ALBERT

Description: Coagulation factor V acts as the cofactor of activated factor X of prothrombinase complex is composed of six domains which are A1, A2, B, A3, C1, C2 arranged from N to C-terminal. Crystalography of C2 domain has been reported along with its three spike-like structures at the base which are important for interaction with phospholipids. But the functional importance of C1 domain which closely resembles C2 domain largely remains unidentified. We have experienced a family with hereditary factor V deficiency whose proband was a compound heterozygote of in-frame deletion located to domain C1 and truncating mutation of domain B. The proband was 25 year old male who suffered from bleeding after tooth extraction. Prothrombin time and activated partial thromboplastin time were both prolonged (35.7 sec, 111.7 sec respectively), and coagulation factor activities were all normal except for factor V which was 4%. The factor V antigen level measured by ELISA method was 3%. We sought for mutations of factor V gene by PCR direct sequencing targeting whole coding region. A truncating mutation (3481C〉T, R1133X) was found in exon 13, where most of the other mutations have been reported. It has already been reported by Van Wijk et al. in 2001. The same mutation was found in his twin brother (factor V activity 5%) but in only one of two sisters exhibiting partial deficiency (factor V activity, 45% and 50% and antigen level, 25% and 37% each). In addition In-frame deletion (nt 6026 del 6 bp, corresponding to deletion of N1982, S1983) in C1 domain was also found in the proband and also in his twin brother and one sister who has not R1133X explaining the partial deficiency in two sisters each possessing different mutations. The putative structural and functional importance of N1982, S1983 was sought by examining protein model based on the crystal structure of bovine factor Va that is inactivated by protein C. N1982, S1983 are located on a loop region that is exposed on surface of domain C1 and have close contact with another loop in A3 domain. This model suggests the possibility that N1982 and S 1983 contribute to maintaining the stable conformation attributable to hydrogen bond formation between K1980 and N1986 of domain C1 with D1604 of domain A3. Mutations implicated in hereditary factor V deficiency involving domains other than A or B are mostly located in or affect the integrity of C2 domain. To the best of our knowledge only five mutations involving C1 domain have been reported till now. Four were truncating mutations and splicing error resulting in gross abnormality in protein structure. One missense mutation in this domain was reported to be subject to increased intracellular degradation. R1985A near to N1982 and A1983 also caused decreased factor V level in scanning mutagenesis study. The novel in-frame deletion can also be susceptible to accelerated degradation. And the in-frame deletion in our patient may also result in unstable factor 5 structure which enhances intracellular degradation. But the possibility of functional defect including decreased phospholipid binding or attenuated cofactor function due to incorrect positioning of domain A3 relative to domain C1, cannot be ruled out and should be further investigated.

Description: Abstract 2229 Poster Board II-206 To determine whether serum B-cell activating factor (BAFF) levels that were previously found to be elevated in patients with chronic graft-versus-host disease (GVHD), and C-reactive protein (CRP) levels known as a predictor for aGVHD as well as a marker for systemic inflammation during the peri-allogeneic stem cell transplantation (SCT) period, could be used to predict the occurrence of acute GVHD (aGVHD), 45 consecutive patients who had undergone myeloablative allogeneic SCT for hematologic malignancies were assessed. Serum BAFF and CRP levels were measured using ELISA (R&D Systems, Minneapolis, MN, USA) before conditioning and on day 0, day +7, and day +14 after transplant. Thirty-three of 45 patients (cumulative incidence, 73=) developed aGVHD between 16 days and 98 days after transplant. Analyses using repeated measures of ANOVA revealed that the serum BAFF levels were significantly lower in patients with aGVHD than in those without aGVHD (P=0.001), whereas no association was detected between CRP levels and aGVHD (P=0.508). Receiver operating characteristic curve (ROC) analysis showed that serum BAFF levels at every time point were available for the prediction of development of aGVHD (pre-conditioning; P=0.005, day 0; P=0.002, day +7; P=0.004, and day +14; P=0.005). Using ROC curve analysis, the identical cutoff value of 43 pg/ml at every time point that divides patients into two groups, high (〉 43 pg/ml) or low (≤ 43 pg/ml) BAFF group, was determined, which could assure 75= sensitivity and 73-82= specificity for the prediction of aGVHD at every time point. The analyses of the cumulative incidence of aGVHD at each time point by BAFF groups (high vs. low) showed that serum BAFF level at every time point plays a significant predictive role for the occurrence of aGVHD (pre-conditioning; P=0.040, day 0; P=0.023, day +7; P=0.003, and day +14; P=0.026). This study is, to the best of our knowledge, the first to show that high serum BAFF levels during the peri-transplant period may play a protective role against aGVHD in humans. The results of this study also show that the BAFF levels during peri-transplant period may be considered to be a predictor for aGVHD. Further trials with a larger cohort will be necessary to determine a definite cutoff value of high BAFF level as well as to construct an index with previously known factors for the prediction of aGVHD. Disclosures: No relevant conflicts of interest to declare.

