ALBERT

Description: Introduction. Elderly patients aged 65 or older with acute myeloid leukemia (AML) are often ineligible for hematopoietic stem cell transplantation (HSCT) and generally have a poor prognosis. The prognostic risk classification based on NCCN Guidelines Version3. 2017; NCCN 2017 (O'Donnell MR, JNCCN. 2017) is widely performed; however, the impact of this classification on the prognosis of such elderly AML patients is unclear. While nutritional status assessment using controlling nutritional status (CONUT score) based on serum level of albumin (Alb), total-cholesterol (T-chol) and total lymphocyte count (TLC) predicts prognosis of elderly patients with solid tumor (Liu X, BMC Cancer. 2018), the prognostic significance of nutritional status in elderly patients with AML remains to be clarified. Methods. Hokkaido Leukemia Net (HLN) is prospective cohort study collecting AML samples from hospitals of North Japan Hematology Study Group (NJHSG). In this study, we focused on newly diagnosed AML patients aged 65 or older treated without HSCT, and investigated cytogenetic and molecular abnormality of leukemic cells including FLT3-ITD, NPM1, CEBPA, and KIT. We stratified the patients into favorable, intermediate, and adverse risk group based on NCCN 2017. In order to adjust the assessment of nutritional status for hematopoietic malignancy, we modified the CONUT score eliminating TLC from evaluation criteria (modified-CONUT score, Table) and defined patients with score 3 or more at diagnosis as high group. We evaluated the impacts of NCCN 2017 and modified-CONUT scores on overall survival (OS) in these patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards. Results. Overall, 181 patients with newly diagnosed AML patients aged 65 or older enrolled in HLN between April 2010 and March 2018. Seven patients undergone HSCT were excluded and 174 patients were reviewed (Age 65-93, median 71; male 104, female 70). In this cohort, classification based on NCCN 2017 successfully divided the prognosis of the patients for 2-year and 5-year OS [2-year OS; favorable group, 59.9%; intermediate group, 43.8%; adverse group, 8.1%, 5-year OS; favorable group, 41.5%, intermediate group, 19.7%; adverse group, 4.1%, P=0.00258, Figure A]. On 112 patients who had available records of serum Alb levels and T-chol levels at diagnosis, OS in patients with high modified-CONUT score was significantly lower than the low score group [2-year OS; low score group, 50.3%; high score group, 18.5%; 5-year OS; low score group, 23.5%; high score group, 9.24%, P=0.00203, Figure B]. In a univariate analysis, adverse group in NCCN 2017 and high modified-CONUT score were associated with poor 2-year OS. A multivariate analysis demonstrated that　adverse group in NCCN 2017 and high modified-CONUT score were independently associated with poor 2-year OS (adverse group in NCCN 2017; HR, 2.464 ; 95% CI, 1.514 to 4.012, P=0.0002854, high modified-CONUT score; HR, 1.664 ; 95% CI, 1.051 to 2.635, P=0.02976; log-rank). Altogether, we demonstrated that risk stratification based on NCCN 2017 and modified-CONUT score are both effective for predicting prognosis in elderly patients with newly diagnosed AML. Conclusion. The prognostic risk classification based on AML disease status using NCCN Guidelines 2017 effectively stratify prognosis of elderly patients with AML. Moreover, new assessment scoring of patients' nutrition status based on modified-CONUT score can easily stratify elderly patients with newly diagnosed AML. Figure Disclosures Teshima: Novartis: Honoraria, Research Funding.

