Search

BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270–360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90–18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (n = 33 vs 34) and non-Asian (n = 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.

Systemic reports on the descriptive epidemiology of non-Hodgkin lymphoma (NHL) from Southeast Asia are scarce. A nationwide multi-institutional registry was conducted to compare the histopathology, clinical features, and survival of Thai adult patients with NHL using large registries, especially those from Far East Asia (FEA). Using a web-based registry system, 13 major medical centers from the 4 geographic regions of Thailand prospectively collected, from 2007 to 2014, the diagnostic pathology, according to the World Health Organization classification, 2008, clinical features and survival of 4056 patients who were newly diagnosed with NHL. The median age of the patients was 56 years (range, 16-99 years). The male-to-female ratio was 1.3:1. From the total of 4056 patients, T/NK-cell lymphoma (TNKCL) accounted for 12.6% of cases, and 5.1% had human immunodeficiency virus-associated lymphoma. The four leading histological subtypes were diffuse large B-cell lymphoma, not otherwise specified (58.1%); follicular lymphoma (5.6%); extranodal mucosa-associated lymphoid tissue lymphoma (5.2%); and peripheral T-cell lymphoma, not otherwise specified (4.0%). With a median follow-up duration of 46.1 months, the median overall survival of B-cell NHL was significantly longer than that of patients with TNKCL (76.5 vs 28.8 months, P = .0001). Compared to FEA, the Thai registry had an approximately one-half lower relative frequency of TNKCL; the prevalence of extranodal mucosa-associated lymphoid tissue lymphoma was much lower than in Korea, and the frequency of extranodal TNKCL, nasal type, was strikingly low compared to China. It is concluded that while the median age of Thai patients with NHL was approximately a decade younger than for Caucasians, the long-term survival rates for most histological subtypes were comparable. While the histological distribution generally complied with the characteristic Asian features, some differences from FEA were observed.

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder characterized by chronic complement-mediated intravascular and extravascular hemolysis (IVH and EVH), and thrombosis. C5 inhibitors reduce IVH by inhibiting membrane attack complex formation and are the current standard of treatment for PNH. EVH persists in the presence of C5 inhibition. Pegcetacoplan is a C3 inhibitor targeted to control both IVH and EVH. The PADDOCK and PALOMINO studies assessed the safety and preliminary efficacy of pegcetacoplan in complement inhibitor-naïve patients. METHODS PADDOCK was a phase 1b, open-label, pilot study (NCT02588833) with 2 cohorts. Subjects in cohort 1 received pegcetacoplan at a suboptimal dose of 180 mg/day for 28 days; subjects in cohort 2 received pegcetacoplan 270 mg/day for up to 1 year. Subjects could participate in both cohorts. PALOMINO was a phase 2a, open-label, single-cohort study (NCT03593200) in which subjects received pegcetacoplan 270 mg/day for up to 1 year. Both studies enrolled subjects ≥18 years old diagnosed with PNH and no prior treatment with eculizumab. Primary efficacy endpoints in both studies were change from baseline in lactate dehydrogenase (LDH), haptoglobin, and hemoglobin. Secondary efficacy endpoints included change from baseline in reticulocyte count, total bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The number of packed red blood cell transfusions was also recorded. Primary safety endpoints were the incidence and severity of treatment emergent adverse events (TEAEs). RESULTS Three subjects were enrolled in PADDOCK cohort 1 and 20 in cohort 2; 1 subject was enrolled in both cohorts. PALOMINO enrolled 4 subjects. PADDOCK cohort 2 and PALOMINO efficacy data are shown in the Table. At baseline, mean LDH levels were >8× upper limit of normal in both studies. At day 365, mean LDH had decreased to CONCLUSIONS In PADDOCK and PALOMINO, pegcetacoplan improved hematological parameters by controlling both IVH and EVH in patients with PNH. Improvements in clinical parameters were also observed. Pegcetacoplan was shown to have an acceptable safety profile and was generally well tolerated in both studies. PADDOCK and PALOMINO demonstrate the therapeutic potential of pegcetacoplan in the treatment of PNH and support further evaluation in the ongoing phase 3 PRINCE trial (NCT04085601) in complement inhibitor-naïve patients. Disclosures Wong: Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sathar:Novo Nordisk: Honoraria; Bayer: Honoraria; Roche: Honoraria. Tse:MSD: Research Funding; Janssen: Research Funding. Roman:Alexion: Speakers Bureau; Novartis: Speakers Bureau. Amine:Acibadem City Clinic Tokuda Hospital: Current Employment. Tan:Apellis: Consultancy, Patents & Royalties. Di Casoli:Apellis: Current Employment, Current equity holder in private company. Deschatelets:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Francois:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Grossi:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Bogdanovic:Takeda (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Investigator fee in clinical trial; Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Event free survival at 24 months (EFS24) has been described as a powerful predictor for outcome in several subtypes of B cell lymphoma. However, it was limitedly described in T cell lymphoma. We explored the implication of EFS24 as a predictor marker for peripheral T cell lymphoma (PTCL). We reviewed 293 systemic PTCL patients at 13 nationwide major university hospitals in Thailand from 2007 to 2014. The median event free survival (EFS) and overall survival (OS) of PTCL patients in our cohort was 16.3 and 27.7 months with corresponding 2-year EFS and 2-year OS of 45.8% and 51.9%, respectively. A total of 118 patients achieved EFS24 (no events during the first 24 mo). Patients who achieved EFS24 had better OS than patients who did not (2-y OS 92% vs 18.8%; HR, 0.1; P < .001). The standardized mortality ratio of patients achieving EFS24 was 18.7 (95% CI, 14.6-22.8). Multivariable analysis demonstrated performance status, histologic subtype, remission status, and EFS24 achievement as independent predictors for OS. Our study affirmed the value of EFS24 as a powerful prognostic factor for PTCL. Further validation in prospective study setting is warranted.