Description: A chimera is an organism whose DNA is derived from multiple zygotes whereas a mosaic individual’s DNA is entirely derived from a single zygote. We report a case of a chimera who also had cytogenetic features of mosaicism. A 39-year old father of one child, healthy, morphologically normal Korean male with apparent B3 blood group was identified at the time of blood donation. On forward typing 50% of his RBCs were strongly agglutinated by monoclonal anti-B in the manual tube method. The remaining RBCs were type O. Reverse typing revealed a strong anti-A. Complete ABO exon and flanking intronic region sequencing unexpectedly revealed an O01/O02 genotype. He had never been transfused nor received a BMT, and denied having a twin. Chimerism or mosaicism was suspected so additional specimens were collected from the propositus and his parents. Extended RBC phenotyping of the propositus by the gel card technique using monoclonal reagents revealed mixed field agglutination in the M, Kpb, Lub and Jka antigens. B allele haplotype-specific PCR, and exon 6 and 7 cloning and sequencing performed on genomic DNA from the propositus revealed a third ABO allele, B101. Sequencing of exons 6 and 7 and flanking intronic regions of his parents’ ABO alleles revealed a B101 allele in both parents along with an O01 allele (maternal) and an O02 allele (paternal). A total of 9 STR loci were analyzed on DNA extracted from blood, buccal swabs and hair from the propositus and on DNA isolated from peripheral blood lymphocytes from both his parents. Four loci demonstrated a pattern consistent with a double paternal DNA contribution, thus confirming the presence of chimerism (Table 1). Sequence-based typing of HLA class I and II loci was performed on DNA from peripheral blood lymphocytes from these 3 family members but revealed only a single allelic contribution from both parents in the propositus. The propositus’ karyotype revealed a mosaic pattern with 32/50 metaphases demonstrating 46, XY and 18/50 metaphases demonstrating 47, XYY. Overall, an extra paternal set of DNA markers was demonstrable by STR analysis in tissues arising from different germ layers. The propositus is thus a dispermic chimera most likely resulting from parthenogenetic division of the ovum and its subsequent fertilization by two spermatozoa: one with a 23, Y DNA complement and the second with a different 24, YY complement. This would explain the apparent single maternal DNA contribution. Alternatively a non-dysjunction event producing the mosaic 47, XYY karyotype could have occurred after fertilization. Given the mixed field blood group his ABO genotype is most likely B101/O01 and O01/O02. Consistent with other cases of mosaic 47, XYY syndrome our propositus is healthy, morphologically normal and fertile. This is the first case of a dispermic chimera with mosaic 47, XYY syndrome detected at the time of blood donation. STR results demonstrating a double paternal DNA contribution in disparate tissues DNA polymorphism Father Mother Propositus (blood) Propositus (buccal swab) Propositus (hair) D3S1358 15,16 16,17 15,16,17 15,16,17 15,16,17 D5S818 10,12 9,13 10,12,13 10,12,13 10,12,13 D13S317 12,14 8,9 9,12,14 9,12,14 9,12,14 D18S51 16,19 14,15 15,16,19 15,16,19 15,16,19

