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Little is known about MYC dysregulation in myeloid malignancies, and the authors were unable to find published studies that evaluated MYC protein expression in primary cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Herein, we describe the clinical, morphologic, immunophenotypic, cytogenetic, and molecular genetic findings in two MDS/AML cases that contained both MYC rearrangement and the JAK2 V617F mutation. We also demonstrate MYC protein expression by immunohistochemistry in both patients.

INTRODUCTION Inherited disorders due to rare structural Hb variants are not included in national, neonatal screening tests and therefore likely underdiagnosed. Hemoglobin New Mexico is one such rare variant with only one case ever reported in 1985 in conjunction heterozygosity for Hb S.1 This Hb variant involves a missense mutation of the β chain substituting the hydrophobic Proline β100 with the hydrophilic Arginine.1 We present here the second case of Hb New Mexico variant ever reported to our knowledge. CASE PRESENTATION An 18-year-old athletic, Latin American female initially presented with episodic chest pain, palpitations, fatigue, headaches, and dyspnea on exertion to the point that she could no longer exercise for one year. Work up revealed erythrocytosis persistent for >1 year with hemoglobin level of 17.3 g/dL, and hematocrit of 47.2 % (Hb went as high as 19g/dL) with normal erythropoietin level, hemoglobin electrophoresis, and JAK2 V617 with reflex to JAK3 exon 12-15 negative. She had extensive evaluation to rule out acquired causes including cardiac, pulmonary, and neurologic evaluation which was all normal. She underwent therapeutic phlebotomies with no clinical improvement over 3 months and symptoms worsened as well as new iron deficiency from phlebotomies so this was discontinued. Evaluation with p50 oxygen dissociation curve revealed high oxygen affinity. Further gene sequencing revealed heterozygous inheritance of Hb New Mexico with HbA: 54.5%, HbA2: 3.6%, and Hb New Mexico: 41.9%. Beta Globin Gene sequencing identified the following mutation: Beta 100, CCT>CGT, Pro>Arg. Her symptoms worsened as well as an episode of syncope but no new neurologic, cardiac, or pulmonary etiologies were identified and at the time Hg 18g/dL. A trial of low dose acetazolamide 125mg daily was given to the patient and her symptoms improved by a 6 week follow up with notable reduction of headache, fatigue, dyspnea, and chest pain. CONCLUSIONS Given the rarity of this hemoglobin variant in a patient with severe symptoms, data is limited. Acetazolamide, a carbonic anhydrase inhibitor often used for migraines, is known to illicit mild acidosis and therefore potentially reduce hemoglobin-oxygen affinity and perhaps allow for relief of our patient's symptoms. Further therapeutic evaluation is warranted but likely challenging given rarity of the condition. Disclosures No relevant conflicts of interest to declare.

Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.

Summary Background Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP. Methods In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression. Findings Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR 4·5 response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3–60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29–0·88, p=0·016), dasatinib (0·28, 0·12–0·66, p=0·004), or nilotinib (0·42, 0·20–0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason. Interpretation Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy. Funding MD Anderson Cancer Center, National Cancer Institute.

Rhabdomyolysis, a syndrome of muscle necrosis, is a life-threatening event. Here we describe the case of a patient with chronic myeloid leukemia who underwent a haploidentical stem cell transplant and subsequently developed rhabdomyolysis after beginning trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis therapy. Rechallenge with TMP/SMX resulted in a repeat episode of rhabdomyolysis and confirmed the association. Withdrawal of TMP/SMX led to sustained normalization of creatine kinase levels in the patient. A high index of suspicion is necessary to identify TMP/SMX as the cause of rhabdomyolysis in immunocompromised patients.

Background Accelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy. Patients and Methods We analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥ 15% (n = 6), basophils ≥ 20% (n = 22), platelets 9 /L (n = 3), cytogenetic clonal evolution (n = 17), or more than 1 feature (n = 3). Patients received initial therapy with imatinib (n = 30), dasatinib (n = 5), or nilotinib (n = 16). Results The rate of complete cytogenetic response for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR) (Breakpoint Cluster Region (BCR)-Abelson (ABL)/ABL ≤ 0.1%, International Scale [IS]) was achieved in 69% of patients including complete molecular response (BCR-ABL/ABL ≤ 0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with 2GTKIs, 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKIs. Conclusion TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.

e15623Background: Unresectable and metastatic BTC portend very poor overall survival (OS), with historical OS less than 1.5 years. Gemcitabine (G) and cisplatin (C) combination has become the stand...

