ALBERT

Description: Background Recent studies have shown that the concurrent expression of MYC and BCL2 protein evaluated by immunohistochemistry (IHC) in patients with de novo diffuse large B-cell lymphoma (DLBCL) is associated with worse survival when treated with standard R-CHOP, but the effect of intensive chemotherapies for such patients is unknown. Thus, we evaluated the impact of the co-expression of MYC and BCL2 protein among patients with advanced DLBCL, who were treated with a dose-intensive immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). Patients and Methods This is a retrospective analysis of patients with de novo DLBCL, who were categorized into high/high-intermediate risk by the age-adjusted International Prognostic Index (aaIPI). They were consecutively treated with the R-Double-CHOP regimen, consisting of rituximab (375 mg/m2, day -2), cyclophosphamide (750 mg/m2, day 1, 2), doxorubicin (50 mg/m2, day 1, 2), vincristine (1.4 mg/m2 [maximum 2.0 mg/body], day 1) and prednisolone (50 mg/m2, day 1-5) followed by consolidative high-dose chemotherapies at our institution from 2001 to 2013. MYC and BCL2 protein were measured by IHC assay using formalin-fixed paraffin-embedded tissue specimens for all available cases. Cut-off values of positivity for MYC and BCL2 protein were set as 40% and 50% of stained tumor cell, respectively. Lymphomas showing concurrent positivity for MYC and BCL2 protein were defined as "Double expressor lymphoma (DEL)". Results A total of 40 patients with a median 53-years (range 19-68) of age were analyzed. Twenty-one patients were at high risk and the other 19 patients were at high-intermediate risk by aaIPI. Cell of origin (COO) subtypes classified by Hans algorithm consisted of 14 germinal center B-cell (GCB) type and 26 non-GCB type. Totally, 10 (25%) patients were categorized into DEL. The overall response (OR) and the complete response (CR) rates to R-Double-CHOP for all patients were 93% and 83%, respectively. The OR and the CR rates were not significantly different between the DEL group and the non-DEL group (100% vs 90%, and 80% vs 83%, respectively). The proportion of patients proceeding to ASCT was not significantly different among these groups (50% vs 60%). With a median 52 months (range 3-155) of follow-up, the 3-year progression-free survival (PFS) and the overall survival (OS) rates for all patients were 55% and 72%, respectively (Figure a, b). Both the PFS and the OS were significantly worse in the DEL group than in the non-DEL group (Figure c, d). As for aaIPI and COO subtyping, either high/high-intermediate risk or GCB/non-GCB subtype were not significantly associated with the outcome of PFS or OS. Conclusion The concurrent expression of MYC/BCL2 protein in advanced DLBCL was associated with shorter remission duration and worse survival despite similar susceptibility to the treatment when a dose-intensive immunochemotherapy was applied. Our findings suggest that patients with advanced DEL may not benefit from dose-intensified therapies, and therefore need highly discrete strategies. Disclosures Miura: Astellas Pharma Inc.: Honoraria; Celgene K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; Meiji Seika Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Hatta:Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Celgene K.K.: Honoraria. Iriyama:Brystol-Myers K.K.: Honoraria. Takei:Kyowa Hakko Kirin CO., Ltd, Japan: Research Funding; Bristol-Myers K.K.: Research Funding; Nippon Kayaku Co.: Research Funding; Shionogi & Co.: Research Funding; Meiji Seika Pharma: Research Funding; Astellas Pharma Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; TEIJIN PHARMA LIMITED: Research Funding; CSL Behring K.K: Research Funding; Japan Blood Products Organization: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; TORII, PHAMACEUTICAL CO: Research Funding; Alexion Pharmaceuticals: Research Funding; YAKULT HONSHA CO., Ltd.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO. LTD: Research Funding.