Description: Background: The entrance of microbes into blood stream results in rapid spreading of infection through circulation system progressing to sepsis with accompanying fever, leukocytosis and circulatory collapse necessitating prompt recognition and treatment. We calculated the difference between white blood cell counts measured in myeloperoxidase and basophil channel, designated as “delta neutrophil”, and found that the value correlates the progression of sepsis. Methods: We categorized patients who were referred for automatic blood cell analysis according to the calculated value of delta neutrophil and analyzed positive rate of blood culture, mortality and laboratory data including hemoglobin, platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, fibrinogen degradation product, D-dimer, ESR, CRP. Delta neutrophil values were calculated as above mentioned from measured values from automatic blood cell analyzer, ADVIA® 120 automated Hematology System (Bayer Diagnostics, New York, USA). Among 1781 patients selected, those with delta neutrophil value less then 5 were categorized as group I, 5 to 10 as group II, 10 to 20 group III, 20 to 30 group IV, 30 to 40 group V, 40 to 50 group VI and greater than 50 as group VII, arbitrarily. Patients with hematologic malignancy or with Gynecologic malignancy were excluded in this study. Results: The mortality and blood culture rate in group VII were 75.0% and 57.1% and in group VI 76% and 46.7%, group V 46.2% and 37.9%, respectively. On the contrary for group I the mortality and isolation rate were 3.3% and 17.1%. (The means of hemoglobin concentration for group I and II were 13.2 g/dL and 12.1 g/dL compared with 10.5 g/dL and 10.2 g/dL in group VI and VII.) With regard to consumptive coagulopathy, the means of platelet count were 263,700/mL and 259,200/mL in group I and II while those for group VI and VII were 107,200/mL and 112,600/mL. Antithrombin activities were 5.20 % and 7.98% in group VII and VI in contrast to 66.6% and 75.8% for group I and II. Conclusion: The categorization by delta neutrophil value correlated with the isolation rate of bacteria from blood culture and mortality. The delta neutrophil value is expected to provide useful information for following up progression of sepsis.

Description: Purpose: The role of allogeneic stem cell transplantation (SCT) for adult acute lymphoblastic leukemia (ALL) remains unclear because interpretation of transplantation outcome is complicated by the criteria used to select patients for transplantation and by the relatively small number of patients studied. Moreover, whether SCT from an unrelated donor could be a treatment option of equal value in a case lacking a compatible related donor remains controversial. The aim of the present study was to determine the graft-versus-leukemia (GVL) effect and risk factors affecting outcome of 218 adults with ALL who received allogeneic SCT during the last 10 years (1995 to 2004). Patients and Methods: The study population was 218 consecutive adults receiving an allogeneic SCT from matched sibling (n=162) or unrelated (n=56; 40 matched, 16 mismatched) donors at the Catholic Hematopoietic Stem Cell Transplantation Center in Korea. Their median age was 30 years (range, 15–61 years). One hundred eighty-three (83.9%) patients had high-risk criteria, and of these, 69 (31.7%) had t(9;22)/BCR-ABL and 7 (3.2%) had t(4;11)/MLL-AF4. One hundred sixty-five patients (75.7%) were transplanted in first complete remission (CR1); 23 (10.5%) in CR2; and 30 (13.8%) were resistant to chemotherapy before transplantation. Most patients (n=206, 94.5%) received a preparative treatment of total body irradiation (TBI)-containing regimen (TBI/cyclophosphamide for CR1, TBI/cytarabine/melphalan for 〉CR1). Graft-versus-host disease (GVHD) prophylaxis was attempted by administering calcineurin inhibitor (cyclosporine for sibling, tacrolimus for unrelated) plus methotrexate. Results: With a median follow-up of 52 months (range, 15+ to 130+ months) after SCT, the 5-year probability of disease-free survival (DFS) was 51.3%±3.5% for all patients; 62.4%±4.3% for patients in CR1; and 11.3%±4.4% for patients in 〉CR1 at transplantation. There was no difference in DFS for sibling and unrelated transplant patients in CR1 (65.2%±4.3% v 62.3%±8.0%). Multivariate Cox regression analysis showed that the most powerful predictive factor affecting relapse and DFS was disease status at transplantation (CR1 v 〉CR1, p

