluated in these pts. Conclusion: For pts in whom TFR is a treatment goal, achievement of a sustained deep MR is a critical milestone. By 4 y in ENESTcmr, 43.6% of pts (17/39) with ≥ 2 y of second-line NIL who achieved MR4.5 by 3 y also sustained this response for an additional ≥ 1 y on NIL (the key ENESTop criteria for attempting TFR). The optimal depth and duration of MR for successful TFR following second-line TKI therapy have not been determined, and the proportion of pts eligible to attempt TFR would be expected to vary between studies, depending on the specific criteria required for attempting TFR. Overall, these results suggest that for pts lacking deep MR on frontline IM, switching to second-line NIL may provide a route to TFR eligibility. Figure 1. Figure 1. Disclosures Hughes: ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: Nilotinib is currently approved for the treatment of patients with newly diagnosed CML in chronic phase and in patients with CML in chronic phase or accelerated phase who are resistant or intolerant to previous therapy including imatinib. The ENESTcmr study (results of which are presented in this abstract) evaluated the safety and efficacy of second-line nilotinib in patients with complete cytogenetic response but with detectable levels of BCR-ABL1 transcripts after 2 y frontline imatinib.. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Spector:Novartis Pharmaceuticals: Research Funding. Leber:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Branford:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Glynos:Novartis Pharmaceuticals: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Dalal:Novartis: Employment, Equity Ownership. Lipton:Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.

Description: Introduction In patients with imatinib-resistant chronic myeloid leukemia (CML) treated with a second generation tyrosine kinase inhibitor (2GTKI), the initial molecular response at 3 months (3m-IMR) has been shown to be predictive of long-term outcomes. However, there is no consensus regarding the best cutoff for the BCR-ABL1 transcript levels, with 1% and 10% being proposed in different studies. Also, additional prognostic factors such as baseline tyrosine kinase (TK) mutations and a prognostic scoring system (PSS) (Jabbour, 2011) have been proposed. In this study, we addressed those issues in an homogeneous group of imatinib-resistant CML patients treated in a single center for a median follow-up of 36 months (14-60). Patients and Methods 134 patients with a diagnosis of CML treated either with dasatinib (N=64) or nilotinib (N=70) due to imatinib failure were included. Imatinib failure was defined as any of the following: no complete hematologic response at 3 months, no cytogenetic response at 6 months, no major cytogenetic response at 12 months, no complete cytogenetic response (CCR) at 18 months, or loss of hematologic or cytogenetic response at any time. Patients with the T315I mutation were excluded. Molecular analysis was performed in a properly standardized laboratory every 3 months from the beginning of the 2GTKI, and results are presented according to the international scale. The study's primary endpoint was the 3-year event-free survival (EFS) after 2GTKI. Secondary endpoints were the best response levels attained under 2GTKI (BMR). The factors analysed were the 3m-IMR, age, gender, Sokal and EUTOS scores at diagnosis, failure to achieve a complete cytogenetic response, TK mutations, PSS score and type of 2GTKI. A multivariate analysis with the factors significant at P