Description: Abstract 4631 Background: DNA cytosine methylation in CpG dinucleotides is an important epigenetic event and critical for the control of gene expression, and appears to play a crucial role in tumorgenesis in hematologic malignancies. To identify novel tumor-specific differentially methylated regions in human leukemia/lymphoma, we performed methylation analysis of new target lesions in hematological malignancies. Methods: The aberrant methylation at 8 new candidate human homologous genomic regions (ZAR1, GATA4, CDH22, SOX3, SLC16A5, PFN2, EHD3 and TBPL1), where hypermethyloation status was identified through a mouse-skin cancer model study by the RLSG method, were analysed with quantitative DNA methylation analysis using the Sequenom MassARRAY system. 8 human leukemia/lymphoma cell lines (HL-60, KG-1, Jurkat, MOLT-4, NALM-6, K562, Ramos, and Raji), and bone marrow or peripheral blood samples from 20 patients with leukemia before treatment were obtained for samples (10 in AML, 4 in Ph- ALL, 2 in Ph+ ALL, 2 in CML-CP, 1 in CML-BC, and 1 in CLL). Normal lymphocyte cells from four healthy individuals were used as normal controls. Each data were assigned as hypermethylaion when the average methylation levels of the entire target regions were more than 50%. Results: In ZAR1, SLC16A5 and EHD3, hypermethylation level was seen in all leukemia/lymphoma cell lines. GATA4, CDH22 and SOX3 showed hypermethylaion in all tumor cell lines except for AML cell line KG-1. PFN2 showed hypermethylation in all cell lines except for KG-1, T-ALL cell line Jurkat and MOLT-4. No aberrant methylation among tumor and normal cells was observed in TBPL1. Interestingly, DNA methylation patterns of ZAR1, GATA4, CDH22, and SOX3 were different between the clinical specimens of AML and ALL. Hypermethylation of those genes were frequently observed in ALL samples but less in AML. The Mann-Whitney U-test showed that the differences were significant in all ZAR1, GATA4, CDH22, and SOX3 (p 〈 0.01, respectively). DNA samples from CML-CP patients showed no abnormal methylation patterns in all genes. DNA from T-CLL patient showed hypermethylation only in EHD3. No abnormal methylation pattern was observed in SLC16A5 and PFN2 in clinical specimens. None of the normal control samples showed aberrant methylation in any genes. Conclusion: We identified regions aberrantly methylated with high frequency among the new candidate genes in leukemia and lymphoma, and demonstrated a distinct methylation pattern between tumors and normal lymphocytes. Aberrant DNA methylation of ZAR1, GATA4, CDH22 and SOX3 may be associated to differentiation to lymphoid populations of leukemia. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3084 With modern intensive chemotherapy, 78% to 93% of adult patients with acute lymphoblastic leukemia (ALL) achieve complete remission (CR). However, the disease-free survival rate is only 30% to 40% due to the high rate of relapse. A part of relapsed patients can achieve second remission (CR2) with salvage therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) in CR2 will be the only curative strategy. Prognosis after relapse in adult patients with ALL is considered to be extremely poor, but reports as to the outcome after relapse have been limited. To elucidate the outcome of relapsed patients and prognostic factors after relapse, we retrospectively collected and analyzed clinical data from 69 institutions in Japan on patients with Philadelphia-chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first CR (CR1) between 1998 and 2008. A total of 332 patients were included in this study. The median age of them was 35 years, and 165 patients were male. Median duration of CR1 was 290 days (range 15–7162 days), and median follow-up time after relapse was 319 days (range 3–3689 days). Fifty-eight and 4 of them relapsed after allogeneic and autologous HSCT in CR1, respectively. The overall survival (OS) rate was not significantly different between patients who relapsed after allogeneic HSCT in CR1 and those who relapsed after chemotherapy only (50.0% vs. 43.4% at 1 year and 10.6% vs. 16.3% at 5 year, respectively). Among 270 patients who relapsed after chemotherapy only, 234 patients received salvage chemotherapy after relapse, and 123 patients achieved CR2 (52.5%). Sixty-two patients out of those 123 patients underwent allogeneic HSCT in CR2. Median duration between the achievement of CR2 with salvage chemotherapy and allogeneic HSCT in CR2 was 76 days. OS rate was significantly better in patients who underwent allogeneic HSCT in CR2 following