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Therapeutic options for chronic myelogenous leukemia (CML) resistant to 400 to 600 mg imatinib are limited. Escalating imatinib doses may overcome resistance. Dasatinib, a significantly more potent inhibitor of BCR-ABL, is safe and effective in this population. Patients with imatinib-resistant chronic-phase (CP) CML were randomized 2:1 to 140 mg dasatinib (n = 101) or 800 mg imatinib (n = 49). With a median follow up of 15 months, complete hematologic responses were observed in 93% and 82% of patients receiving dasatinib and high-dose imatinib (P = .034), respectively. Dasatinib resulted in higher major cytogenetic response rates (52%) than high-dose imatinib (33%) (P = .023); this included complete cytogenetic response in 40% and 16% (P = .004). Major molecular responses were also more frequent with dasatinib (16% versus 4%; P = 0.038). Treatment failure (hazard ratio [HR], 0.16; P < .001) and progression-free survival (HR, 0.14; P < .001) both favored dasatinib. Superficial edema (42% versus 15%) and fluid retention (45% versus 30%) were more prevalent with imatinib; pleural effusion was more common with dasatinib (17% versus 0%). Grade 3 to 4 nonhematologic toxicity was minimal. Cytopenias were more frequent and severe with dasatinib. Dasatinib represents a safe and effective therapy for CP-CML resistant to conventional imatinib doses with improved cytogenetic and molecular response rates and progression-free survival relative to high-dose imatinib.

Background Myeloproliferative diseases (MPD) rarely occur in women of reproductive age. But in recent years it becomes more often that young women suffer from these diseases. The development of new drugs and therapeutic strategies provides good results in survival rate and life prognosis for these patients. All this requires special options for management of pregnancy in women with MPD. Aims To develop the protocol of preconception planning and pregnancy management and to evaluate pregnancy outcomes and complications in women with MPD. Methods We have analyzed 110 pregnancies in 90 women. The prospective group (group 1) included 67 women who were treated according to our algorithm. Retrospectively we have analyzed 43pregnancies in 23 women (group 2) who did not receive a special treatment of MPD during pregnancy. Our trial included women with main MPD: essential thrombocythemia, polycythemia vera, primary myelofibrosis. Pregnancy management included examination of blood cell count and hemostasis system twice a month, besides this the inherited trombophylia testing, lupus anticoagulant, homocystein level, antiphospholipid syndrome diagnostics and hematologic examination including trepanobiopsy and JAK2V617F mutation. Besides thorough laboratory examination our algorithm of pregnancy planning and management included cytoreductive therapy, antiaggregants, low molecular weight heparin, plasmapheresis, vitamins of group B. For the cytoreductive therapy we prescribed Interferon alfa which is the safest option in preconception planning and pregnancy management for women with MPD. Results Termination of pregnancy was made in 2 (3%) women of group 1 and in 3 (6,9%) women of group 2 (OR – 2,44; 95% C.I.: 0,265; 30,109). In the group of women who were treated according to our algorithm 6% of women (4 pregnancies) developed spontaneous abortions. In group 2 without special treatment spontaneous miscarriages occurred in 62,8% in comparison with group 1 (OR – 16,88; 95% C.I.: 4,655; 74,177). First and second trimester spontaneous abortions in group 2 prevailed among all the miscarriages – 15 (34,9%) cases, stillbirth occurred in 12 (27,9%) cases. Preterm labor were in 5 (7,4%) and 6 (14%) pregnancies in 1 and 2 groups respectively (OR – 2,01; 95% C.I.: 0,471; 8,899). Full-term delivery occurred in 83,6% (56 pregnancies) and 16,3% of cases (7 pregnancies) in two groups (OR – 26,18; 95% C.I.: 8,441; 85,448). Complications of pregnancy were analysed in 61 and 13 women in 1 and 2 groups respectively. Pregnancy was uncomplicated in 21 (34,4%) and 2 (15,4%) cases in 1 and 2 groups respectively (OR – 2,89; 95% C.I.: 0,544; 28,852). The most often pregnancy complications were threatening miscarriage - 25 (41%) and 10 (76,9%) cases (OR – 0,21; 95% C.I.: 0,034; 0,937), anemia – 22 (36%) and 4 (30,8%) cases in 1 and 2 groups respectively (OR – 1,27; 95% C.I.: 0,307; 6,289). Although all pregnancies in group 1 were carefully observed and treated 14,8% of them (9 pregnancies) were complicated by placental isufficiency with IUGR in 5 (8,2%) cases. Placental insufficiency complicated 30,8% pregnancies (4 cases) including intrauterine growth retardation (IUGR) in 2 cases in group 2 (OR – 0,95; 95% C.I.: 0,161; 10,263). Conclusion Thus pregnancy losses in women suffering from MPD occur in 62,8% without special treatment and complications of pregnancy – in 84,6% cases. The development of algorithm for preconception planning and pregnancy management resulted in considerable decrease in miscarriages to 6% (P Disclosures: No relevant conflicts of interest to declare.

