ALBERT

Description: Imatinib (IM) at 400 mg daily is the first line therapy for newly diagnosed CML patients (pts); however, less than 50% of major molecular responses (MMR) are obtained at 12 months. To improve these results, we designed a phase III, multicenter, open-label, prospective randomized trial. The reference arm was IM 400 mg daily (n=159). The 3 experimental arms were IM 600 mg daily (n=160), IM 400mg daily in combination with Ara-C, (20 mg/m2/day, days 15–28 of 28-day cycles)(n=158) and IM 400mg in combination with Peg-IFN alfa-2a (Peg-IFN2a, 90 μg weekly) (n=159). Treatment was delivered at least 12 months or until treatment failure (disease progression) or major toxicity. The primary endpoint is the overall survival. Other endpoints are: rate and duration of hematologic and cytogenetic responses, major (MCyR) and complete (CCyR), molecular response (major molecular response ie MMR) and the tolerability. Using treatment allocation ratio 1.1.1.1, randomization was stratified according to Sokal risk groups. The current interim analysis of the first 636 patients (α=0.85%, β=10%) at 1 year from randomization was planned in order to select the best experimental arm for further comparison with IM 400. The increased dose of IM or a combination regimen would be considered as promising if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability. Evaluation of molecular response up to 12 months was centralized, blinded and calculated according to International score (IS). Pts were recruited between 9/2003 and 10/2007.[median age 51 yrs (18–82), 62% of pts were male; Sokal distribution was low risk 33%, intermediate risk 41% and 27% high risk]. Median follow-up is 36 months (range 8–57) at the time of analysis. Overall, at 3 months 86 % of pts achieved complete hematologic response. The MCyR, CCyR and MMR rates at 6 and 12 months are: IM-400 IM-600 IM-Ara-c IM-PegIFN *p〈 10−2 (overall); ** p

Description: In chronic phase-chronic myeloid leukemia (CP-CML), a complete cytogenetic response (CCR) along with a major molecular response (MMR) on imatinib mesylate (IM) at 400mg/d represents a strong factor predicting survival. Suboptimal cytogenetic responders (minimal or minor CR (mCR) by 6 months or partial CR (pCR) by 12 months, ELN) have a probability of further achievement of CCR of only 50%. Suboptimal molecular responders (CCR without MMR by 18 months, ELN) have a decreased probability of remaining event-free survivors when compared to optimal responders. Since non-randomized trials suggest that high-dose IM at CML diagnosis produces high rates of optimal responses, dose escalation can be recommended for suboptimal responders to standard dose of IM, but this strategy has not been yet evaluated. Here, we present the results from a series of 24 CP-CML patients who experienced IM-dose escalation for cytogenetic or molecular suboptimal response to standard doses of IM. Suboptimal cytogenetic responders (n=10) included 9 males, median age was 51.3 years-old (27.7–64.2), all were in early CP. Sokal scores were low (n=5), int (n=2), high (n=2) and unknown (n=1). All patients were treated with IM frontline at 400mg/d (n=9) or 600mg/d (n=1) and 2 received PEGIFN associated with IM at 400mg/d (withdrawn after 3 months for intolerance in 1). Prior to dose escalation, 7 patients were in pCR at 12 months and 3 in mCR at 6 months. The search for BCR-ABL mutations was negative in 6 patients tested. IM was increased to 600mg/d (n=7) or 800mg/d (n=3) after a median time of 13.7 months (5.6–15.2) on initial IM treatment. Median follow-up from IM at standard and escalated doses were respectively 28 (16.1–79.1) and 14.9 months (2.2–73.5). Of 9 patients with cytogenetic evaluation, 100% obtained CCR after a median duration of high-dose IM of 6.2 months (2.4–12.6). Five patients (50%) achieved a MMR after a median duration of high-dose IM of 9.7 months (2.9–45). Only one patient treated with PEGIFN and IM increased to 600mg/d obtained a complete molecular response (CMR) 19.9 months after high-dose IM. Suboptimal molecular responders (n=14) included 11 males, median age was 38.2 years-old (20.9–63.2), 9 were in early CP and 5 in late CP. Six had previously received IFN for a median of 4 months (4–53). Sokal scores were low (n=5), int (n=5), high (n=3) and unknown (n=1). All patients had received IM at 400mg/d, for a median duration of 27.3 months (16.7–73.3). BCR-ABL mutations were detected in 2/8 patients tested (M244V and Q252R). IM was increased to 600mg/d (n=13) or to 800mg/d (n=1). Median BCR-ABL prior to dose increase was 0.79% (0.15–3.06). Median follow-up from standard and escalated doses of IM were respectively 45.2 (26.9–85.9) and 12.5 months (3.3–38.1). Six patients (43%) obtained a MMR after a median of 6.7 months (2–25.4) of high-dose IM, including 1 with the M244V mutation. None achieved a CMR. To conclude, IM-dose escalation is beneficial to suboptimal cytogenetic responders with a rate of achievement of CCR and MMR of respectively 100 and 50%. Regarding molecular suboptimal responders, the rate of MMR after dose increase in only 43% and other strategies should be considered.