Acquired von Willebrand Syndrome (AVWS) is a bleeding disorder characterized by a non-inherited low activity of von Willebrand factor (VWF), occurring in patients with no prior medical or family hi...

Introduction Since 2000, different TKI modalities have been used as initial therapy for CML-CP. We analyzed the responses and long-term clinical impact among pts treated with 4 TKI modalities as frontline CML-CP therapy in a single institution. Methods Outcomes of 476 consecutive pts (median age 49 yrs, range 15-86) receiving initial therapy with TKI from 2000 to 2013 were analysed. Patients received imatinib 400 mg/d (IM400; n=71), imatinib 800 mg/d (IM800; n=202), dasatinib (n=98) or nilotinib (n=105) in consecutive or parallel trials. Median follow-up was 85 months (mo) (3-154). Pts were followed uniformly with cytogenetics and PCR every 3 mo for the first 12 mo, then every 6 mo. Results Median follow-up was 144 mo for IM400, 112 mo for IM800, 52 mo for dasatinib and 48 mo for nilotinib. Overall CCyR rates were 85%, 92%, 96% and 96%, respectively. Corresponding rates of MMR were 83%, 88%, 91%, and 93%, respectively. The median time to achieve MMR was 11 mo for patients treated with IM400 and 6 mo with IM800, 5.8 mo with dasatinib, and 5.8 mo with nilotinib. Rates of MR4.5 were 61%, 76%, 75% and 68%. Rates of the CMR (5-log) were 48%, 54%, 55% and 46%. Because of the difference in follow-up between cohorts, we analyzed response at specific time points. Higher proportions of pts receiving IM800 and 2nd generation TKI achieved CCyR, MMR and MR4.5 at all time-points analyzed (3-60 months). Disease transformation occurred in 34 pts (7%), events occurred in 72 (15%) and 53 pts (11%) died. Overall, 195 (41%) pts have discontinued therapy, including 54% of pts treated with IM400, 46% with IM800, 28% with dasatinib and 27% with nilotinib. For pts taking IM400, 25% had lost CCyR by 60 mo, compared to 13% with IM800, 12% with dasatinib, and 5% with nilotinib. Estimated 60 mo outcomes for the total population were event-free survival (EFS) 85%, failure-free survival (FFS) 68%, transformation-free survival (TFS) 93%, and overall survival (OS) 93%. The 60 mo EFS was 69% with IM400, 87% with IM800, 91% with dasatinib, and 86% with nilotinib (P≤0.001). Pts who achieved a CCyR at 6 months (i.e., optimal response by ELN) had a better EFS rate at 60 mo (92%) compared to those not achieving this response (60%) (P≤0.001). Similarly, achievement of MMR at 12 mo (optimal response) resulted in 60 mo EFS probability of 92% vs. 74% for those without MMR (P≤0.001). Table -1depicts the time to event outcomes based on responses achieved by each TKI modality. The differences were similar regardless of the TKI modality used. Conclusions Excellent results are obtained with all TKI modalities with a suggestion for better long-term outcomes with IM800, dasatinib or nilotinib as compared to IM400. Higher proportions of pts who received imatinib discontinued treatment as compared to 2ndgeneration TKI. Achievement of CCyR and MMR at different time points has similar correlations with long-term outcome, regardless of the TKI used. Most patients with CML-CP can have an excellent outcome with TKI frontline therapy. Disclosures: Kantarjian: ARIAD: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