Abstract 4447 Background: High efficiency of imatinib (IM) in CML therapy has been proven in clinical trials. However, the outcomes of CML treatment by IM in clinical practice are not covered in the literature. Objectives: To evaluate the results of CML treatment by TKI in clinical practice in the Russian Federation. Patients and treatment: The data analysis from 28 administrative regions of theRussian Federation was performed. The selection of regions was based on the quality of the data from CML pts registry. 524 CML pts were included in this study. Inclusion criteria were: Ph/bcr-abl-positive CML diagnosed in 2002– 2006, age of pts ≥ 18 years (y), initiation of IM therapy ≤ 6 months (mo) from the date of diagnosis. Median (Me) age was 47(18 – 81) y, sex ratio (M/F (%)) 250/274 (48/52) pts, Me time from diagnosis to IM treatment was 2.4(0 – 6) mo. Pretreatment: Hydrea 398 (76%) pts; Mielosan 3 (0.5%) pts, chemotherapy 21(4%)pts, IFN-α 30 (5.7%) pts. Me follow-up since the beginning of CML treatment was 55.2 (1 – 108) mo (*6 pts have not data on the date of analysis). In Chronic Phase (CP) were 478 (91.2%) pts, in Accelerated Phase (AP) - 40 (7.6%) pts and in Blast Crisis (BC) - 6 (1.2%). Sokal risk stratification, %: 52 low (L)/22 intermediate (Int)/26 high(H) (78 pts with no baseline data. Statistical analysis was performed using a package SAS9.1.3. Result: 427 (89%) from 478 CP CML pts were alive on May2011, 51(11%) pts were died. In this cohort of CP CML pts 5-year Overall Survival (OS) and Progression Free Survival (PFS) to AP/BC were 89% and 95% respectively (Me 56.4 (1 – 108) mo). The slow achievement of complete hematologic response (CHR) and complete cytogenetic response (CCyR) should be noted. On the IM therapy, 48% pts have achieved CHR by 3 mo only and 86% pts have achieved CHR by 12 mo (Me 3.2 (0.1 – 85) mo); CCyR at any time was achieved in 77% of pts, but by 12 mo – in only 40% of pts (Me 15 mo (0.7 – 75). There was no clear evidence of the dependence of OS rate from % of Ph’-positive cells in bone marrow after 6, 12, 18 and 36 mo were not received (p>0.5 in all cases). Analysis of molecular response (MR) was performed in 338 (70%) pts (not standardized rtPCR method): major MR was achieved in 241 (71%) pts (Me 42 (6–86) mo), complete MR - in 172 (50%) pts (Me 53(6–100) mo). OS by Sokal in pts with L and Int risk groups was identical and better than in pts with H, consistent with 90 and 83%, respectively (p=0.04). The probability of CCyR by Sokal were 85, 80 and 70% for the L, Int and H risk of disease progression, respectively (p=0,0002). IM therapy is still ongoing in 362 (85%) pts in doses 400/600/800mg/day-54%/33%/13%, respectively. 41(10%) pts were switched to 2nd line TKI (25 pts to Nilotinib, 10 pts- Dasatinib, 6 pts-Bosutinib). In total, 51 (11%) pts died (21 pts with progression to AP/BC, 30pts with associated diseases). Conclusion: The research program EUTOS enabled Russian hematologists to cooperate with an international research group (ELN) and this cooperation allows to improve the quality of CML treatment, monitoring MRD and data collection in the Russian CML registry. The analysis of data shows high rates of OS and PFS in CP CML, despite the delay of CHR and CCyR achievement. In clinical practice the low significanse of Sokal risk criteria and the absence of the influence of cytogenetic response achievement on OS was established that differ from clinical trial data and that may be due to a non-standardized approach to treatment and retrospective data collection. Disclosures: Turkina: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Kulikov:Novartis: statistical tasks. Kutsev:Novartis: Research Funding, Speakers Bureau. Golenkov:Novartis: Speakers Bureau. Ivanova:Novartis: Honoraria, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pospelova:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Konstantinova:Novartis: Speakers Bureau. Lazareva:Novartis: Research Funding, Speakers Bureau, work with CML Registry. Khoroshko:Novartis: Speakers Bureau.