Description: Background Recurrent somatic mutation in RNA splicing machinery genes have been identified in a substantial proportion of patients with myelodysplastic syndrome (MDS). The majority of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) or with therapy-related acute myeloid leukemia (tAML) are associated with multilineage dysplasia. However, the clinical and biologic characteristics of AML-MRC and tAML with spliceosome mutations have not been elucidated. Thus, the objective of this study was to evaluate the frequency, clinical associations, and prognostic significance of spliceosome mutations in patients with AML-MRC and tAML. Methods A total of 224 patients were included in this study, consisting 190 cases of AML-MRC and 34 of tAML. U2AF1, SRSF2, and SF3B1 mutations are the three most frequent genes involved with spliceosome mutations in myeloid malignancies, and these mutations were detected using standard PCR techniques and direct sequencing. Results Spliceosome mutations in U2AF1 (S34 and Q157), SRSF2 (P95), and SF3B1 (primarily K700E) were found in 19 (8.5%), 13 (5.8%), and 7 (3.1%) of the 224 patients, respectively. These mutations were mutually exclusive and 17.4% of the patients had one of these mutations. As shown in Table 1, patients with spliceosome mutations had a higher rate of AML-MRC, a prior history of MDS or MDS/myeloproliferative neoplasm (MPN), and intermediate cytogenetic risk compared to patients without mutations. Only one patient with tAML had a spliceosome mutation. Of the patients with AML-MRC diagnosed based solely on MDS-related cytogenetics, only one patient had the U2AF1 mutation. Within the mutation-positive patients, the U2AF1 mutation was associated with younger age (median 47 vs. 66.5 years for other types; P 〈 0.001), lower WBC count (median 2.4 vs. 10.75 • 109/L for other types; P 〈 0.001), and higher rate of trisomy 8 (36.8% vs. 0.0% for other types; P = 0.003). The SRSF2 mutation was associated with normal karyotype (61.5% vs. 23.1% for other types, P = 0.03), and the SF3B1 mutation was associated with the presence of ring sideroblasts (71.4% vs. 18.8% for other types, P = 0.012) and a higher rate of complex karyotype (42.9% vs. 3.1% for other types, P = 0.01). There was a trend of male dominance (76.9%) for SRSF2 mutation and a higher frequency of adverse cytogenetic risk (57.1%) for SF3B1 mutation. At the median follow-up of 7.3 months, 122 (54.5%) deaths and 161 (71.9%) events were documented. Overall survival (P = 0.752) and event-free survival (P = 0.864) were similar among patients with or without one of the three mutations, U2AF1, SRSF2, or SF3B1 mutations. Conclusion U2AF1 was the most frequently mutated spliceosome gene among patients with AML-MRC and tAML. The association of spliceosome mutation with a preceding MDS or MDS/MPN suggests that spliceosome mutation has a unique role in the pathogenesis of progression. Although spliceosome mutations were associated with distinct clinical and biologic features in the cohort presented in this study, none of the features were prognostically relevant. Disclosures: Cho: Asan Institute for Life Sciences: Research Funding. Chi:Asan Institute for Life Sciences: Research Funding. Park:Asan Institute for Life Sciences: Research Funding.

