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 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 : 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

Description: Abstract 4855 Background: Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of non-Hodgkin lymphomas, often resulting in poor prognoses. The CHOP chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, and prednisone, had been used previously to treat other types of lymphomas. Here, we examined the efficacy and safety of a dose-intensified CHOP regimen (Double-CHOP), which was followed by autologous stem-cell transplantation (ASCT) or high-dose methotrexate (HDMTX), in PTCL patients. Patients and Methods: Twenty-eight PTCL patients, who received 3 courses of Double-CHOP at our institution, were retrospectively studied from 1996 to 2012. Patients with anaplastic lymphoma-kinase-positive anaplastic large-cell lymphoma (ALK+–ALCL) were excluded from this study. The Double-CHOP regimen consisted of 3 courses of intravenous (iv) administration of cyclophosphamide (750 mg/m2, days 1–2, over 2 h), doxorubicin (50 mg/m2, days 1–2, over 30 min), vincristine (1.4 mg/m2, day 1, max 2 mg/Kg body weight), and per os (p.o.) prednisone (50 mg/m2, days 1–5). For patients aged 〉60, cyclophosphamide and doxorubicin doses were modified. The third cycle of Double-CHOP regimen was used for stem cell mobilization. Consolidating high-dose therapy (HDT) regimen consisted of cyclophosphamide (60 mg/kg, day 6 and 7, iv, over 3 h), etoposide (500 mg/m2; day 4, 5, and 6; iv; over 6–8 h), and ranimustine (250 mg/m2, day 2 and 3, iv, over 1 h). ASCT was performed on day 0 and G-CSF administered from day 1 until neutrophil engraftment. As an alternative to HDT/ASCT, HDMTX (8 g/m2, day 1, iv, over 4 h) was indicated for patients who could not yield a sufficient number of stem cells or were ineligible for HDT/ASCT. Results: Patients' median age was 58 years (range: 17–69). They had low-intermediate (n = 11), high-intermediate (n = 10), or high (n = 7) risk according to the International Prognostic Index (IPI). The overall complete remission (CR) rate following Double-CHOP treatment was 68%. Of all the CR patients, 10 could successfully tolerate a consolidated HDT followed by ASCT, and 7 received HDMTX. Only a single case of treatment-related mortality was recorded during the study. On a median 31-month follow-up, the estimated 3-year overall survival (OS) rate and 3-year relapse-free survival (RFS) rate after CR were 68% and 60%, respectively. Conclusion: Although this study included elderly and excluded low-risk IPI and ALK+–ALCL patients, both RFS and OS results were superiorly favorable, indicating the efficacy of this Double-CHOP regimen and Double-CHOP followed by ASCT/HDMTX consolidations is safe and may achieve prolonged EFS, especially in patients with poor prognostic factors. However, an effective treatment strategy for refractory or relapsing patients needs to be validated and established. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1039 Background: The association between increase in body mass index (BMI) and development of acute promyelocytic leukemia (APL) has been reported. Interaction of APL cells with bone marrow adipocytes in vitro induces phosphorylation of STAT3 and MAPK, resulting in an anti-apoptotic effect in APL cells. However, the influence of obesity on the prognosis of APL is not well understood. Materials and Methods: To evaluate the effect of obesity on the prognosis of adult APL, we retrospectively analyzed 62 patients under the age of 65 with newly diagnosed APL. Patients who could not be administered intensified chemotherapy, because of either poor performance status or adverse events of chemotherapy, were excluded. Results: Median age of patients was 40 years (range, 14–63). Twenty-five were male and 37 were female. Median follow-up period was 646 days (range, 3–12,558). Median BMI was 22.7 (range, 16.0–33.0). Twenty-six patients diagnosed with APL between 1970 and 1992 had been treated with chemotherapy alone (chemotherapy group), and 36 patients diagnosed between 1995 and 2010 had been treated with all-trans retinoic acid (ATRA) ± chemotherapy (ATRA group). In both groups, the outcome was compared between high-BMI (BMI ≥ 24) and low-BMI (BMI 〈 24) patients. Eight out of 26 in the chemotherapy group and 16 out of 36 in the ATRA group were high-BMI patients. In the chemotherapy group, complete remission (CR) was obtained in 13 out of 18 (72.2%) low-BMI patients and in only 3 out of 8 (37.5%) high-BMI patients. By day 498, all 3 CR patients with high BMI had relapsed, whereas only 6 out of 13 (46.2%) low-BMI CR patients had relapsed. The 2-year relapse-free survival (RFS) rate, event-free survival (EFS) rate, and overall survival (OS) rate in high-BMI versus low-BMI patients were 0% v 50.5%, 0% v 61.1%, and 