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p

Background Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices. Objectives Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis. Methods VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only. Results A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC). Conclusion AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to.

Background Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic antimyeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Methods PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1.3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. Findings 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6.47 months (IQR 1.81-13.47) in the panobinostat group and 5.59 months (2.14-11.30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11.99 months [95% CI 10.33-12.94] vs 8.08 months [7.56-9.23]; hazard ratio [HR] 0.63, 95% CI 0.52-0.76; p

Introduction: Stage I disease represents a minor subset of aggressive Non-Hodgkin Lymphoma (NHL) accounting around 10%. Overall prognosis is generally good but varied upon different histologic subtypes and topographic presentation. Herein, we describe an implication of event free survival at 12 months (EFS12) as a predictor for outcomes of stage I aggressive NHL including real-world data on clinical characteristics and treatment patterns of stage I aggressive NHL in a resource-limited country. Patients and methods: Thai lymphoma study group conducted the lymphoma registry which prospectively enrolled and systematically followed newly diagnosed lymphoma patients between 2007 and 2014 from 13 nationwide major University hospitals. We abstracted data of stage I aggressive NHL patients from the registry and obtained additional information from medical record. Clinical characteristics, treatment patterns and survival outcomes were described. EFS12 was a binary endpoint defined as whether patients developed events at 12 months after treatment initiation. Overall survival (OS) was defined as duration from a specific time-point either at the time of diagnosis, at EFS12 time-point to or at the event to death from any causes. Logistic regression model was used to evaluate the association between clinical characteristics and EFS12. Cox regression with EFS12 as a time-dependent co-variate and other clinical parameters were applied to evaluate association between EFS12 and OS. Results: Of 4,371 newly diagnosed lymphomas, there was a total of 636 stage I lymphoma patients (6.86%) including 590 NHL (519 B cell, 71 T/NK cell) and 46 HL. Among 590 stage 1 NHL, 435 were considered patients (356 diffuse large B cell lymphoma (DLBCL) and 8 Burkitt lymphoma (BL), 19 peripheral T cell lymphoma not otherwise specified (PTCL-NOS), 7 angioimmunoblastic T cell lymphoma (AITL), 11 anaplastic large cell lymphoma (ALCL), 1 other PTCL subtypes and 33 extranodal NK T cell lymphoma (ENKTL)). Table 1 summarizes baseline characteristics and treatment data of stage I aggressive NHL. At the time of analysis 61 patients relapsed and 146 patients had died. Major causes of death included infection related events (n=37, 25.3%), non-infectious related complication (n=21, 14.4%) and disease progression (n=60, 41.1%) respectively. With a median follow up of 47.3 months, both median event free survival (EFS) and overall survival (OS) were not reached with corresponding 4 years EFS and 4 years OS of 79.0% and 68.9% respectively (Figure 1A). Four-years OS of patients with aggressive B cell NHL, PTCL and ENKTL was 70.2%, 75.5% and 48.0% respectively. A total of 328 patients achieved EFS12 (No event within the first 12 months after first line treatment initiation). Patients who achieved EFS12 had significant better OS than patients who failed to achieve EFS12 (4-years OS 89.1% vs 7.1%, Hazard ratio 25.9, 95% Confidence Interval 17.7-37.9, P Conclusion: Stage I disease represented a small proportion of aggressive NHL. Natural history and prognosis were highly varied depending upon histology. EFS12 was a power prognostic factor for stage I aggressive NHL and could be used as a clinical tool to stratify patients. Optimal treatment is to be defined to improve outcome and meanwhile minimize toxicities for stage I aggressive NHL patients. Disclosures No relevant conflicts of interest to declare.