Description: Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.

Description: Abstract 3410 The ABL T315I mutation confers resistance to all approved tyrosine kinase inhibitors (TKIs) for the treatment of CML and Ph1+ ALL. The survival of patients harboring a T315I mutation, associated or not with other factors, is dependent on disease phase at the time of mutation detection. In vitro, in cell lines, this mutation alters kinase function and phosphorylation activity that increases oncogenicity (Skaggs et al., PNAS 2006). Using a matched-pair analysis, we aim to confirm whether or not these in vitro findings correlate into the clinic and provide higher rates of progression and poorer outcome specifically among CML patients remaining in chronic phase (CP) at T315I detection. A cohort of CP CML patients at T315I detection were identified from a database of an earlier epidemiologic study (Gr 1) was compared to a single-center, matched cohort of CML patients resistant to imatinib (IM), in CP, but not harboring the T315I mutation (Gr 2). All patients had had IM. These patients were matched on the 3 following variables: i) age at diagnosis, ii) time from diagnosis to IM initiation, iii) IM duration. The general characteristics of the 2 groups are displayed in table 1. Univariate analysis demonstrated that patients were equivalent for all factors except for the intervals from diagnosis to IM resistance and from diagnosis to TKI2 initiation that were significantly longer in Gr 1. Sixty-two percent of the patients in Gr 1 and 100% in Gr 2 took a TKI2. The duration of treatment with a 1st TKI2 was significantly longer in Gr 2, as a significant proportion of IM-resistant patients might respond to these agents. The cumulative incidence of switches for TKI2 was similar between the 2 groups (p=0.33). In a multivariate analysis the presence of the T315I mutation had a highly significant negative impact on overall survival (OS) from any time-point (HR since IM resistance=21.6, [5.4-87.3], p

Description: BACKGROUND: Few therapeutic options are currently available for patients (pts) with severe aplastic anemia (SAA) refractory to antithymocyte globulin (ATG) plus ciclosporine (CsA) and not eligible for allogeneic stem cell transplantation. It has recently been reported that eltrombopag (ELT), a TPO receptor agonist, is efficient to improve tri-lineage blood counts in this setting. However, real-life use of this drug is still largely unknown. In pts with SAA refractory to ATG, physicians can accede to ELT in France through a compassionate use program. We took advantage of this program to assess the efficacy and safety of ELT in SAA pts. PATIENTS AND METHODS: The French National Reference Center for Aplastic Anemia conducted this study in pts who received ELT for the treatment of SAA. Latest guidelines were used to define disease severity, treatment indication, and response rates (Marsh et al, BJH 2014). The diagnosis of SAA was confirmed by marrow biopsy and Camita criteria for all pts. Pts were eligible if they received at least 2 months of ELT alone or in combination with other treatment in case of relapsed/refractory disease or front-line therapy for pts not eligible to the association of ATG and CsA. Pts were identified through a national e-mailing on behalf of the French reference center for SAA and the French Society of Hematology. All data presented here were collected at the reference date of June 26th, 2016. The study was conducted according to Helsinki's Declaration. RESULTS: Forty-six pts (male, 54%) who received ELT between July 2012 and February 2016 were identified in 17 French centers. Indications for ELT were relapsed/refractory SAA in 35 pts (76%) after 1 (49%), 2 (29%) or 3 (9%) courses of CsA+ATG. Eleven pts considered unfit for ATG also received the drug as first line therapy. The characteristics of the pts according to ELT indications are shown in Table 1. Median age at time of ELT initiation was 61 years [IQR 40 to 70]. 