salvage chemotherapy than those who did not (74.1% vs. 55.1% at 1 year and 44.7% vs. 11.6% at 5 year, respectively) by a landmark analysis limiting patients who were surviving without disease at 76 days after the achievement of CR2. In multivariate analysis of factors that included allogeneic HSCT in CR2 following salvage chemotherapy as a time-dependent covariate, lower white blood cell count at relapse (less than 10000/μl) and allogeneic HSCT in CR2 were associated with better OS rate among patients who achieved CR2 following salvage chemotherapy. Forty-six patients underwent allogeneic HSCT in non-CR after receiving salvage chemotherapy. A part of them survived long, and 5 year OS rate was 20.9%. In conclusion, the prognosis of adult patients with relapsed Ph-negative ALL is poor. Allogeneic HSCT after first relapse could improve the prognosis. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3948 Background: The central nervous system (CNS) is considered a sanctuary because drugs at standard doses rarely reach it. CNS event is defined as disease recurrence in the CNS during complete systemic remission or CNS progression as concurrent disease in the CNS during active systemic disease. These CNS events are associated with extremely poor patient prognosis. To evaluate the risk of CNS events in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab (R) era, we performed a retrospective study with a large cohort in Japan. Materials and Methods: All patients were diagnosed as having DLBCL and underwent primary therapy from September 2003 to December 2006. Patients with distinct forms of DLBCL, such as intravascular lymphoma, primary effusion lymphoma, and pyothorax-associated lymphoma were excluded. Those who had received any prophylactic CNS treatment; and those with CNS involvement at the beginning of therapy were also excluded. Primary therapy comprised standard R-CHOP therapy or R-THP-COP therapy (pirarubicin instead of doxorubicin hydrochloride). CNS involvement was considered when malignant cells were detected in cytocentrifuged preparations of cerebrospinal fluid (leptomeningeal type) and/or when an intracranial or spinal mass was detected by radiologic imaging such as computed tomography or magnetic resonance imaging (parenchymal type). Results: (1) Baseline characteristics. Clinical data from 1,492 patients were collected from 48 institutions. The median age was 67 years (range, 15–93 years). R-CHOP therapy was administered in 1,227 patients (82.2%) and R-THP-COP therapy, in 265 patients (17.8%). Therapy for 6–8 cycles was administered to 1099 patients (73.7%). Local irradiation was included for 344 patients (23.1%). The 5-year overall survival (OS) rate in the entire cohort was 72.8%, and the median observation period for the surviving patients was 47.6 months. (2) Incidence of CNS events. In total, 94 CNS events (6.3%) were recorded. More than half were of the parenchymal type (57.4%); the rest were mostly of the leptomeningeal type (29.8%), and some were of both types (12.8%). The events occurred during the first complete remission (CR) in 40 patients (42.6%) and in the second or later CR in 11 patients (11.6%). Death from any cause was recorded in 64 of the 94 patients (68.1%) during the observation period, and most deaths were due to lymphoma. The cumulative 5-year probability of CNS events was 8.0%. (3) Risk factors for CNS events. Multivariate Cox regression analysis identified involvement of the breast (relative risk (RR), 7.9), adrenal gland (RR, 3.3), paranasal sinus (RR, 2.9), and bone (RR, 2.3). as risk factors for CNS events. Time to CNS event curves differed significantly between patients with and without CNS risk sites (P 〈 0.001). (4) Survival after CNS events. Patients with CNS events demonstrated significantly poorer OS (P 〈 0.001). The 2-year OS rate after a CNS event was 25.7%, and the 50% survival duration was 4.6 months. No significant differences were observed between any 2 of the 3 types of CNS events. Depending on the systemic lymphoma status at the time of the CNS events, patients in first CR showed better survival than the others (P = 0.019). Patients in any CR also showed superior survival than those not in CR (P = 0.015). Conclusions: We concluded that DLBCL patients in the R era with any of these risk factors (breast, adrenal gland, paranasal sinus, or bone involvement), in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events. The efficacy and manner of CNS prophylaxis for each involvement sites should be evaluated further. Disclosures: No relevant conflicts of interest to declare.