Background: PNH is characterized by a degree of bone marrow failure and hemolysis resulting in debilitating hemolytic anemia and an increased risk of thrombosis. Uncontrolled complement activation leads to intravascular hemolysis mediated by the membrane attack complex and extravascular hemolysis mediated by accumulation of C3 fragments, such as C3b, at the cell surface. The only approved treatment for PNH is Soliris®, a C5 inhibitor which targets intravascular hemolysis however, a significant number of patients treated with Soliris® continue to experience ongoing anemia and its associated symptoms. Due to the key role of C3 in the complement cascade, upstream of C5, APL-2, a cyclic peptide inhibitor of C3, acts to prevent both intravascular and extravascular hemolysis. To our knowledge these data represent the first time that PNH patients have experienced significant increases in haemoglobin (Hb) combined with normalisation of lactate dehydrogenase (LDH), absolute reticulocyte count (ARC) and total bilirubin. Aims: This Phase Ib open-label, dose-escalation study being conducted in New Zealand, Thailand, Malaysia and Hong Kong was designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of multiple doses of APL-2, administered by daily subcutaneous injection (SC), in patients with PNH. Methods: To be eligible for entry, PNH patients are required to have Hb levels < 105 g/L (normal range [NR] 119-180), LDH levels >2 times upper limit of normal (x ULN) at screening and have received ≥ 1 blood transfusion in the prior 12 months. The study will recruit 3 subjects into Cohort 1 and up to 20 subjects in Cohort 2 receiving 180 mg/d or 270 mg/d of APL-2, respectively. Efficacy is assessed by change from baseline in Hb, LDH, ARC, total bilirubin and transfusion requirements. Change from baseline in FACIT fatigue score is also reported. Results: As of 24 July 2018, Cohort 1 has been fully recruited and 17 subjects have been dosed in Cohort 2. Of the 17 subjects dosed in Cohort 2, 15 have been treated with APL-2 for >28 days and 9 have been treated for >84 days. Data is summarized for 14 (and 10) subjects in Cohort 2 who have received 270 mg/d of APL-2 for at least 28 (and 84) days; not included in the summary are 2 subjects who have not yet reached Day 28 and one subject who had underlying metastatic ovarian cancer with a chronic low gastrointestinal bleed, unknown at time of screening, resulting in artificially low Hb and high LDH levels determined to be unrelated to PNH. Baseline Hb was 84 g/L (range 55-110) which increased to 110 (74-135) and 116 (71-145) g/L at Days 29 and 85 respectively, representing a mean increase in Hb of 29 g/L and 33 g/L. At Day 29, Hb levels had increased in 100% of subjects with 57% achieving levels within the normal range. Hb increases were maintained in the 10 subjects with Day 85 data available. In the 12 months prior to APL-2 dosing, subjects received a total of 67 transfusions (average 4.8 per year per patient; range 0 to 15). Except for 2 subjects, each of whom received a single transfusion within the first two weeks of treatment i.e. before APL-2 had reached steady state concentration, no transfusions have been reported for any patient during the APL-2 treatment period. Mean baseline LDH of 2459 I/U (9.8x ULN) was reduced to 197 I/U (0.8x ULN) by Day 29. Mean baseline ARC and total bilirubin were reduced from 193 to 89 10^9/L (NR 30-100 10^9/L) and 39 umol/L to 10 umol/L (NR 3-15 umol/L), respectively. Of the 14 subjects, 13 (92%) had LDH and bilirubin within the normal range, and 11 (79%) had ARC in the normal range at Day 29. The Figure shows mean +/- SE for all available data for the 14 subjects through to Week 12. To date, APL-2 has been well-tolerated. No significant infections or thromboembolic events have been observed. One subject was withdrawn from the study due to progression of aplastic anemia related to underlying PNH. In clinical trials in PNH patients more than 5000 SC doses of APL-2 ≥ 270 mg/day have been administered, representing a cumulative systemic exposure of >700 patient weeks of APL-2 treatment. Summary/Conclusions: We demonstrate that systemic inhibition of C3 with APL-2, controls both intravascular and extravascular hemolysis in patients with PNH as shown by significant reductions in LDH, total bilirubin and ARC. Broad control of hemolysis leads to significant and sustained increases in Hb in the absence of transfusions. APL-2 was safe and well tolerated. Disclosures Wong: Alexion: Honoraria. Deschatelets:Apellis Pharmaceuticals: Employment, Equity Ownership. Francois:Apellis Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hamdani:Apellis Pharmaceuticals: Employment, Equity Ownership. Johnson:Apellis Pharmaceuticals: Consultancy, Equity Ownership. Tan:Apellis Pharmacueticals: Consultancy. Tse:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Roche Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Grossi:Apellis Pharmaceuticals: Employment, Equity Ownership.