Description: Background Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disease characterized by the intravascular lysis of red blood cells. The three major pathophysiological features of the disease-hemolysis, bone marrow failure (BMF) and thrombosis-historically have been managed with blood transfusions, steroids and anticoagulation. For optimum management, the relative contribution of both hemolysis and BMF to the complex anemia of PNH should be determined. Aplastic anemia (AA) is the most frequently associated BMF syndrome in PNH. In recent years, eculizumab, a humanized monoclonal antibody that binds specifically to human complement protein C5 and inhibits the formation of the terminal complement complex, has been used to prevent the hemolysis associated with PNH. The aim of this study is to evaluate clinical outcomes with eculizumab in patients with PNH concomitant with AA (PNH-AA) and without AA (classic PNH) in a Korean PNH population. Methods Thirty-five patients 〉18 years of age with PNH diagnosed by flow cytometry and treated with eculizumab for ≥6 months were analyzed in the prospective PNH registry study. Patients were categorized into two groups: PNH-AA and classic PNH. Patients with severe AA were excluded from eculizumab treatment. Biochemical indicators of intravascular hemolysis and hematological laboratory values were assessed at least every 6 months after initiation of eculizumab treatment. Results The median age of the study population was 35 years (range, 21-76 years) at eculizumab initiation and the median duration of eculizumab treatment was 28 months (range, 6-31 months). The treatment effect for reducing hemolysis remained consistent after 6 months of follow up. All patients showed a reduction in LDH levels, which was sustained over the course of treatment (median LDH level, 6.7-fold at baseline to 1.0-fold at 6 months), reflecting inhibition of chronic hemolysis. Fourteen patients (40%) had been diagnosed with aplastic anemia in PNH, and 5 of these patients had received immunosuppressive therapy (IST) for AA management. Of these, 2 achieved complete remission (CR) with hematological recovery before eculizumab initiation, whereas 3 had partial response. Of 35 total patients, 12 were classified as having PNH-AA and 23 with classic PNH, including the 2 patients with CR from IST for management of AA. The mean PNH clone did not change significantly after 6 months of follow up in PNH-AA or classic PNH patients (p=0.575 and 0.965, respectively). Patients receiving eculizumab in both groups had significant changes in mean hemoglobin level after 6 months (p=0.028 and p= 0.035, respectively). The mean number of packed RBC units transfused in patients with PNH-AA was significantly reduced, from 7 units during the previous 6 months to 2 units during the first 6 months of eculizumab use (p=0.009). Thereafter, 1.0, 0.8, and 1.6 units per every 6 months were required from month 6‒12, 12‒18, and 18‒24, respectively. In classic PNH patients, transfusion independence was achieved by 57% (13 of 23) within the first 6 months of treatment and 89% by the last 24 months. Eculizumab also resulted in sustained hematological improvement for patients. There were no significant differences in clinical outcomes (ie, LDH and hemoglobin levels, transfusion requirements) with eculizumab between the two groups. Conclusions Clinical outcomes with eculizumab were significantly improved compared with baseline in patients with both PNH-AA and classic PNH. All patients have been followed up without any recurrence of hemolytic events; overall, the population achieved improvement in hemoglobin levels and a significant reduction in frequency of blood transfusions required. Some PNH-AA patients still required transfusion, reflecting in part a production defect of the bone marrow, whereas classic PNH patients became transfusion-independent over time. These results demonstrate that eculizumab has a role in in the management of patients with PNH-AA, similar to that of classic PNH, to inhibit hemolysis and reduce transfusion requirements. Disclosures Jang: Alexion Pharmaceuticals: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Jo:Alexion Pharmaceuticals: Research Funding. Lee:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Won:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Kim:Celgene: Research Funding; Il-Yang: Research Funding; Alexion Pharmaceuticals: Research Funding; Novartis: Research Funding. Lee:Alexion Pharmaceuticals: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Lee:Alexion Pharmaceuticals: Research Funding.