Description: Background Elderly patients with diffuse large B-cell lymphoma (DLBCL) are more likely to face severe adverse events and/or insufficient dose intensity when treated with R-CHOP. The International Prognostic Index (IPI) predicts treatment outcome of patients with DLBCL, but risk stratification for such patients remains uncertain. Thus, we developed a new decision making model, which serves as a guide to the optimal personalized therapy for elderly DLBCL. Patients and methods This is a multicenter, retrospective study conducted by Society of Lymphoma Treatment in Japan (SoLT-J). Clinical features and treatment records of patients aged ≥ 65-years old, who had been diagnosed with de novo DLBCL and given at least one cycle of R-CHOP between 2001and 2012, were collected and analyzed for their prognostic significance after receiving approval from each institutional review board. Charlson Comorbidity Index (CCI) (Charlson et al, 1987) was used to access the co-existing medical status. Relative dose intensity (RDI) (i.e. the percentage of actual dose administered per protocol specified dose) for the average of cyclophosphamide and doxorubicin, adjusted by the effect of radiation therapy, was calculated for all patients. Results A total of 633 patients with a median 75-years old (range 65-96) treated with a median 6 cycles of R-CHOP (range 1-8) was analyzed. Ninety-six (15%) patients received planned or additional radiation therapy. R-CHOP therapy was discontinued in 129 (20%) patients because of treatment related toxicities, of which 30 (5%) patients died. The advanced age, hypoalbuminemia, and high score of CCI were identified as independent prognostic factors by the backward stepwise analysis for survival. The multivariate Cox regression analysis revealed that age 〉 75-years, serum albumin concentration 〈 3.7 g/dl, and CCI score ≥ 3 were significantly associated with worse overall survival (OS), progression free survival (PFS), and treatment related mortality (TRM), independently of IPI score ≥ 3 (Table 1). Regarding the index consisting of these three new risk factors, 135, 270, 184 and 44 patients were scored 0, 1, 2, and 3 point(s), respectively. The elevation of this score was significantly associated with lower average RDI (72% vs 63% vs 48% vs 41%, P 〈 .0001) and more frequent unanticipated discontinuance of the treatment (10% vs 16% vs 31% vs 34%, P 〈 .0001). Accompanied by IPI score ≥ 3, this index discriminated five risk groups with 3-year OS of 88%, 79%, 59%, 38%, and 6% (P 〈 .0001), respectively (Figure 1). Conclusion The combination of age, serum albumin concentration, and comorbidities predicts adherence to R-CHOP-and outcome, as well as the IPI-in elderly patients with DLBCL. This prognostic model may help physicians to decide the intensity of the treatment, and needs to be validated further. Table 1. Multivariate analysis for overall survival, progression free survival, and treatment related mortality. OS PFS TRM Prognostic Factor HR P HR P HR P Age 〉 75-years 2.16

Description: Abstract 3121 Background We evaluated the safety and efficacy of the CEM regimen containing ranimustine (MCNU) with autologous peripheral blood stem cell transplantation (PBSCT) in adult patients with relapsed or high-risk de novo DLBCL or DLBCL associated with follicular lymphoma (FL/DLBCL) in our institution. Patients and methods We retrospectively analyzed 55 consecutive patients who underwent autologous PBSCT following the CEM regimen between March 1999 and June 2011 for the treatment of relapsed or high-risk DLBCL and FL/DLBCL. High-risk DLBCL was defined as partial or no response to initial treatment or high-intermediate/high risk disease according to international prognostic index (IPI) at initial diagnosis. Age-adjusted IPI was used for patients under 60. The CEM regimen consisted of CY (60 mg/kg on days -7 and -6), etoposide (500 mg/m2 on days -6 to -4) and MCNU (250 mg/m2on day -3 and -2), followed by PBSCT. Results Median age at transplant was 51 years (range, 23–66), and median time from diagnosis to transplant was 5 months (range, 3–241). Of them, 7 patients received radiation therapy before transplant, and 11 had no history of rituximab use before transplant. The 36 patients in CR1 at transplant were with high or high-intermediate risk according to international prognostic index at diagnosis. Other 15 patients in CR2, and 4 patients who were not in CR1/2 at transplant were included. CY dose was reduced in five patients by physicians choice. The median number of infused CD34-positive cells was 3.98 × 106/kg (range, 1.36–26.87). The median post-transplant days of neutrophil recovery and platelet were 11 days (range, 9–20) and 12 days (range, 7–53), respectively. Common grade 3/4 non-hematological treatment-related toxicities within the first 100 days after transplant were nausea (24%), vomit (4%), stomatitis (15%), and diarrhea (9%). Infections included febrile neutropenia (85%), sepsis (15%) which contained catheter-related bacteremia (n=4) and pneumonia (n=2). Other less common severe toxicities were acute renal impairment (n=3), and pleural effusion (n=1). No sever cardiac, neurologic toxicity, or veno-occlusive disease of the liver was observed in any of the patients. Late-onset adverse effects during follow-up period includes chronic renal impairment (n= 5), therapy-related myelodysplastic syndrome (refractory anemia) (n=1, 120 months), and prostate cancer (n=1, 83 months). Serious late cardiac or pulmonary impairment was not diagnosed in this cohort. Median follow-up duration of 42 patients surviving at the time of the analysis was 52 months (range, 1–159). Relapse or disease progression after PBSCT was documented in 21 cases (range, 0–81 months after PBSCT). No therapy related mortality (TRM) associated with PBSCT was observed, and all the 13 deaths were due to disease relapse/progression. The 5-year estimated overall survival (OS) and progression-free survival (PFS) were 70.6% (95% CI, 54.0–82.1)% and 57.0% (95% CI, 39.5–71.2)% for all patients, respectively. In a univariate analysis for factors affecting OS and PFS, no significant factors associated with unfavorable OS and PFS was found including age at transplant, gender, history of rituximab use, histology, disease status at transplant, and previous BM involvement. Conclusion We conclude that the CEM regimen using MCNU would be a tolerable, effective conditioning regimen of autologous PBSCT for high-risk or relapsed de novo DLBCL or FL/DLBCL. Although no TRM was observed, relapse was the major cause of treatment failure. Late-onset complications in long-term survivors can occur, and should be carefully monitored. Disclosures: No relevant conflicts of interest to declare.