Abstract 1463 Background: Myeloid sarcoma of the orbit and ocular adnexae (OMS) is a rare extramedullary manifestation of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs). Currently there are no standard treatment guidelines for OMS. Methods: On a retrospective review of the medical records, we identified 10 patients (pts) with OMS evaluated at our institution. We explored the pathologic, conventional cytogenetic and molecular cytogenetic features of these pts and analyzed their clinical features, treatments, and outcomes. Results: Among 10 acute leukemia pts with OMS, 6 (60%) were male; the median age of OMS onset was 49 yrs (range, 19 to 79). Morphological review of bone marrow (BM) aspirate smears and core biopsy specimens revealed treatment-related AML (t-AML) (n=4), AML with t(8;21) (q22;q22) (n=2), AML without maturation (n=1), AML with mutated NPM1 (n=1), CML-blast phase (n=1), and myeloperoxidase (MPO)-positive acute leukemia of ambiguous lineage (n=1). Monocytic or myelomonocytic differentiation was noted in 5 pts (50%). Conventional and/or FISH analyses performed on bone marrow in 10 pts demonstrated: +8 (n=3), t(8;21)(q22;q22) (n=2), −7 (n=2), del(7q) (n=2), t(1;3)(q21;q21) (n=1), t(2;11)(q14;q24) (n=1), t(10;11)(p13;q21) (n=1), diploid (n=2), and BCR/ABL1 rearrangement (n=1). Molecular genetic analysis, available in 8 cases, demonstrated NPM1 mutation (n=1) and NRAS mutation (n=1). Ocular symptoms were the first sign of leukemia in 4 pts, 2 with concurrent BM disease. Of the 2 presenting with isolated OMS without BM disease, one developed BM disease 321 days after OMS, while the other remained without BM disease. Six pts developed OMS after the initial leukemia diagnosis: during disease progression before treatment initiation (n=1), during AML treatment of resistant disease (n=1), at relapse with concurrent BM relapse (n=2), or as the site of isolated relapse without concurrent BM involvement (n=2). Clinical manifestations of OMS included: conjunctivitis, iris infiltration, lacrimal gland lesion, episcleritis, orbital mass, periorbital erythema or swelling, ocular secretions, ocular pain, visual problems, and/or retinal infiltrates. The diagnosis of OMS was confirmed by histologic and immunophenotypic analyses of biopsy specimens in the 8 pts from whom tissue could be obtained safely. Of the 2 pts who were not candidates for biopsy, 1 had a conjunctival lesion that involved the lacrimal gland and biopsy-confirmed skin and mediastinal disease. The second pt had intermittent bilateral blurred vision, with fundoscopically-visualized leukemic retinal infiltrates, intraretinal hemorrhages, and cotton wool spots. In both pts the ocular symptoms and lesions resolved with chemotherapy. Treatment modalities included chemotherapy alone (n=3, including 2 who received intrathecal chemotherapy), chemotherapy and surgery (n=5), chemotherapy with focal radiation (XRT) (n=1), and XRT with surgery (n=1). Three pts underwent allogeneic stem cell transplantation (SCT) after OMS diagnosis. In addition to OMS, 7 pts developed extramedullary disease in at least one other site, either concurrently with OMS or at other times during the disease course, including: CSF (n=1), breast (n=1), skin (n=3), lymph node (n=1), lung/mediastinum (n=2), and bone (n=1). Two pts are in CR, 3 and 4 years after OMS diagnosis. Six died either of progressive leukemia or treatment complications. The median time from OMS diagnosis to death was 278 days (range, 39–779 days). Of the 6 pts who died, the OMS either improved or resolved with local or systemic treatment. Two pts have been lost to follow-up, 1 in CR 2 years after OMS diagnosis, and 1 with breast and BM relapse 10 months after OMS diagnosis. Conclusion: OMS may be the initial sign of AML, with or without concurrent BM disease. OMS may also present as an isolated manifestation of relapse, without BM relapse. Extramedullary disease often develops in other sites during the disease course in AML pts with OMS. While OMS symptoms are non-specific, leukemic ocular involvement should be considered and a complete ocular exam is warranted. While t(8,21) is known to occur with extramedullary myeloid sarcoma and OMS, we also identified trisomy 8 in 30% of pts in our series. Disclosures: No relevant conflicts of interest to declare.