Description: Background Rituximab, a chimeric monoclonal antibody against CD20 B-cell antigen, is widely used to treat B-cell lymphomas. One of the mechanisms through which rituximab works is antibody-dependent cellular cytotoxicity (ADCC). Granulocyte colony-stimulating factor (G-CSF) enhances the cytotoxicity of neutrophils through ADCC. The issue on the optimal timing of rituximab administration during standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) to exert a maximal effect against tumor cells remains to be determined. We conducted a clinical trial in which rituximab administration was synchronized with G-CSF during standard CHOP in patients with follicular (FL) or diffuse large B-cell (DLBCL) lymphomas. Methods We administered G-CSF for several days to treat neutropenia caused by CHOP regimen for patients with B-cell lymphoma (n=5). In these patients CD64 expressions on both neutrophils and monocytes and ADCC activity were examined at the several time points during one cycle of CHOP. Then, 9 patients with FL and 7 patients with DLBCL were enrolled to receive six to eight cycles of CHOP every three weeks. In each cycle from the second course, rituximab was given in synchronization with several daily administration of G-CSF. Results CD64 expression was enhanced in patients given G-CSF during CHOP, whereas CD64 expression remained unchanged in patients not given G-CSF. CD64 expression levels on both neutrophils and monocytes were significantly up-regulated by the multiple daily administration of G-CSF and reached peak levels at day5 after the start of G-CSF (p=.0007). In ADCC activity, we found that rituximab-mediated cell lysis was correspondingly enhanced at day5 after starting G-CSF (p=.01). Taken together with these finding, we speculated that the administration of rituximab synchronized with multiple daily doses of G-CSF could augment the treatment efficacy of CHOP plus rituximab. First, we commenced G-CSF on day10 of each cycle from the second course of CHOP regimen and continued for at least 5 days to treat enrolled patients who developed neutropenia. Then, we administered rituximab on day5 after the start of G-CSF in the each cycle. In 9 patients with FL, the response rate was 100%, with complete remission (CR) in 8 patients and partial remission in 1 patient. With a median follow-up of 20 months (range; 8–37 months), no relapsed or flare-up patients were observed. In 7 patients with DLBCL, the CR rate was 100%. With a median follow-up of 10.2 months (range; 7–18 months), 2 of 7 patients had relapsed. There were no significant differences in clinically adverse reactions compared with CHOP alone or R-CHOP. Conclusions The administration of rituximab synchronized with G-CSF in standard CHOP regimen may improve clinical response rate and survival without a significant increase in toxicity.

Description: IL-12 is a cytokine comprised of two disulfide-linked proteins (p35 and p40). The highly coordinated expression of p40 and p35 genes to form IL-12 (also called p70) in the same cell type at the same time is essential for the initiation of effective immuno response. It is known that IL-12 p70 promotes the differentiation of type-1 helper T cells, whereas IL-12 p40 acts as an antagonist of IL-12 p70. Granulocyte-colony stimulating factor (G-CSF) affects the balance in the production of anti-inflammatory cytokines. We had previously examined various cytokine productions (such as IL-4, IL-12, IFN-γ) in Non Hodgkin Lymphoma (NHL) patients. We found that only IL-12 production was associated with the disease status in NHL patients. In the present study, we investigated the plasma IL-12 p40, IL-12 p70 production in patients with B-cell lineage NHL treated with chemotherapy (e.g., CHOP) with or without G-CSF administration. Forty-nine patients were analyzed in this study. Plasma IL-12 p40 and IL-12 p70 were measured separately by enzyme-linked immunosorbent assay (ELISA) before chemotherapy and day 17 after chemotherapy. The survival rates was calculated by the Kaplan-Meier method. Eleven of 49 patients were excluded from this study by the ineligibility. The remaining 38 patients were analyzed in this study. Median age was 61 years old. Clinical stage was I(9), II(10), III(12), IV(7). Eleven patients were received chemotherapy only (C) and 27 patients were received chemotherapy with G-CSF (CG). The patient characteristics in each group were not significantly different. Plasma IL-12 p40 concentration decreased no significantly after chemotherapy than before with G-CSF (median, from 141 pg/ml to 111.1 pg/ml) and without G-CSF (median, from166.9 to 197 pg/ml) (P=0.37). However, median plasma IL-12 p40 concentration decreased significantly after chemotherapy than before chemotherapy with G-CSF (median, from148.4 to 130 pg/ml, P=0.009) and without G-CSF (median, from153.5 to 156.8 pg/ml) (P=0.140) by the classification of each chemotherapy course. Plasma IL-12 p40 concentration in CG group patients with clinical stage III and IV was significantly decreased after chemotherapy than before chemotherapy (median 73.3 pg/ml) compared with C group (0.1 pg/ml)(P=0.006). Plasma IL-12 p70 could not be detected in almost all patients. After chemotherapy, 22 patients showed complete remission (CR), 8 patients showed partial response (PR), 3 patients showed no change (NC), 2 patients showed progressive disease (PD) and 3 patients showed unclear disease status. The overall survival (OS) at 24 months was not significantly differed between both groups(C 64.0% VS GC 89.4%, P=0.67). Interestingly, one of the 2 patients of progressive disease showed high IL-12 p40 concentration in association with disease progression and IL-12 p40 concentration remained high in the other patient. We found that chemotherapy with G-CSF decreased IL-12 p40 production. We did not find the difference in overall survival at the present time, however, a longer administration of G-CSF appears to influence on the survival rate by reducing an immunosuppressive IL-12 p40 production.