12.5% v 42.8%, respectively. Although the relapsed patients were salvaged with ATRA, arsenic trioxide, or allogeneic bone marrow transplantation, OS was significantly worse in high-BMI patients. On the contrary, in the ATRA group, prognosis between high-BMI and low-BMI patients was not statistically different. Rates of CR, relapse, 2-year RFS, EFS, and OS in high-BMI versus low-BMI patients were 87.5% v 94.7%, 35.7% v 38.9%, 73.3% v 46.2%, 55.0% v 52.5%, and 87.5% v 81.1%, respectively. The initial white blood cell (WBC) and platelet counts have been previously reported to be prognostic factors in APL; however, they were not associated with BMI in our study. A WBC count of 〉10 × 109/L and a platelet count of ≤40 × 109/L were observed in 4 (10.5%) and 28 (73.8%) out of 38 low-BMI, and 4 (16.5%) and 19 (79.2%) out of 24 high-BMI patients, respectively. Conclusions: Our results demonstrate that obesity at diagnosis is a poor prognostic factor in APL, especially in patients not administered ATRA. ATRA overcomes the anti-apoptotic effect of adipocytes for APL cells. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Patients with hematological malignancies are at high-risk for severe infections with drug-resistant gram-positive bacteria, as typified by methicillin-resistant staphylococcus aureus (MRSA). Vancomycin (VCM) is widely used as empirical therapy for these high-risk infections, but the global decline in their susceptibilities to VCM is at issue. Arbekacin sulfate (ABK), a unique aminoglycoside with anti-MRSA activity, has not yet been evaluated in this setting. Patients and methods This is a phase 4 study to evaluate the efficacy and safety of ABK for adult patients with hematological malignancies complicated with infections including febrile neutropenia, who are at high-risk for MRSA. All participant provided written informed consent and this study was approved by the institutional review board of the hospital. ABK was administered intravenously at a dose of 100–400mg every 24–48 hours based on the patients’ body weight and the renal function. Therapeutic drug monitoring (TDM) using Habekacin TDM software (Meiji Seika Pharma, Tokyo, Japan) was performed 48–96 hours after the initiation of ABK. The clinical response was rated as “effective” if the symptoms of infection disappeared or significantly improved, taking into account the vital signs, the serum C-reactive protein (CRP) concentration, and other clinical parameters at baseline and after completion/discontinuation of the treatment. Results From December 2010 to June 2012, 35 eligible patients were treated with ABK up to 4 times with intervals of at least 2 weeks. Consequently, a total of 54 febrile or infectious episodes were registered. The median age, serum creatinine concentration, absolute neutrophil count, axillary temperature, and serum CRP concentration for all cases at baseline were 59 (range 34–77) years, 0.64 (range 0.34–1.31) mg/dl, 0.2 X 109/L (range 0–15.1), 38.4°C (range 37.2–40.5), and 8.2 mg/dl (range 0.7–40.6), respectively. Primary diseases consisted of 34 cases of acute myeloid leukemia, 12 cases of relapsed/advanced non-Hodgkin lymphoma, 3 cases of acute lymphoblastic lymphoma/leukemia, 3 cases of myelodysplastic syndrome/aplastic anemia, and 2 cases of multiple myeloma. Diagnosis of infections consisted of 26 cases of febrile neutropenia, 18 cases of septicemia (methicillin-resistant coagulase negative staphylococci in most cases), 7 cases of pneumonia (MRSA pneumonia in one case), 2 cases of cellulitis, and 1 case of neutropenic colitis. Fifty-two cases (96%) had already received oral prophylaxis using fluoroquinolones and/or intravenous therapy with broad-spectrum antibacterials, and 47 (87%) had received cytotoxic chemotherapies. ABK was initiated with a median of 2 days (range 0–14) after the onset of fever/infection, concomitantly with a variety of broad-spectrum beta-lactams. Overall, 43 cases (80%) attained afebrile states with the absence of symptoms and rated as “effective” at the end of treatment with a median of 10 days (range 4–35). All grade renal toxicity was observed in 6 cases (11%), but they were generally mild and reversible. There were 3 deaths within 30 days of the treatment, but all of them were associated with the progression of the primary disease. Conclusion This study demonstrated for the first time the high efficacy of ABK for persistent or high-risk infections in patients with hematological malignancies. Further evaluations­—e.g. randomized controlled trials comparing ABK with VCM for these populations—are therefore warranted. Disclosures Miura: Meiji Seika Pharma: Consultancy, Research Funding. Iriyama:Meiji Seika Pharma: Research Funding. Kobayashi:Meiji Seika Pharma: Research Funding. Hatta:Meiji Seika Pharma: Research Funding. Takei:Meiji Seika Pharma: Research Funding.