Abstract 1456 Background: Cytogenetic analysis of large pt cohorts allows us to evaluate the prognostic impact of rare and unique translocations. Little is known about the clinical outcomes of pts with t(3,5), which generally results in fusion of NPM and MLF1 in pts with MDS and AML. Methods: We retrospectively reviewed the charts of 8,215 pts with a diagnosis of MDS or AML evaluated at our institution from 1985–2011. Results: A total of 17 pts with a t(3,5) either at diagnosis or post-treatment were identified (10 pts, as the sole cytogenetic abnormality, and 7 pts, as part of other/complex karyotype). Among evaluable cases (15/17), frequently occurring breakpoints included q25;q34 (n=4), p21;q15 (n=2), and p21;q13 (n=2).10 pts had MDS with IPSS of Int-1(n=5) and Int-2(n=5), and 7 pts had AML. Four pts had therapy-related MDS (3 pts with prior lymphoma, 1 pt small cell lung cancer) and one pt with MDS had PNH. Median age was 56 years (range, 20–78) at diagnosis. Four pts (24%) had a FLT3-ITD mutation (3 with AML and 1 with MDS), 1 of these FLT3-mutated pts had additional mutations in c-KIT and NRAS mutation, 9 pts were tested and negative for molecular abnormalities, and 4 pts did not have molecular analysis available. Therapies were diverse, with two most common: cytarabine-based regimens (n=6) and hypomethylating agent-based therapy (n=6). Overall, median number of therapies for all pts was 1 (range, 0–5), including 2 pts treated with upfront stem cell transplant (SCT) and 1 pt treated with only growth factors/supportive care. Six pts (35%) (MDS 3 pts, AML 3 pts) underwent SCT during their course of therapy (including 1 cord blood, 1 SCT with NK cells, and 4 allogeneic MUD SCT). Overall median survival for pts with MDS was 8.1 months (range, 1–57) and for pts with AML, 21 months (range, 2–53). CR was achieved overall in 12 pts (71%) with median CR duration of 3.2 months (range, 1–60 months). Three (18%) pts were refractory to all chemotherapy and one pt died during induction chemotherapy (infection and diffuse alveolar hemorrhage). One pt never received treatment. Conclusions: Survival is particularly poor among patients with MDS and t(3;5) while those with AML have survival comparable to normal karyotype (NK) AML. Further investigation with novel treatment approaches is warranted in this subpopulation of MDS/AML pts. Disclosures: No relevant conflicts of interest to declare.

Abstract 1519 Background: The outcome of patients (pts) with acute myeloid leukemia (AML) and FLT3-ITD mutation is poor, particularly in the relapse setting. Sorafenib is a potent inhibitor of FLT3 kinase with reported clinical activity as a single agent (Metzelder S, Blood, 2009), and in combination with chemotherapy (Ravandi F, JCO, 2010). A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) as seen after myelosuppressive chemotherapy. We hypothesized that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may lead to higher and more durable responses than cytotoxic chemotherapy. Furthermore, both drugs have demonstrated a potential for inducing differentiation in AML cells, thereby providing further rationale for the combination. Methods: Pts were eligible if they had relapsed or refractory AML, were 18 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Older pts without prior therapy were also eligible, if they were deemed unsuitable to receive chemotherapy. Presence of FLT3-ITD was not a requirement but these pts were targeted for enrollment. Treatment regimen included AZA 75 mg/m2 daily for 7 days together with sorafenib 400 mg twice daily for 28 days; cycles were repeated in approximately 4 to 5-week intervals. Overall responses were assessed after the completion of at least one cycle of therapy and at the time of the best peripheral blood and bone marrow response. Plasma samples were collected on approximately Day 1 and Day 10 of each cycle. To assess the degree of FLT3 inhibition, the plasma inhibitory activity (PIA) assay was performed using the Molm-14 cell line (Levis M, Blood, 2006). Plasma FL concentrations were measured using an ELISA kit (R&D Systems). Results: 43 pts with AML with a median age of 64 years (range, 24–87) were enrolled. They included 19 (44%) pts with diploid cytogenetics, 11 (26%) with chromosome 5/7 or complex cytogenetic abnormalities, and 13 (30%) with miscellaneous abnormalities. Prior to the initiation of treatment, FLT3-ITD was detected in 40/43 (93%) pts with a median allelic ratio of 0.28 (range, 0 – 0.93). They had received a median of 2 prior treatments (range, 0–7). 16 (37%) pts had received ≥3 prior regimens and 9 had failed therapy with FLT3 kinase inhibitors (5 with AC220, 1 with PKC412, and 6 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 3 had failed 2 prior FLT3 inhibitors. 6 pts were inevaluable as they discontinued therapy before response assessment at one month and 3 are too early for response assessment. The overall CR/CRi/PR rate among the 34 evaluable pts is 44%, including 10 (29%) with CRi and 4 (12%) with CR and 1 (3%) with PR (in this pt, bone marrow blast declined from 51% to 6% with normalization of blood counts). Overall, pts have received a median of 3 (range, 1–9) treatment cycles with the median number of cycles to response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 2.1 months (range, 0.9 – 4.6 months). The median duration of CR/CRi Is 2.3 months (range, 1 – 12.2+ months). Six pts have proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. One pt developed grade 3 cardiomyopathy suspected to be related to the study regimen. Of the 34 pts included in the clinical analysis, there were 22 pts from whom plasma samples spanning at least one cycle of therapy were available. Among them, 64% achieved FLT3 inhibition to a targeted level of less than 15% of baseline during their first cycle of therapy. Median survival in pts who achieved this degree of inhibition was 238 days, while median survival in pts who did not reach this level was 154 days (p=0.13). Mean FL levels at cycle 1, day 1 and cycle 1, day 10 were 9 pg/mL and 17 pg/mL, respectively. Mean FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively. Conclusions: Combination of AZA and Sorafenib is effective for the treatment of older pts and pts with relapsed and refractory AML and FLT3-ITD mutation. While not statistically significant, there was a trend toward improved survival in pts with adequate FLT3 inhibition during cycle 1. FL levels did not rise to the levels seen in pts receiving cytotoxic chemotherapy. Disclosures: Ravandi: Bayer/Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Off-label use of sorafenib and 5-azacytidine in patients with acute myeloid leukemia. Levis:Astellas Pharma: Consultancy; Plexxikon: Consultancy; Symphogen: Consultancy. Garcia-Manero:Celgene: Research Funding. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other. Cortes:Celgene: Research Funding.