Description: Abstract 3089 Adult T-cell leukemia/lymphoma (ATL) mainly occurs in HTLV-1 endemic areas such as the southwest island in Japan (Kyushu) and Caribbean countries. A recent report showed that the incidence of ATL was increasing in HTLV-I non-endemic areas (1). Although allogeneic stem cell transplantation (allo-SCT) has been considered to be the only curative treatment for ATL (2, 3), there has been no report about the treatment strategy for ATL occurring in HTLV-1 non-endemic area. We therefore conducted a retrospective analysis for all of the patients who developed ATL and received allo-SCT in an HTLV-1 non-endemic area of Japan, Hokkaido (a northernmost island). Clinical data for 56 patients who received allo-SCT were collected from 12 SCT centers in Hokkaido, Japan. The median age of the patients was 57 years (range: 37 – 69 years). Twenty-eight of the patients had acute type and 22 had lymphoma type. Median count of white blood cells and median levels of serum LDH and serum soluble interleukin-2 receptor (sIL-2R) at diagnosis were 10900/mL, 352 IU/L and 11153 mg/dL, respectively. After chemotherapies mainly using CHOP or VCAP–AMP–VECP regimens, twenty-three of the patents received allo-SCT in complete remission (CR), and the other patients received allo-SCT in non-CR (partial remission, n=16; primary refractory, n=9; relapse, n=23). Median levels of serum LDH and sIL-2R before the conditioning regimen were 218 IU/L and 1153 mg/dL, respectively. HCT-CI scoring was available in 42 of the patients, and the scores were 0 in 15 patients, 1 in 10 patients, 2 in 5 patients and more than 3 in 9 patients. Thirty-nine of the patients received bone marrow, 11 of the patients received peripheral blood stem cells and 6 of the patients received cord blood. Thirty of the patients received SCT from HLA-matched siblings, 22 of the patients received SCT from HLA-matched unrelated donors and 14 of the patients received SCT from HLA-mismatched donors. Seventeen patients received myeloablative conditioning and the other 39 patients received reduced-intensity conditioning. Fifty-three (95%) of the patients achieved neutrophil engraftment at median day of 16. Acute graft-versus-host disease (AGVHD) and grade II-IV AGVHD occurred in 40 (75%) and 31 (58%) evaluable patients, respectively, at median onset day of 29. Chronic GVHD (CGVHD) occurred in 24 (38%) evaluable patients at the median onset day of 168. After a median follow-up period of 48 months, 1-year overall survival (OS) and 5-year OS rates were 56.3% and 46.5%, respectively The survival curve reached a plateau at 22 months after SCT. Univariate analysis showed that year in which SCT was performed, male sex, high level of sIL-2R both at diagnosis and at SCT, and disease status (non-CR at SCT) were significant risk factors for overall survival. SIL-2R at SCT (P=0.02) was determined to be a significant risk factor for disease progression and male sex was marginally significant (P=0.06) by univariate analysis. Non-CR at SCT was marginally significant for transplant-related mortality (P=0.07). Worse survival for male patients and patients in non-CR at SCT were confirmed by using multivariate analysis with Cox's regression model [hazard ratio of 3.15 (95% confidence interval: 1.36–7.30) for male patients and hazard ratio of 2.70 (95% confidence interval: 1.01–7.24) for non-CR patients]. This is the first report on ATL patients in a non-endemic area who received allo-SCT, and we think that this report shows very important information for management of ATL patients in non-endemic areas. Disclosures: No relevant conflicts of interest to declare.