44 pts had idiopathic SAA including 17 (37%) with a detectable PNH clone (median size 7%). Two pts (4%) with dyskeratosis congenita also received ELT. ELT was introduced 17 months [8-50] after the initial diagnosis of SAA and with a median of 6 months [3-14] after the last course of immunosuppressive therapy. The maximal dose was 150 mg/day [100-150] for a median duration time of 6 months [4-12]. At last follow-up 22(48%) pts were still on treatment, 4(9%) pts stopped because of good hematological response, 1(2%) and 15(33%) after limited toxicity and failure to improve hematological status. Before treatment, median neutrophils count was 790/mm3 [500-1215] and pts received a median number of 4 red blood cells packs [2-4] and 3 platelets apheresis units [2-4] every month. Neutrophils counts were 765 [515-1475], 1100 [600-1800], 1200 [670-1915] and 1200/mm3 [757-2300] at 1, 3, 6 months and at last follow-up respectively. The rates of transfusion independence for both red cells and platelets were 7%, 33%, 46% and 46% at 1, 3, 6 months and at last follow-up. In pts achieving transfusion independence, hemoglobin and platelets level improved of 3 gr/dL [1.4, 4.5] and 42 G/L [11, 100], respectively. The rate of transfusion independence was not different among first line and refractory pts (p=0,5). We did not observe any response in the 2 patients with dyskeratosis congenita. No factor associated with hematological response to ELT was identified. Liver toxicity (cytolysis) occurred in 11 pts (1 grade 3 that required withdrawal of the treatment and 10 grade 1 who responded to dose reduction). 2 pts had a grade 2 intestinal toxicity which improved after dose reduction. Other side effects where related to SAA (28% infections, 13% hemorrhages). Bone marrow karyotype analysis after ELT was done in twelve pts (26%) (median time 14 months [5-22] after ELT start). In 10 pts the karyotype was normal, in one, trisomy 8 was identified (already seen at SAA diagnosis), and karyotype was a failure in 1 pt. CONCLUSION: We report here the first real-life multicenter study about the use of ELT in SAA. In a particular severe pts population with no other treatment possibility, we confirm a 40% rate of hematological improvement with transfusion independence. Some of the pts who were not eligible to ATG plus CsA (comorbidities) also received ELT first line with similar response rates. Elderly pts unfit for ATG may thus benefit from this treatment which at the best should be given through prospective clinical trials. Table 1 Table 1. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terriou:Novartis: Consultancy; amgen: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Description: Most CML patients are sensitive to Imatinib Mesylate (IM), however, a small fraction develop resistance, mostly through the onset of BCR-ABL mutations. More than 30 mutations have been described, mostly in advanced phase, and confer different levels of clinical resistance. In this setting, clinical trials with 2nd generation tyrosine kinase inhibitors (TKI) provide encouraging results, however neither in vitro nor clinical activity has been demonstrated when the most frequent BCR-ABL mutation, T315I, has been identified. In this retrospective study from 5 French centers, we analysed the features and clinical outcomes of 27 CML patients treated with IM and presenting either clinical, cytological, cytogenetic resistance or molecular progression, and harboring a BCR-ABLT315I mutation detected by direct sequencing (same method in the 5 different laboratories, quality control exchanges). The 27 patients were in chronic phase (CP) at diagnosis, with 17 M and 10 F with a median age at diagnosis of 52 (25–70). Sokal scores were high for 8 pts, intermediate for 6 pts, low for 3 pts and unknown for 8, 2 were in blast crisis (BC) at CML diagnosis. Transcripts were M-BCR for 22 patients and m-BCR for 2 patients and unknown for 3 pts. At diagnosis 4 pts had additional chromosomal abnormalities