24 Background: Outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Elevated FLT3 ligand levels (FL) secondary to cytotoxic chemotherapy is a putative mechanism of resistance to the FLT3 kinase inhibitors. We hypothesized that FL levels will be lower when combining sorafenib with less intensive therapy such as 5-Azacytidine (5-Aza). This study was conducted to evaluate the efficacy and tolerability of the combination of sorafenib and 5-Aza in patients with refractory or relapsed AML with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 IV daily x 7 days and sorafenib 400 mg PO BID continuously; cycles were repeated in approximately one month intervals. Results: 38 patients with AML with a median age of 60 years (range, 24-87) were enrolled. 4 were inevaluable as they never received therapy or discontinued it before response assessment. FLT-3-ITD was detected in 30 (88%) patients. They had received a median of 2 prior treatments (range, 0-6); 13 (38%) had received ≥ 3 prior regimens and 8 had failed prior FLT3 kinase inhibitor. Response rate was 41%, including 6 (17%) with CRi, 4 (12) with CRp, 3 (9%) with CR, and 1(3%) PR. The median time to achieving CR/CRi was 2 cycles (Range, 1-6) and the median duration of CR/CRi was 3 months (Range, 1–12). Conclusions: Combination of 5-Aza and sorafenib is effective for patients with relapsed AML with FLT-3-ITD mutation.

6558 Background: The outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Sorafenib is an inhibitor of FLT-3 kinase activity in nanomolar concentrations. We conducted this phase II study to evaluate the efficacy and tolerability of the combination of Sorafenib and 5-Aza for the treatment of patients with refractory or relapsed AML with the particular emphasis on those with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 daily x 7 together with Sorafenib 200 mg BID X 28 days; cycles were repeated in approximately 1-month intervals. Responses were assessed after first cycle and then at the discretion of the treating physician at the time of the best peripheral blood response. Results: 32 patients with AML with a median age of 61 years (range, 24-87) were enrolled. They included 13 (41%) with diploid cytogenetics, 9 (28%) with complex cytogenetics, and 10 (31%) with miscellaneous chromosomal abnormalities. FLT-3-ITD was detected prior to the initiation of treatment in 30/32 patients. Patients had received a median of 2 prior treatments (range, 1-6). 12 (38%) patients had received ≥3 prior regimens and 11 had failed therapy with a FLT3 kinase inhibitor (6 with AC220, 1 with PKC412, and 5 with sorafenib, either as monotherapy or with plerixafor); 2 had failed 2 prior FLT3 inhibitors. 10 patients were inevaluable as they never received therapy or discontinued it before response assessment at one month. The overall CR/CRi rate among the 22 evaluable patients is 50%, including 9 (41%) with CRi and 2 (9%) with CR; with a median of 3 (range, 1-9) treatment cycles. The median time to achieving CR/CRi was 3 months (range, 1-4) and the median duration of CR/CRi was 3 months (range