Description: Abstract 606FN2 Background: Recent studies have demonstrated that about 40% of very highly selected CML-CP pts treated with imatinib achieve durable CMR and may be able to cease therapy without disease recurrence. However, most CML pts don't achieve CMR on imatinib even with long-term therapy. Results from ENESTnd demonstrated that significantly more patients achieved MMR (≤ 0.1%IS), CMR4 (≤ 0.01%IS), and CMR4.5 (≤ 0.0032%IS) with nilotinib vs imatinib by 12, 18, and 24 months (mo). No pt in ENESTnd who achieved CMR4.5 has progressed to AP/BC. In this study we asked whether pts on long-term imatinib would be more likely to achieve undetectable BCR-ABL levels if they switched to nilotinib, allowing for participation in potential cessation studies in the future. Methods: This open label, 1:1 randomized, prospective, multi-center, phase 3 study enrolled 207 pts with CML-CP who had achieved a complete cytogenetic response (CCyR) but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib. CMR (primary endpoint) was defined as undetectable BCR-ABL by RQ-PCR where there was no detectable BCR-ABL with a sample sensitivity of ≥ 4.5-logs. CMR4 and CMR4.5 were defined as BCR-ABL levels of ≤ 0.01% and ≤ 0.0032% expressed on the International Scale (IS), respectively and included patients with undetectable BCR-ABL levels with high sample sensitivity (4 or 4.5 logs). Patients were randomized to nilotinib 400 mg BID vs continuing imatinib 400 or 600 mg daily (same dose as at study entry.) The randomization was stratified by prior use of IFN (none, ≤ 12 mo, 〉 12 mo) and prior duration of imatinib therapy (〉 36 mo or ≤ 36 mo). The primary endpoint was the rate of confirmed best cumulative CMR by 12 mo of study therapy with nilotinib or imatinib. Secondary objectives included the kinetics of CMR at different timepoints, duration of CMR, progression-free survival, and overall survival in both arms. During the study, RQ-PCR for BCR-ABL was performed at baseline (BL) and every 3 mo and expressed on the IS in national reference laboratories in Australia, Brazil, and Canada. For this report: BL, 6 mo, and 12 mo results were analyzed in a central laboratory in Australia. Assessment of the primary efficacy endpoint has not been completed for 2% of the randomized pts; unblinded data will be available for all pts and will be presented by treatment arm. Results: BL results were available for 205/207 randomized pts. Overall, 56% of pts had no prior IFN exposure, while 21% and 23% had IFN exposure of ≤ 12 mo or 〉 12 mo, respectively; 81% of pts had been on imatinib 〉 36 mos. At BL, 153 pts (74%) were known to be in MMR and 54 pts (26%) had 〈 MMR (including 2 pts with missing PCR samples); 53 pts (26%), and 20 pts (10%) had CMR4 or CMR4.5 (with detectable BCR-ABL) at BL, respectively. Overall, 67 pts (32%) had at least a half-log reduction in BCR-ABL levels from BL by 12 mo. Of the 52 pts (25%) known not to have MMR at BL, 24 pts (46%) achieved MMR or better by 12 mo in the study. To date, no pt experienced a loss of MMR or CCyR on study. By 12 mo, 50% of pts with a molecular assessment had CMR4 and 27% had CMR4.5. Of the 152 pts who did not have CMR4 at baseline, 30% had achieved CMR4 (unconfirmed) by 12 mo. Of the 185 pts who did not have CMR4.5 at baseline, 21% had achieved CMR4.5 (unconfirmed) by 12 mo. Undetectable levels of BCR-ABL transcripts (with a test sensitivity of ≥ 4.5 log), were achieved by 12 mo by 12% of pts who did not have undetectable BCR-ABL transcript levels at BL. By 12 mo, 20 (10%) pts discontinued study (none due to progression, 1 due to death). Grade 3/4 adverse events were uncommon. Conclusions: ENESTcmr is the first phase 3 randomized study in CML-CP pts to assess the achievement of CMR as the primary endpoint. Unblinded results from this ongoing study will be presented and will provide information on the ability of pts to achieve confirmed CMR on nilotinib vs imatinib following extended treatment with imatinib. These aggregate data demonstrate that 12% of pts achieved undetectable BCR-ABL levels by 12 months after study entry. This is in contrast to observations in previous trials where the increase in the proportion of pts with undetectable BCR-ABL levels over time is more gradual. Further follow-up will identify pts with sustained CMR over time, which may offer these pts an opportunity to discontinue therapy. Disclosures: Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lipton:Novartis Pharmaceuticals Canada Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leber:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Spector:Novartis: Membership on an entity's Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; BMS: Speakers Bureau. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Schwarer:Novartis: Honoraria; BMS: Honoraria. Mahon:Novartis: Honoraria, Research Funding. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Kamel-Reid:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Reynolds:Novartis: Employment, Equity Ownership. Williams:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding.

Description: The outcome of patients with hematologic malignancies (HM) requiring admission to the intensive care unit (ICU) seems to be improving as a consequence of recent advances in oncology and intensive care. However, their mortality remains exceedingly high, and a reappraisal of their outcome predictors might provide useful clinical insights. During 45 months, every consecutive patient with HM admitted to an exclusively oncologic ICU because of a severe illness was studied. Patients with an ICU stay

Description: Introduction The 12- and 24-mo results of the Evaluating Nilotinib Efficacy and Safety in clinical Trials–complete molecular response (ENESTcmr) trial showed that pts with CML-CP with minimal residual disease after ≥ 2 y on imatinib achieved deeper molecular responses with switch to nilotinib. Results from ENESTcmr with 36-mo follow-up will be presented. Methods Pts with Philadelphia chromosome–positive (Ph+) CML-CP who had achieved complete cytogenetic response (CCyR) but had detectable BCR-ABL after ≥ 2 y on imatinib were included. Pts (N = 207) were randomized 1:1 to continue the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103) or switch to nilotinib 400 mg twice daily (BID; n = 104). Rates of major molecular response (MMR; BCR-ABL ≤ 0.1% according to the International Scale [IS]) and MR4.5 (BCR-ABLIS ≤ 0.0032%) were evaluated by real-time quantitative polymerase chain reaction (RQ-PCR). Confirmed undetectable BCR-ABL was measured by RQ-PCR with a sensitivity of ≥ 4.5 logs, confirmed with a sensitivity of at least 4 logs in the next sample. Predictors of response were evaluated by multivariate logistic regression. Pts receiving imatinib were allowed to cross over to nilotinib if they had not achieved confirmed undetectable BCR-ABL by 24 mo or if they experienced treatment failure or confirmed loss of undetectable BCR-ABL at any time. Results By 24 mo, 77% of pts in the nilotinib arm and 91% in the imatinib arm remained on study treatment. Discontinuation rates were comparable between arms during year 2; 7% and 5% of pts discontinued study treatment in the nilotinib and imatinib arms, respectively, between years 1 and 2. Three pts crossed over to nilotinib before 24 mo; the no. of pts who crossed over at or after 24 mo will be presented. By 24 mo, more pts in the nilotinib arm achieved confirmed undetectable BCR-ABL compared with imatinib (22.1% vs 8.7%; P = .0087; Table). Regardless of molecular response at study start, more pts in the nilotinib arm than the imatinib arm achieved MR4.5 by 24 mo. None of the pts in the imatinib arm who lacked MMR at study start achieved confirmed MR4.5 or confirmed undetectable BCR-ABL by 24 mo (vs 20.8% and 16.7% in the nilotinib arm, respectively). Twice as many pts achieved and maintained MR4.5 in 3 consecutive assessments in the nilotinib vs imatinib arm (n = 12 vs 6). Age, sex, BCR-ABL level at study start, duration of prior imatinib (≤ 36 mo vs 〉 36 mo), and prior interferon were analyzed as predictors of response in univariate and multivariate analyses. None of these was clearly predictive of achieving MR4.5 or undetectable BCR-ABL in multivariate logistic regression. No cases of progression to accelerated phase/blast phase were observed with 24 mo follow-up. Three pts in the imatinib arm had confirmed loss of CCyR vs 0 in the nilotinib arm. Conclusions Switching to nilotinib continues to induce deeper molecular responses in pts with minimal residual disease on long-term imatinib therapy. More pts achieved confirmed undetectable BCR-ABL in the nilotinib arm vs the imatinib arm, with the difference between arms increasing between 12 and 24 mo and notably marked in pts lacking MMR at study start. Maintenance of deeper molecular responses achieved with nilotinib therapy may enable more pts to benefit from treatment-free remission trials. Disclosures: Leber: novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Spector:Novartis: Honoraria, Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Guerci-Bresler:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis : Honoraria, Membership on an entity’s Board of Directors or advisory committees; AMGEN: Honoraria. Forrest:Bristol Myers Squibb: Consultancy. Schwarer:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Collins:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Hughes:Araid: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Research Funding; Novarits: Consultancy, Honoraria, Research Funding; CSL: Research Funding.