as a variant Ph1 chromosome, a -7, a -Y, and an additional t(3;7;12) to the Ph1. Progression has been defined as a 2-fold rise in BCR-ABL transcripts levels, loss of any previous response to IM, and a transition towards a more advanced phase of the disease. At T315I discovery, 11 pts were in CP, 4 in accelerated phase, and a majority in BC [7 in myeloid and 5 in lymphoid]. The median interval between diagnosis and IM was 20 Mo. (0–145.2). The median initial dose of IM was 464 mg/day. Most of the patients were poor responders to IM of which 12 pts that obtained no more than a CHR, 2 pts a PCyR, 7 pts a CcyR, 2 pts a MMR, 1 pt no response, and 3 unknown. Twenty-one pts harboured a T315I alone, 1 a T315I with a Y253H, 2 with a M351T, 1 with a E255K+E255V, 1 with a L324Q, and 1 with a F311L, with no impact on survival. The median time for progression from day 1 IM was short [13 Mo. (0–49.6)] regardless of the phase of the disease at T315I identification, and the median interval IM start-T315I identification was 20 Mo. (0–57.6). Median overall survival from D1 of IM was 17.5 Mo. for advanced phases and 42.5 Mo. for CP (p=0.08). All patients progressed with no difference for time to progression between phases (p〉0.05). Figure Figure Neither additional mutations (p=0.91), nor additional chromosomal abnormalities (p=0.11), nor Dasatinib treatment (p=0.15) modified overall survival. In conclusion, the onset of BCR-ABLT315I mutations occurs preferentially in high-risk CML, seems more frequent in advanced phases, and is always responsible for progression and poor survival, underlying the need for alternative treatments, in patients lacking a histocompatible donor.

Description: Background: Myelofibrosis (MF) is the less frequent Philadelphia-negative myeloproliferative neoplasms (MPN). We have included in a nationwide database primary (P), post-polycythemia (PPV) and post-essential thrombocythemia (PET) MF diagnosed in France since 2005. Methods: Inclusion criteria were: diagnostic of MF after 2005; according strictly to WHO (bone marrow biopsy mandatory); informed consent. The registry was launched in Oct. 2013, and 26 hematology centers included patients (pts). Summary statistics were reported, namely median [Interquartile range, IQR] or percentage. Baseline characteristics were compared across IPSS groups using chi-square test or Mann and Whitney test. Kaplan-Meier survival curves were plotted and compared by the log-rank test. Results: At time of analysis (June 2016) a total of 527 pts were included in the registry, complete baseline data were available in 499 (95%), and follow-up (FU) data in 433 (87%). Median [IQR] age and M/F sex ratio were 71 [63-78] years and 315/184 (1.7), respectively (resp). 301 (60%) pts had PMF, 182 (36%) had secondary MF (including 64 PPVMF and 118 PETMF) and 16 had pre-fibrotic MF. Five percent of pts had a familial history of hematologic malignancy, and 22% a history of thrombosis or hemorrhage. Splenomegaly was present in 386 (77%) with a median [IQR] spleen size of 4 cm [1-8] below costal margin, and was symptomatic in 11% of pts. Constitutional symptoms were present in 107 (21%) (weight loss in 56, night sweats in 61, fever in 14), and ECOG score was 0, 1, 2, and 3 in 53%, 36%, 11% and 0.3% of pts, resp. Median [IQR] Hemoglobin, WBC and platelet counts were 109 g/L [94-122], 9.3 G/L [5.7-16.0] and 257 G/L [138-430], resp. Circulating blast cells were present in 41%, LDH was above normal value in 95% of pts, median EPO level was 54 [11 - 57] U/L. Grade of fibrosis (WHO) was 1, 2, and 3 in 2%, 66% and 32% of pts, resp. Karyotype was done in 321 pts, normal in 173 (54%), abnormal with favorable prognostic value in 89 (30%) and unfavorable in 30 (10%) (29 failures). A total of 461 (92%) pts had molecular testing: 60% were JAK2V617F positive, 4% had MPL and 7% had CALR mutations, and 99 (28%) over the 352 pts with triple testing were triple negative. IPSS risk categories were low, int-1, int-2 and high in 68 (14%), 168 (34%), 158 (32%), and 105 (21%) pts, resp. In addition to constitutional symptoms, there was a significant increase in the prevalence of clinical signs across IPSS categories (from low to high risk): symptomatic spleen (p=0.016) -though no difference in spleen size was found (p=0.18)-, early satiety (p=0.013), ECOG score (p= 0.0001), bone pain (p=0.002). Moreover, among biological parameters, there was an increase across IPSS groups in WBC (p=0.029), LDH (p=0.0007), ferritin (p=0.003), circulating CD34+ cells (p=0.020), EPO level (p=0.035). In contrast, a decrease was seen for hemoglobin and platelets (p=0.0001 for both). Lastly, frequency of grade 3 fibrosis increased with IPSS (p=0.043), while no evidence of difference was found regarding abnormal karyotype and mutational pattern. Median FU was 33 months [9-63 months]. Among those 433 pts with FU data, median FU was 38 months [19-68], and 124 (29 %) pts had died at the time of analysis, including 13%, 17%, 31%, and 40% of pts from the Low, Int-1, Int-2, and High risk groups, resp (p= 0.0001, figure 1). In the 450 pts with treatment data, treatments received during FU included cytoreductive drug (41%), Jak-inhibitors (35%), Interferon alpha (18%), IMIDs (4%). Splenectomy was performed in only 14 (3%) pts. Forty percent of pts received packed red blood cells, and 12% platelets transfusions. 49 (11%) patients participated in a clinical trial, and 27 (6%) were allografted. Conclusion: This is the first analysis of the French MF observatory after inclusion of more than 500 pts diagnosed and treated during the past 10 years. Complete baseline data and follow-up information available for the majority of pts should allow for new studies of outcomes and influence of clinical and biological parameters, as well as reassessment of prognostic models in the era of new targeted therapies. Figure 1 Comparison of overall survival according to IPPS Figure 1. Comparison of overall survival according to IPPS Figure 2 Figure 2. Disclosures Etienne: Pfizer: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Tavitian:Novartis: Membership on an entity's Board of Directors or advisory committees. Ugo:Novartis: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Imatinib (IM) at 400 mg daily has emerged as the preferred therapy for newly diagnosed CML pts. Despite impressive results, only a minority of pts treated with IM achieved a molecular remission. To improve upon these results, the CML French Group designed a phase III, multicentre, open-label, prospective randomized trial. The experimental arms are IM 400mg daily in combination with Peg-IFN-α2a (Peg-IFNα2a, 90 μg weekly) or IM 400mg daily in combination with Ara-C, (20 mg/m2/day, days 15–28 of 28-day cycles) or IM 600mg daily. The reference arm is IM 400mg daily. All pts (over 18 years of age with Bcr-Abl positive CML in chronic phase within 3 months of diagnosis) receive IM 400 mg/day as monotherapy days 1–14 and then start the assigned randomized regimen. Treatment continues at least 12 months or until treatment failure (disease progression by hematologic criteria) or major toxicity. The primary endpoint will be the overall survival. Other endpoints will be: rate and duration of hematologic and cytogenetic responses, major (MCyR) and complete (CCyR), molecular response and the tolerability. Using treatment allocation ratio 1.1.1.1, randomization is stratified according to Sokal risk groups. An interim analysis of the first 636 patients (α=0.85%, β=10%) at 1 year from randomization will allow evaluation of molecular response rates, one of the experimental arm being selected for further comparison with IM 400. The increased dose of IM or a combination regimen would be considered as promising if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability. Evaluation of molecular response up to 12 months is centralized and blinded. This evaluation is based on a cohort of 315 pts with a median time of observation of 12 months, recruited between 9/2003 and 6/2005.