Description: Background: The primary clinical manifestations of paroxysmal nocturnal hemoglobinuria (PNH) are hemolytic anemia, bone marrow failure (BMF), and thromboembolism (TE). For optimum management, the contribution of both hemolysis and BMF to the complex anemia of PNH should be determined. The treatment of a hemolytic episode should aim at diminishing hemolysis and preventing complications. Corticosteroids as treatment, for both chronic hemolysis and acute hemolytic exacerbations have been used with a variety of side effects of long term use. In the Korean PNH population, corticosteroid (77.4%) represented the most common supportive care which provided with patients who had a history of corticosteroid use during the disease course (Lee JW et al. IJH. 2013 Jun; 97:749-57). There are no experimental data that provide a plausible explanation for why steroids should ameliorate the hemolysis of PNH. Aims: To evaluate the role of corticosteroid for treating chronic hemolysis in patients with PNH enrolled in the Korean prospective PNH registry. Methods: Korean patients with a diagnosis of PNH are eligible for inclusion in the prospective registry study designed to identify disease burden of PNH. Patient medical information data and other laboratory parameters were collected at the last 6 month follow-up.Here we analyzed patients with corticosteroid use within the past 6 months. 97 patients who were followed up at least 6 months after study enrollment was categorized into two groups. Patients have received eculizumab treatment or bone marrow transplantation (BMT) during the last 6month of follow up was excluded. Results: Among the 97 patients, 23% (22 patients) had corticosteroid therapy in the past 6 months. Mean age was 46 years (range 20-87; standard deviation, 16.3) and 51 patients (53 %) were female. At the time of analysis, 74 of 97 patients had recorded lactate dehydrogenase (LDH) levels. The mean LDH at 6months follow up after enrollment was 4.75-fold above the upper limit of normal (ULN) of the patients with corticosteroid use and 4.16-fold above ULN was reported in patients without corticosteroid use for the past 6 months (p=0.446). Hemolysis (LDH≥1.5 x ULN) was reported in 86% of patients with corticosteroid use and 77% of patients without corticosteroid use; there was no statistically significant difference between these two patient populations (p=0.420). The mean granulocyte clone size at enrollment in patients with corticosteroid use was 50.7% (range 1-98) and patients without corticosteroid use reported 52.3% (range 1-99) (p=0.850). The mean reticulocyte percent between two groups was 4.87% and 4.0%, respectively (p=0.317). Red blood cell was transfused to 15 (68.1%) of the 22 patients with corticosteroid use and 23 (30.7.%) of patients without corticosteroid use during the last 6 month follow-up; there was a significant difference between the two groups for mean unit of transfusion (p=0.005) (Table1). There was no new thromboembolism event reported during the past 6 months. Each group experienced abdominal pain and dyspnea during the last 6 months of follow up: patients with corticosteroid use vs. patients without corticosteroid use (p=0.121 and p= 0.055, respectively) (Table1). Conclusions: In the past, the main value of corticosteroids may have been to treat chronic hemolysis although it is limited by toxicity and the harm that can accrue from long term use. However, our results demonstrated that the management of hemolysis of PNH with corticosteroid could be ineffective and unsatisfactory. These data confirm that PNH patients with corticosteroid had ineffective hemolysis management (LDH ≥1.5 x ULN) and also suffer from disabling clinical signs and symptoms, such as continuous transfusion requirement with anemia, abdominal pain and dyspnea. Awareness of the potentially debilitating effects of corticosteroid myopathy and sensitivity to the disfiguring consequences of long term use are essential for proper management and also careful follow-up should be recommended. [Table 1] Total (N=97) Patients with corticosteroid use (n=22) Patients without corticosteroid use (n=75) p -value LDH fold above ULN (n=74), Mean (SD) Hemolysis (LDH ≥ 1.5xULN), n (%) 4.75 fold (3.02) 18/21 (85.7) 4.16 fold (2.89) 41/53 (77.4) 0.446 0.420 Transfusion (n=38), Mean unit (SD) 6.1 (9.43) 2.0 (3.99) 0.005 Abdominal pain (n=16) , n (%) 6/22 (27.3) 10/75 (11.2) 0.121 Dyspnea (n=11) , n (%) 5/22 (22.7) 6/75 (8.0) 0.055 Disclosures Lee: Alexion Pharmaceuticals: Consultancy. Jang:Alexion Pharmaceuticals: Consultancy. Lee:Alexion Pharmaceuticals: Consultancy. Jo:Alexion Pharmaceuticals: Consultancy. Kim:Alexion Pharmaceuticals: Consultancy.