Description: Background; Cytogenetic abnormalities (CA) have been reported as one of the independent prognostic factors for patients with acute lymphoblastic leukemia (ALL). The most common CA in ALL is the Philadelphia chromosome (Ph). Recently, by the introduction of tyrosine kinase inhibitors for Ph+ALL patients and pediatric-inspired protocol for adolescent/young-adult (AYA) patients, the management of ALL has progressed dramatically. We therefore retrospectively analyzed the impact of CA for patients with ALL in the era of TKIs and pediatric-inspired protocol for AYA. Methods; Clinical data for 512 patients who were diagnosed as having ALL between 2007 and 2017 were collected from 21 centers in Hokkaido, Japan. Patients with lymphoblastic lymphoma and Burkitt leukemia were excluded from this study. Results; The median age of the patients was 55 years (range: 15-84 years). Ninety-two of the patients were pediatric (0-14 years), 86 were AYA (15-35 years), 195 were adult (36-65 years) and 148 were elderly patients (66- years). Cytogenetic (G-banding) results were available in 486 patients. Three hundred forty-seven patients had abnormal karyotypes (AK), and 139 patients had normal karyotype (NK). BCR-ABL, including masked Ph, was positive in 193 patients, and 181 (93.8%) of them were more than 36 years. Abnormalities of -7/del (7), +8, +21, 11q32 (MLL), E2A/PBX1 or complex karyotype were seen in 38, 34, 46, 13, 10 and 94 of the patients, respectively. After a first remission induction therapy, 418 of 467 (89.5%) evaluable patients achieved complete remission (CR), and BCR-ABL+ patients showed better CR rate than those without BCR-ABL (93.7% vs. 87.4%, P=0.04). At the median follow-up of 1180 days (9-4049 days), overall survival (OS) was superior in patients with NK than those with AK (P=0.01), and BCR-ABL+ patients showed poorer OS than those without BCR-ABL (P=0.01). However, by subgroup analyses of the age groups, there were no difference of OS between NK and AK (P=0.56 for pediatric, P=0.19 for AYA, P=0.32 for adult and P=0.98 for elderly). In adult and elderly patients, OS was not different between BCR-ABL+ and BCR-ABL-, though in patients over 70 years, BCR-ABL positivity was associated with superior OS (Hazard ratio, 3.2; 95% confidence intervals, 1.04-4.78, P=0.02). The abnormalities of +8 or +21 showed excellent OS in pediatric or AYA patients, however, they showed poor OS in adult or elderly patients. In adult or elderly BCR-ABL- patients, OS of patients with complex karyotype was inferior to those without complex karyotype. Conclusion; BCR-ABL was not associated with poor outcome in the era of TKI. We need to evaluate the effect of CA on patients' outcome depending on age groups. Disclosures No relevant conflicts of interest to declare.

Description: Hemophagocytic lymphohistiocytosis (HLH) is often associated with malignant diseases, mainly B-cell or T/NK-cell lymphoma. However, to date, few studies have examined lymphoma-associated hemophagocytic syndrome (LAHS). Our aim was to clarify the risk factors and prognostic factors of LAHS. A total of 1,181 patients with non-Hodgkin lymphoma were analyzed at 12 institutions in Hokkaido prefecture between April 2007 and December 2011 to assess the incidence, prognosis, and risk factors of LAHS. To evaluate the risk factors for developing LAHS, patient characteristics including age, gender, and histopathology were compared between patients with and without LAHS. The cumulative incidence rate of LAHS was 3.0% (35/1,181). The mortality rate of patients with LAHS was 69% (24/35), which was significantly higher than that of patients without LAHS (29%, P

Description: Background: Chronic phase chronic myeloid leukemia (CML-CP) has become a manageable disease for most patients treated with tyrosine kinase inhibitors (TKIs). However, all TKIs have broad spectrum of toxic effects, and have to be managed by cessation, reduction and supportive care. The objective of this study is to analyze the adverse events (AEs) with different TKIs used as initial therapy for CML and their impact on outcome. Methods: We retrospectively evaluated a total of 494 patients with CML who received at least one TKI, imatinib, dasatinib, nilotinib and bosutinib in a practice setting between 2004 and 2014 at multicenter participating in the Hokkaido hematology study group. Results: Of the 494 patients (315 males and 179 females), with a median age of 59.5 years (range 2-93), imatinib, dasatinib or nilotinib were prescribed as the first line TKI in 283 (62.3%), 109 (24%) and 102 (22.5%) patients, respectively. Disease status at primary diagnosis was composed of chronic phase (450), accelerated phase (21) and blastic phase (23). With a median follow-up of 4.7 years in patients with CML-CP, the 5-year overall survival (OS), event-free survival (EFS) were 94.5% and 92.3%, respectively. The patients with complication or organ dysfunction (61/450, 13.6%) and age 〉60 (227/450, 50.4%) at diagnosis had significantly inferior OS (p= 0.0089 and p= 0.0012). The patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib, nilotinib vs imatinib (41.5%, 42.6% vs 12.5% and 54.3%, 54.5% vs 41.5%, p