[median age 53 yrs (18–78), 60% of pts were male; Sokal risk distribution: 39% of pts low risk, 38% intermediate risk, and 23% high risk]. At 3 months 82% of pts achieved complete hematologic response. Cytogenetic data are available from 154 pts. At 6 months, 135 pts (87%) achieved a MCyR, being complete in 105 pts (68%). Grade 3/4 neutropenia and thrombocytopenia occurred in 5% and 0% of IM400 pts, in 5% and 1% of IM600 pts, in 30% and 4% of IM+IFN pts and in 24% and 13% of IM+Ara-c pts respectively. Dose of Peg IFN was reduced in 16% of pts, 45 μg per week being well tolerated. Grade 3/4 non hematological toxicity occurred in 6% of IM400 pts (mainly skin rash and muscle cramps), in 10% of IM600 pts, in 5% of IM+IFN pts (maily skin rash) and in 13% of IM+Ara-c pts (mainly diarrhea). Discontinuation of experimental treatment occurred in 15% of IM600 pts, 28% of IM+IFN pts and in 13% of IM+Ara-c pts. This first analysis of a randomized trial has proven feasibility of IM combinations in addition to high response rates. However a substantial hematological toxicity was recorded with IFN or Ara-c combination, which requires a careful assessment during the first 6 months of treatment. Long-term observation will demonstrate whether these promising results will have the potential to improve survival of CML pts.

Description: This prospective phase II trial (Nov 2011- Dec 2012), supported by the LYSA group, aimed to evaluate the impact on PFS of the RiBVD regimen in newly diagnosed, previously untreated, elderly MCL patients (〉65 years or not eligible for ASCT) (NCT01457144). Inclusion criteria were: WHO 2008 MCL not previously treated, CD20 positive, ECOG 0-2, AA stage II-IV, no CNS involvement or active HBV/HCV/HIV infection. Patients were scheduled to receive a total of 6 cycles of the RiBVD regimen, if they responded (IWG criteria) after 4 cycles. The regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1 and 2, Dexamethasone 40 mg/m² IV on D2 and bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with acyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Herein we present preliminary analysis of the trial after 4 RiBVD cycles. Results: A total of 76 patients were included, one was excluded because of HBV active disease and 5 had insufficient data reported in the database. To date we analyzed 70 patients. Patients characteristics: sex ratio M/F 49/21, median age 72 years (y) [64-83] (2 patients were 64 y old), AAstage II/III-IV 5/65, ECOG 0-1/2 59/11, MIPI score low/intermediate/high 3/19/48. Response: 61 responded (ORR=87%), with 19 in PR (26%) and 42 in CR/CRu (60%). Four patients died from pneumonia (n=1), cardiac arrest (n=2) and one following Progressive Multifocal Leukoencephalopathy. Three patients have progressed after 3 cycles. Sixty one patients were analysed by PETscan after 4 cycles, 39 (64%) reached a CR (30 were in CR/CRu and 9 in PR) and 22 remained PET positive (11 patients were in CR/CRu, 10 in PR and 1 stable). RiBVD cycles: 271 cycles were administered out of 280 planned (97%). Twenty four (9%) were delayed, 10 for toxicity. All but one planned Bendamustine doses (n=542) were administered with dosing modified 17 times (3%), mostly for hematological toxicity (n=14). Regarding Bortezomib, 79% (1028/1084) of planned doses were administered, it was prematurely stopped (56, 4%) for neurotoxicity (10 instances) or hematological side effects (46). Rituximab was not administered in 4 instances. Hematologic toxicities: Over the 271 cycles administered, neutropenia was reported in 104 cycles [56 grade 3/4 (g3/4) (21%)], 2.5% with fever; thrombopenia in 181 cycles [41 g3/4 (15%)]; anemia in 210 cycles, [6 g3/4 (2%)]. Non-hematologic toxicities:Reported in 〉10% of the cycles were : allergic reactions (10.3%, g3/4