Abstract 1683 Introduction. Additional chromosomal abnormalities (ACA) in Ph'-positive (Ph'+) cells firstly described more than 30 years ago were associated with progression of chronic myeloid leukemia (CML) and often were founded in advanced stages of the disease. Prognostic significance of ACA in Ph'+ cells in the era of tyrosine kinase inhibitors (TKI) are not yet fully clarified. The ACA in Ph'-negative (Ph'-) cells seem to have no adverse prognostic impact, but it is not possible to exclude the development of myelodisplasia within the long lasting persistence of such clones. Long-term cytogenetic monitoring can better understand the biological aspects of CML. Aim. To estimate the clinical significance of ACA in Ph'+ and Ph'- cells in CML patients (pts) treated by TKI 1st and 2nd generation (TKI-1 or 2). Materials and methods. The complete peripheral blood count, morphological and cytogenetic examination of bone marrow (BM) cells have been done for 435 CML pts in different disease stages: chronic phase (CP)/accelerated phase (AP)/blast crisis (BC) pts were 336/78/21 respectively. The median (Me) age was 50 years (y) (16–61), Me follow-up- 97 months (mo) (5−265). Results and discussion. The ACA in Ph'+ cells were revealed by conventional cytogenetic study generally in 50 (11,5%) of 435 CML pts. ACA in Ph'+ cells were a rare event for CP and AP: 9% and 14% of pts respectively and more frequent for BC: 43% of pts. The most frequent ACA was the additional Ph'-chromosome (addPh'+) found in 50% of cases. 17pts had addPh'+ alone, while 13pts had also other ACA: trisomy 8 (8 cases), deletion or monosomy 7 (3 cases) and complex abnormalities (2 cases in CP & AP); dominated by male (M: F=23: 7). The duration of IM treatment in 16pts with addPh'+ was from 6mo to 5,5y. The follow-up duration of pts with addPh'+ was from 26 to 176 mo (Me 107 mo). All 16 pts have achieved complete hematological response (CHR) after 3 to 6mo of Imatinib (IM) treatment, but all pts with standard IM doses had primary cytogenetic resistance. Complete cytogenetic response (CCyR) was achieved in 56%pts without ACA, in 24% with ACA, and only in 7% with addPh'+. Due to IM resistance, 14 pts were switched to TKI-2 (Dasatinib – 10pts, Nilotinib – 3pts, Bosutinib – 1pt); 3 of these pts later progressed to AP; for 2 of them T315I mutation was found. All of the 11 pts still in CP have achieved CHR; partial cytogenetic response was founded in 45% and CCyR in 36% cases. At present, 43% pts with ACA died: 11% in CP, 82% in AP and all in BC. The 8-year overall survival (OS) for CML CP pts with ACA was 83%, no statistically significant (p>0,5) difference with the general CML CP pts group, treated by TKI. The assessment by multifactorial Cox model with variable risk factors revealed the increased probability of fatal outcome in CML CP more than 16 times higher in pts with ACA vs. patients without ACA. The variant chromosome abnormalities were rare: 13pts (3 %), but in 77% of them there was cytogenetic resistance pts and high risk of progression. ACA in Ph'- cells were founded in 13 (3%) pts only after the achievement of major cytogenetic response. 10 of them received IM 600–800mg daily; 3pts received 2nd generation of TKI. All those patients got the MCR only after 18–36 mo of treatment and 11 (85%) of 13pts achieved the CCyR. Ph'- clone was constantly founded only in 1 patient, in all other cases it was not constant but persisted from one analyses to other. No myelodisplastic changes were founded in the BM of 5 examined pts after IM treatment within 3–7y. All pts with ACA in Ph'- cells are alive. Conclusion. The durable persistence of Ph'+ cells in CML CP pts is a marker of therapy resistance but not all cases are associated with disease progression. The addPh'+ during IM treatment was associated with cytogenetic resistance. The dose escalation of IM was ineffective in the majority of cases, only TKI-2 therapy could restore Ph'- neg. hematopoiesis and suppressed addPh'+ clone more effectively. This finding should be tested in large-scale studies. The male predominance in pts with addPh'+ also needs further investigation. In contrast to other reported data, we founded that the prognosis for 77% of pts with the variant chromosome abnormalities was poor and associated with cytogenetic resistance and high risk of progression on TKI-1 and 2 therapy. In most pts with ACA in Ph'- cells a dose escalation of IM and switching to TKI-2 was needed but generally the disease prognosis was favorable. Disclosures: Turkina: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Vinogradova:Novartis: Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Chelysheva:Novartis: CML registry, Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Lazareva:Novartis: CML registry, Research Funding, Speakers Bureau. Gusarova:Novartis: Honoraria, Speakers Bureau. Khoroshko:Novartis: Speakers Bureau; Bristol: Speakers Bureau.