Description: BACKGROUND. Synergistic or additive activities for rituximab and cladribine have been shown in preclinical studies. Indolent Non-Hodgkin’s lymphoma (I-NHL) tends to recur with shortening intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Therefore, we evaluated the feasibility, efficacy, and toxicity of combined regimen that consisted of rituximab plus cladribine plus mitoxantrone (the RCM regimen) in the treatment of patients with relapsed or refractory I-NHL. METHODS. The RCM protocol consisted of rituximab at a dose of 375 mg/m2 on Day 1, cladribine at a dose of 0.09 mg/kg per day on Days 2 through 6, and intravenous mitoxantrone at a dose of 6 mg or 10 mg/m2 per day on Day 2. The RCM courses were repeated at 4-week intervals, for up to 4 cycles. RESULTS. Fourteen patients with I-NHL and one patient with mantle cell lymphoma entered in the study. The median age was 60 (range 47–77) and 8 were females. Histology was small lymphocytic lymphoma (n=1), follicular lymphoma (n=13), mantle cell lymphoma (n=1). Median time from diagnosis to RCM treatment was 3.6 (range 0.2–8.1) years and median number of prior treatment regimen was 2 (range 1–4). Twelve patients (80%) had recurrent disease after prior therapy including high dose therapy with autologous stem cell transplant, and 3 patients (20%) had refractory disease. Thirteen patients were treated on the RCM regimen, and 8 patients (61.5%) achieved a complete response, 3 patients (23.1%) achieved a partial response. Therefore, the overall response rate was 92.3%. Median time to response was 2.8 months (range 1.0–6.7). Median progression free survival of responders was 16.5 (range 1.3–25.5) months. The treatment revealed tolerability, with episodes of severe neutropenia (grade 3 and 4) observed in 12 patients (85.7%), episodes of grade 3 and 4 thrombocytopenia observed in 2 patients (15.4%). However, severe infections were not observed in any patients. CONCLUSIONS. The RCM regimen is highly effective and well tolerated modalities of treatment in heavily pretreated and relapsed or refractory patients with I-NHL.

Description: High costs of molecule-targeted drugs such as rituximab, ibritumomab and tositumomab have given rise to an economical issue for treating patients with non-Hodgkin’s lymphoma (NHL). Granulocyte colony-stimulating factors (G-CSF), which are also expensive, are widely used for treating neutropenia after chemotherapy. In Japan, lenograstim at 2 μg/kg (almost 100 μg/body) or filgrastim at 50 μg/m2 (almost 75 μg/body) is commonly administered for patients with NHL after chemotherapy. Therefore, cost-effectiveness is an important issue in treatment for NHL. Patients with advanced-stage NHL who needed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen with or without rituximab were enrolled in this randomized cross-over trial to investigate the efficacy and safety of low-dose G-CSF. Half of the patients were administered 75 μg filgrastim in the first course after neutropenia and 50 μg lenograstim in the second course, and the other half were crossed over. Forty-seven patients were enrolled in this cross-over trial, and twenty-four patients completed the trial. Frequencies of leukocytopenia and neutropenia of grade 4 were similar in patients who received filgrastim courses and those who received lenograstim courses (p=0.6366 in leukocytopenia and p=0.2207 in neutropenia, respectively). Durations of leukocytopenia and netropenia of grade 4 in each treatment course were not different statistically (p=0.3892 in leukocytopenia and p=0.1476 in neutropenia, respectively), and each period of G-CSF administration in both courses was not different statistically (p=0.0676). Frequency of fever higher than 37.5 degrees (p=0.6826) and duration of fever (p=0.7455) were also not statistically different in the two treatment courses. Documented infection containing FN after chemotherapy was not statistically different (p=0.1213). Although the administration dose of G-CSF was not determined on the basis of body weight or body surface area, eight febrile patients were not administered insufficient dose of G-CSF. Therefore, compared with the standard-dose G-CSF course (filgrastim at 75 μg), there was no statistically increased frequency of antibiotic usage in the low-dose G-CSF course (lenograstim at 50 μg) (p=0.2199). The total cost of G-CSF in the low-dose G-CSF (lenograstim at 50 μg) course was significantly lower than that in the standard-dose G-CSF (filgrastim at 75 μg) course (p