Description: Abstract 644 Background: Omacetaxine is a first-in-class cetaxine with clinical activity against Ph+ CML and a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML patients (Pts) who harbor the Bcr-Abl T315I mutation. Study Goals: To evaluate the safety and efficacy of subcutaneously (SC) administered omacetaxine in Pts with imatinib (IM)-resistant T315I+ Ph+ CML. Methods: Eligible Pts include adult CML Pts in chronic, accelerated, or blast disease phase (CP, AP, BP) with a confirmed Bcr-Abl T315I mutation and resistance to IM therapy. Induction schedule: 1.25 mg/m2 SC omacetaxine twice daily for 14 days every 28 days until hematologic response. Maintenance dosing: 1.25 mg/m2 SC omacetaxine twice daily for 7 days every 28 days. Study Results: To date, 90 Pts have been enrolled, with data available for analysis on 66 Pts (40 CP, 16 AP and 10 BP). The median age was 58 yrs (19-83) with 70% male Pts and a median disease duration of 54 mo (5-285). All Pts failed prior IM therapy, and 79% failed two or more prior TKIs. The presence of baseline T315I mutation was confirmed in all Pts. Baseline clonal evolution was evident in 10 (25%) CP, 6 (38%) AP, and 7 (70%) BP Pts. Eight CP Pts entered the study in CHR. The median follow-up for all Pts was 6.4 mo (0.2 to 29.6). Efficacy: In CP Pts, CHR was achieved in 26 Pts and maintained in 8 Pts for an overall CHR rate of 85%; the median duration of CHR was 7.7+ mo (1.7 to 23.6). Overall cytogenetic response was 27.5% with 6 (15%) Pts achieving a major cytogenetic response (MCyR, 4 complete, 2 partial). The median duration of MCyR was 6+ mo (0.8 to 16.1). Major molecular response was achieved in 15% of Pts and a reduction of baseline T315I mutated clone occurred in 56.7% of CP Pts. In AP Pts, overall hematologic response was achieved in 6 (37.5%) Pts with 5 CHR and 1 return to chronic phase (RCP). Median duration of response was 3.9+ mo (1.7 to 14.8). One AP Pt achieved a complete cytogenetic response; duration 1.9+ mo. In BP Pts, overall hematologic response was achieved in 3 (30%) Pts with 2 CHR and 1 RCP. The median overall survival for CP Pts has not been reached and 35 (88%) Pts were alive at the time of data cut- off. The median overall survival was 18.8 mo for AP and 1.8 mo for BP Pts. Median time to progression was 11.2, 3.1, and 1.2 mo for CP, AP, and BP Pts, respectively. Safety: Grade 3/4 related events occurred in 45 of 66 (68%) Pts. The most commonly reported events were thrombocytopenia (58%), anemia (36%) and neutropenia (33%). Non-hematologic toxicities were primarily grade 1/2 with the most frequently reported events of diarrhea (44%), fatigue (35%), pyrexia (32%), nausea (26%), and asthenia (21%). Grade 3/4 non-hematologic toxicities were uncommon with no events occurring in 〉5% of Pts and infection (3%) the most common event. Treatment delays occurred in approximately 50% of the Pts with median duration of approximately 12 days for all disease phases and cycles (CP=12, AP=10, and BP=12 days). The primary causes of delay were thrombocytopenia, neutropenia and pancytopenia. Sixteen deaths occurred during the study (5 CP, 4 AP, and 7 BP).Three deaths (1 CP, 1 AP, and 1 BP) were considered to have a possible relationship to omacetaxine: sepsis, pancytopenia, and sudden death with unknown cause, respectively. Conclusions: Omacetaxine administered by subcutaneous injection produces durable hematologic and cytogenetic responses with a safety profile consisting mainly of hematologic toxicities. Omacetaxine may provide a treatment option for this patient population who currently has no available approved drug therapies. Disclosures: Cortes-Franco: ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoury:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicolini:ChemGenex: Research Funding. Corm:ChemGenex: Research Funding. Lipton:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jones:ChemGenex: Research Funding. Hochhaus:ChemGenex: Research Funding. Craig:ChemGenex: Employment. Benichou:ChemGenex: Employment. Humphriss:ChemGenex: Employment. Kantarjian:ChemGenex: Membership on an entity's Board of Directors or advisory committees, Research Funding.