Abstract 2749 Background: The long-term outcome of patients with chronic phase chronic myeloid leukemia treated with imatinib after failure of interferon alpha therapy has not been detailed. Patients and Methods: 368 patients were analyzed. Univariate and multivariate analyses for survival were conducted using standard statistical methods. Results: Overall, 247 patients (67%) achieved complete cytogenetic response (CCyR). Of 327 patients studied, 207(63%) achieved major molecular response (MMR), and 99 (30%) had undetectable BCR-ABL levels at some time on therapy. The estimated 10-year survival rate was 68%, progression-free survival rate 67%, and event-free survival rate 51%. By multivariate analysis, age ≥ 60 years, hemoglobin < 10g/dl, marrow basophils ≥ 5%, any peripheral blasts, and clonal evolution were independent adverse factors for survival. The estimated 7-year survival by the presence of none (n=154), 1–2 (n=190), or ≥ 3 factors (n=24) were 93%, 70%, and 25% respectively (p Disclosures: Cortes: Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

Abstract 745FN2 Background: Recent studies have shown that treatment of CML-CP with second generation tyrosine kinase inhibitors (2G-TKI) dasatinib and nilotinib result in a higher rate of CCyR and MMR and these responses are achieved earlier. Whether the same level of response at a given time-point achieved with different treatment modalities has the same implications for long-term outcome is unclear. Aim: To determine whether the early achievement of CCyR or MMR with different treatment modalities has similar long-term prognostic implications among patients with CML CP. Methods: The outcome of 485 patients treated in consecutive or parallel clinical trials of TKI's as initial therapy for CML-CP were analyzed. Patients were treated with imatinib 400mg (IM400) (n=73), imatinib 800mg (IM800) (n=208), nilotinib (n=105), and dasatinib (n=99). Patients were followed uniformly with cytogenetics and PCR every 3 months for the first 12 months, then every 6 months. We reviewed the rates of CCyR and MMR at early time points, and analyzed the probability of long-term event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS) according to the achievement of early responses. We then compared whether such outcome was similar for patients who achieved such response with different treatment modalities. For EFS an event was defined to include any of the following: loss of CCyR, in addition to standard IRIS definition of loss of complete hematologic remission (CHR), loss of major cytogenetic remission (MCyR), progression to accelerated phase (AC) or blast crisis (BC), or death due to any cause on treatment. Results: CCyR at any time was achieved by 94% of patients treated with nilotinib, 96% of those on dasatinib, 87% with IM400 and 91% with IM800. Rates of MMR (as defined by BCR-ABL/ABL ≤0.1% IS) of patients receiving nilotinib was 88%, dasatinib 86%, IM800 87% and IM400 73%. At six months, the rates of CCyR were 91%, 94%, 85%, 53% respectively. Corresponding rates at 12 months were 95%, 96%, 90% and 66%. The rate of MMR at 12 months was 86%, 74%, 81%, and 55%, respectively, and at 18 months 88%, 80%, 83%, and 67%. For patients taking nilotinib 9% had lost CCyR at 36mo, with dasatinib 6%, IM800 5%, and IM 400 13%. The median time to achieve MMR was 6 months for patients treated with nilotinib and dasatanib, compared to 6 months with IM800 and 9 months with IM400. For the total population, those achieving a CCyR at 6 months had a better EFS rate at 24 months (97%) compared to those not achieving this response (79%). Similarly, CCyR at 12 months correlated with a similar benefit in EFS (98% vs 72%). Achievement of CCyR and MMR at 18 months resulted in a 24 month probability of EFS of 98% compared to 87% for those with CCyR but no MMR and 71% for those with no CCyR. We then compared the results by treatment arm. Results are shown in Table 1. At two-year landmark, early achievement of CCyR by 6-mo was associated with higher EFS (but not OS) with all treatment modalities. Achieving MMR by 18 mo was a positive predictor of 24-mo EFS with IM and Dasatinib, but pts with Nilotinib so far had an excellent outcome regardless of 18-mo response. Conclusions: Time to achieving CCyR and MMR with frontline TKI's in CML-CP, reflects similar prognostic implications regardless of the modality of frontline therapy used to achieve it. However, earlier achievement of CCyR with nilotinib or dasatinib results in a higher percentage of patients obtaining the long-term benefit associated with early responses. Disclosures: No relevant conflicts of interest to declare.