Description: Mast cells are responsible for IgE-mediated allergic reactions. Phospholipase D1 (PLD1) and PLD2 regulate mast cell activation, but the mechanisms remain unclear. Here we show that PLD2 associates with and promotes activation of Syk, a key enzyme in mast cell activation. Antigen stimulation resulted in increased association and colocalization of Syk with PLD2 on the plasma membrane as indicated by coimmunoprecipitation and confocal microscopy. This association was dependent on tyrosine phosphorylation of Syk but not on PLD2 activity. In vitro, PLD2 interacted via its Phox homology (PX) domain with recombinant Syk to induce phosphorylation and activation of Syk. Furthermore, overexpression of PLD2 or catalytically inactive PLD2K758R enhanced antigen-induced phosphorylations of Syk and its downstream targets, the adaptor proteins LAT and SLP-76, while expression of a PLD2 siRNA blocked these phosphorylations. Apparently, the interaction of PLD2 with Syk is an early critical event in the activation of mast cells.

Description: Abstract 1516 Background: Front-line combination of imatinib with conventional chemotherapy has demonstrated an improved complete remission (CR) rate, an increased transplantation proceeding rate with CR, and a better survival in adults with Ph+ ALL. However, in the light of disease aggressiveness and recurrence, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant mutations, an improved strategy to induce more effective leukemic cell clearance is clearly needed. Dasatinib, a potent dual BCR-ABL/SRC family kinase inhibitor, has been shown to be effective in patients with imatinib-resistant chronic myeloid leukemia and Ph+ ALL. Methods: We present the first interim results of the Korean prospective phase II study protocol designed to evaluate the clinical efficacy of first-line dasatinib plus conventional chemotherapy for adults with newly diagnosed Ph+ ALL. This study is registered at www.ClinicalTrials.gov as NCT01004497. The protocol is designed for 51 patients, and recruitment started in March, 2010. The protocol enrolls patients (15–65 years) who receive dasatinib (100 mg once daily for 4 weeks) as an alternative schedule after each conventional chemotherapy course (alternating modified hyper-CVAD and high-dose cytarabine/mitoxantrone). Patients in CR who have a suitable related/unrelated donor undergo allogeneic transplantation as early as possible (depending on the speed of coordination process). Patients without a donor continue to receive dasatinib plus conventional chemotherapy (up to 4 courses; depending on the patient's tolerability) followed by dasatinib maintenance therapy (100 mg once daily for up to 2 years). Minimal residual disease monitoring for BCR-ABL transcript is centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples from all patients (Research Institute of Molecular Genetics, The Catholic University of Korea, Seoul, Korea). Results: A total of 36 patients have been enrolled to date. Of these, 3 patients are receiving the first dasatinib cycle (too early); 3 patients died before starting the first dasatinib cycle from infections. Thus, 30 patients are evaluable for assessment of response to dasatinib plus conventional chemotherapy. Median age was 47 years (range, 19 to 64 years). Karyotype analysis revealed additional chromosomal changes in 18 (60%) of the 30 patients. Twenty patients (67%) had m-BCR transcript. All patients (100%) have achieved CR with a decrease in the minimal residual disease by the first dasatinib cycle, and of these, 13 patients (43%) have achieved major molecular response [MMR; including 5 complete molecular response (CMR4.5)]. By the second dasatinib cycle, 25 patients (83%) have achieved MMR (including 11 CMR4.5). So far, no dasatinib-related serious adverse events (≥grade 3 toxicity) have been observed. Twenty-four (80%) of the 30 patients have undergone allogeneic transplantation in CR; 6 patients are receiving continuous dasatinib plus conventional chemotherapy in CR. With a median follow-up duration of 10 months (range, 5 to 17 months), 25 patients are at present alive in continuous CR, and 4 patients have died (2 infections during consolidation chemotherapy, 2 transplant-related complications). Only 1 patient who failed to achieve MMR has relapsed at 11 months from diagnosis (at 5 months after allogeneic transplantation). The estimated probabilities of disease-free survival and overall survival at 1 year were 76% and 83%, respectively. Conclusions: Our interim analysis indicates that first-line combination of dasatinib with conventional chemotherapy appears to be effective in achieving a good quality of molecular response (MMR/CMR4.5) in adults with Ph+ ALL. Whether this would translate to an improved long-term survival remains to be investigated. Disclosures: Lee: Bristol Myers Squibb: Honoraria, Research Funding. Kim:Bristol Myers Squibb: Honoraria, Research Funding.