Description: Background:Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of abnormal plasma cells in the bone marrow. D-type cyclins (CCNDs), an important family of cell cycle regulators, are thought to be implicated in multiple myeloma (MM) development because CCNDs are commonly expressed in myeloma cells. CCND is known to positively regulate the cell cycle from G1 to S-phase initiation by binding to cyclin-dependent kinase (CDK) 4/6, resulting in potentiation of myeloma cell growth. These findings suggest a possible role for CDK4/6-targeting therapy in MM, yet the details remain incompletely understood. In this regard, we investigated the biological activity of abemaciclib, a potent, highly selective CDK4/6 inhibitor, in myeloma cell lines, to elucidate the mechanisms underlying the involvement of the CCND-CDK4/6 complex in cell cycle regulation and survival. Methods:The effects of abemaciclib on myeloma cells were investigated using three myeloma cell lines, KMS12-PE (CCND1-positive and CCND2-negative), RPMI8226 (CCND1-negative and CCND2-positive), and IM-9 (both CCND1- and CCND2-positive). Cell growth was assessed by trypan blue exclusion assay. Cell cycle analysis was performed using propidium iodide (PI) and apoptosis was measured using annexin V/PI staining via flow cytometry. Cell cycle regulated proteins, including p21 and p27, and phosphorylated proteins, including STAT1, STAT3, ERK, JNK, p38, and AKT, were evaluated using a phospho-flow method. Autophagy was assessed using CYTO-ID via flow cytometry. PARP cleavage was investigated via western blotting. Clarithromycin, an antibiotic agent belonging to the macrolide class, was used as an autophagy inhibitor. Results:Abemaciclib inhibited myeloma cell growth in a dose-dependent manner in all the cell lines evaluated, with significant differences seen at a concentration of 320 nM. Annexin V/PI staining revealed that 1 μM abemaciclib showed little or no effect on apoptosis, but 3.2 μM abemaciclib induced apparent myeloma cell apoptosis, with an increase in both the early and late apoptotic fractions. Therefore, 1 and 3.2 μM of abemaciclib were used in subsequent experiments for the assessment of cell growth and apoptosis, respectively. Cell cycle analyses revealed that 1 μM abemaciclib increased the fraction of cells in G0/G1 phase and decreased the fraction in S-G2/M phase. Furthermore, this effect was associated with the upregulation of p21 and p27 in the evaluated myeloma cells. PARP cleavage was observed in KMS12-PE cells treated with 3.2 μM abemaciclib, but not 1 μM, suggesting a close connection between the degree of PARP cleavage and apoptosis in myeloma cells. Importantly, abemaciclib induced autophagy in a dose-dependent manner. However, no apparent inhibitory effect on the autophagy-related phosphorylated proteins STAT1 (Y701), STAT3 (Y705), ERK (T202/Y204), JNK (T183/Y185), p38 (T180/Y182), or AKT (Y315) was observed in myeloma cells treated with 3.2 μM abemaciclib. To investigate the role of abemaciclib-induced autophagy on myeloma cell apoptosis, we further assessed the apoptotic effect of 3.2 μM abemaciclib or 50 μg/mL clarithromycin, alone or in combination. Clarithromycin did not induce apoptosis of myeloma cells. Importantly, clarithromycin treatment in combination with abemaciclib attenuated the apoptotic effect of abemaciclib. Discussion & Conclusions: Although the underlying mechanisms conferring the level of CCND expression are known to differ greatly (e.g., CCND translocation, hyperdiploidy, or activation of upstream pathways of CCND transcription), the results of the current study indicate that the CCND-CDK4/6 complex is closely involved in myeloma cell growth and survival regardless of the CCND family member present. In addition, we demonstrate that abemaciclib exerts multiple effects, such as myeloma cell apoptosis, via the PARP pathway or autophagy, as well as cell cycle regulation. Because abemaciclib in combination with clarithromycin inhibits myeloma cell apoptosis, the autophagy induced by abemaciclib is considered to have a critical role in the induction of apoptosis, so-called "autophagic cell death." These results provide novel insights into a possible therapeutic approach using abemaciclib to target CDK4/6 in patients with MM, and offer new possibilities for combination therapy with CDK4/6 inhibitors and autophagy regulators. Disclosures Iriyama: Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Hatta:Novartis Pharma: Honoraria.