Abstract 3789 Background. The treatment of patients with chronic phase (CP) Ph-positive chronic myeloid leukemia (CML) with imatinib has resulted in high rates of cytogenetic and molecular responses. There are evidences that the achievement of CCyR and MMR to imatinib therapy is related with Imatinib plasma level (IPL) in some studies1,2 but not in others 3. This discrepancy may be possibly explained by the heterogeneity in the analysed cohort patients differing with respect to the phase of the disease and imatinib dose. The Aim of our study was to elucidate the trough role of IPL in the achievement of CCyR in homogeneous cohort of CP CML patients. Methods. IPL were detected in 321 CP CML patients with Imatinib treatment duration more than 12 months (the median – 90,3). Imatinib doses was 400 mg QD. The age of patients was 54,6 (24–76). Male/female ratio was 157/164. All patients gave informed consent before blood sampling. Blood samples were collected in 21–27h after the last Imatinib dose intake. Imatinib concentrations (C trough) were determined by validated LC/MS/MS method. Results. The patients were subdivided in 4 quartiles (Q): Q1 (n=81) with IPL 0 – 670 ng/ml, Q2 (n=80) with IPL 671 – 1042ng/ml, Q3 (n=80) with IPL 1043 – 1362ng/ml, Q4 (n=80) with IPL 1363 – 3826/ml. The results of imatinib treatment in each quartile were estimated according ELN recommendation. The obtained findings have shown that 48,1% CP CML patients in Q1 have achieved CCyR whereas 77,5%, 81,3% and 85% - in Q2,Q3 and Q4 respectively (Fig.1.). Conclusion. Our findings show that the achievement of CCyR in large cohort of CP CML patients (n=321) on imatinib with 400 mg/QD depends on IPL. The low level of IPL may indicate the nonadherence of some CML patients as well as some intrinsic mechanisms of imatinib plasma concentration decrease. Disclosures: Kutsev: Novartis: Research Funding, Speakers Bureau. Pospelova:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Khoroshko:Novartis: Speakers Bureau.

Dasatinib (SPRYCEL®) is the most potent BCR-ABL inhibitor and is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Previous studies have demonstrated the efficacy and safety of dasatinib 70 mg BID for patients with CML-AP who are intolerant or resistant to imatinib. In the phase III CA180-035 study, patients with CML-AP, blast phase CML, or Ph+ ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary trial objective was to compare major hematologic response (MaHR) rates between the two schedules. Secondary objectives included a comparison of major cytogenetic response (MCyR) rates, time to and duration of responses, progression-free survival (PFS), overall survival (OS), and safety profiles between the two schedules. Previous analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, 2-year results from the subgroup with CML-AP (n=317) recruited from 97 international sites are reported. Among patients randomized to QD (n=158) or BID (n=159) treatment with dasatinib, rates of MaHR and MCyR were similar (MaHR: 66% vs 68%; MCyR: 39% vs 43%, respectively; Table). Excluding patients that were BCR-ABL positive, Ph negative (n=3), rates of MCyR were nearly identical. Most MaHRs were achieved within 4 months of therapy and most MCyRs were achieved within 6 months. Based on Kaplan-Meier analyses, an estimated 65% vs 60% of patients had maintained a durable MaHR in QD and BID groups, respectively, at 24 months. Estimated PFS rates were 51% vs 55% and OS rates were 63% vs 72%, respectively. Although dasatinib was generally well tolerated with both dose schedules, QD treatment was associated with an improved safety profile compared with BID treatment. Only small increases in AE rates were observed compared with 1-year data. Cytopenias were the most common AEs and for QD vs BID treatment, rates of grade 3/4 events were 59% vs 69% for neutropenia and 64% vs 67% for thrombocytopenia. Fewer drug-related fluid retention events (including pleural effusion, superficial edema, and peripheral edema) were reported in the QD (34%) vs BID (48%) group. In particular, significantly fewer patients experienced a pleural effusion with QD vs BID treatment (p