Description: Abstract 1701 Mutations within the BCR-ABL domain are the most frequent mechanism of imatinib (IM) resistance. The second generation inhibitors (SGI) are indicated for imatinib intolerance or resistance and the initials trials showed similar response rates in IM resistant patients after IM failure, independent of mutation status, with exception of T315I. The aim of this work was to report the frequency of BCR-ABL mutations in chronic myeloid leukemia (CML) patients of a Latin American population and to evaluate the clinical impact of the presence and type of mutations in overall survival (OS), progression free survival (PFS) and in the response to second generation inhibitors (SGI). Methods: retrospective analysis of 17 centers from Latin America. A total of 529 CML patients with mutation analysis performed in samples collected between 2002 and 2011 were included. Mutations were detected by direct sequencing from bone marrow or peripheral blood samples, collected from CML patients. After imatinib resistance, patients were treated with SGI (69%) or other treatments. Overall survival (OS) was calculated from date of mutation detection until last follow-up or death, and progression-free survival (PFS) from date of mutation detection until progression to accelerated phase or blast crisis, last follow-up or death. Survival curves were calculated using the log-rang test (SPSS 14.0 software).Results: the median age of patients at diagnosis was 45 years (5–87). 81% were in chronic phase (CP), 13% in accelerated phase (AP), 6% in blast crisis (BC). According to Sokal score, patients were stratified in low (36%), intermediate (30%) and high risk (34%); 36% had previously used Interferon. The median time from diagnosis until Imatinib treatment was 8 months (0–310) and from Imatinib start until mutation detection was 31 months (1–104). Mutations were found in 188 patients, in the following sites: P-loop (75/40%), nucleotide contact site (34/18%), catalytic domain (44/23%), A-loop (11/6%) and others (24/13%). The most frequent mutations detected were: T315I (30/16%), F359V/C/I (27/14%), M244V (18/9.6%), E255K/V (17/9%), G250E (17/9%), Y253H/F/Y (15/8%), M351T/L (12/6%); Ten patients presented concomitant mutations. On dasatinib treatment 29 mutations (27% T315I) were detected whereas 18 during nilotinib (16.5% T315I). Overall survival in the total group was 61% (95%CI: 51–71%) with a median time of 12 months. There was a significant difference in OS and PFS between non-mutated and mutated patients (76% vs 44% and 64% vs 44% respectively (P= 0.008 and P= 0.001). There was no difference in survival comparing P-loop mutations and others, excluding T315I. Patients with T315I mutations had a poorer outcome in comparison with other mutations (OS 21% vs 62%; PFS 35% vs 55%) (P= 0.04 and 0.06, respectively). In the group with BCR-AL mutations, OS was superior in patients that received a SGI in comparison with other treatments after resistance (50% vs 36% P= 0.007). One hundred patients (19%) died due to: disease progression (72), infections (8), graft versus host disease (2), central nervous system bleeding (2), cardiac failure (1), second neoplasia (1). 14 causes were not reported. Conclusions: Patients with BCR-ABL mutations had an inferior OS and PFS. T315I mutations were associated to a poor outcome. Treatment with SGI prolonged survival of patients after imatinib failure. Disclosures: Pagnano: Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Boquimpani:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Spector:Novartis: Membership on an entity's Board of Directors or advisory committees.