Description: Abstract 3090 Poster Board III-27 The outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has dramatically improved since the start of treatment with imatinib. The Japan Adult Leukemia Study Group (JALSG) has reported a high complete remission (CR) rate for Ph+ALL treated with imatinib-combined chemotherapy (Yanada et al, J Clin Oncol 2006). Here we report a follow-up analysis of the results of the JALSG imatinib-combined chemotherapy. In the study, remission was induced by administering imatinib from day 8 to day 62 in combination with cyclophosphamide, daunorubicin, vincristine (VCR), and prednisolone (PSL). Consolidation regimen consisted of an odd course comprising high-dose methotrexate and high-dose cytarabine and an even course with 28 days administration of single-agent imatinib. The consolidation regimens were alternated for four courses each. Maintenance consisting of VCR, PSL, and imatinib was continued for two years after a CR. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was recommended if HLA identical sibling donor was available and was allowed from an alternative donor. A total of 103 newly diagnosed Ph+ALL patients were enrolled in the study between August 2002 and August 2004. Median age of the patients was 45 years (range, 15-64 years), and there were 57 males and 46 females. Median follow-up period was 2.6 years (range, 0.1-5.1 years). A CR was achieved in 100 (97.1%) of the 103 patients and not achieved in a patient in whom imatinib was discontinued because of ileus. There were two early deaths during induction. The probability of overall survival (OS) rate for the entire group at three years was 56.8%. No severe adverse effects were observed. Allo-HSCT was performed in the 1st CR (CR1) in 54 of the 74 CR patients under 55 years of age. Relapse occurred in 18 of 20 patients (90.0%) in whom allo-HSCT was not performed in CR1, but in only seven of the 54 patients (13.0%) who underwent allo-HSCT. At three years, the probability of OS rate for patients under 55 years of age was 75.0% in the transplanted group and 36.4% in the non-transplanted group. Allo-HSCT was performed in CR1 in eight of the 25 patients over 55 years of age. Two were myeloablative and six reduced intensity conditionings. Seven of eight patients who underwent HSCT are still alive in a CR. However, the probability of OS rate at three years in the non-transplanted group was 43.2%. In the group that did not receive allo-HSCT in CR1, age (55〈 years or 55〉 years), WBC count, bcr/abl transcript level, bcr/abl transcript type (major or minor), co-expression of myeloid antigens (CD13 and/or CD33), and additional chromosomal abnormalities at diagnosis were not associated with OS. The results demonstrated that the imatinib-combined chemotherapy regimen was effective and feasible. The regimen provided a better chance to receive allo-HSCT which resulted in an excellent outcome. However, relapse still remains a problem, especially in patients who are not candidates for allo-HSCT. Disclosures No relevant conflicts of interest to declare.

Description: Background : In myeloproliferative neoplasms, especially essential thrombocythemia (ET), platelet (Plt) counts and von Willebrand factor (vWF):Ristocetin cofactor (RCo) levels have been reported to be inversely correlated. However, there have been no reports of the comparison of high vs. low values of JAK2 allele burden and necessary of Plt counts reduction to achieve vWF:RCo levels ≥50%, which is required for major surgery. We investigated the correlation between vWF level and Plt counts for JAK2V617F mutation positive (JAK2V617F+) polycythemia vera (PV) and ET (allele burdens ≥50% and