The purpose of the study was to compare conventional cyclophosphamide/doxorubicin/vincristine/prednisolone (CHOP) chemotherapy with CHOP (3 courses) plus etoposide/methylprednisolone/high-dose cytarabine/cisplatin (ESHAP), high-dose therapy (HDT), and autologous peripheral blood progenitor cell transplantation (PBPCT) as front-line treatment for poor-prognosis aggressive non-Hodgkin's lymphoma (NHL). Between May 1, 1995, and April 30, 1998, 58 patients, aged 15-55 years, newly diagnosed with poor-prognosis aggressive NHL (category F-H by the Working Formulation) were enrolled. According to the age-adjusted international prognostic index, 65% of the patients were high-risk cases and 35% made up the high-intermediate group. After 3 courses of CHOP, 25 of 48 patients were randomized to continue with CHOP, and 23 were randomized to receive 2-4 cycles of ESHAP followed by HDT and PBPCT. There was no significant difference in the rate of complete remission between the two groups (36%, 95% confidence interval [CI]: 18%–57% in CHOP vs. 43%, 95% CI: 23%–65% in ESHAP/HDT) ( P = 0.77). With a median follow-up duration of 39 months, the 4-year failure-free survival (FFS) was superior in the ESHAP/HDT group (38%, 95% CI: 18%–58% vs. 15%, 95% CI: 4%–32%) ( P = 0.04). The disease-free survival was marginally different in favor of the ESHAP/HDT arm (90%, 95% CI: 47%–98% vs. 37%, 95% CI: 7%–69%) ( P = 0.06). The 4-year overall survival between the two treatment arms was comparable (51%, 95% CI: 28%–70% for ESHAP/HDT vs. 30%, 95% CI: 13%–48% for CHOP) ( P = 0.25). Treatment-related mortalities were not significantly different between both groups (17%, 95% CI: 5%–39% for ESHAP/HDT vs. 8%, 95% CI: 1%–26% for CHOP) ( P = 0.41). However, only 61% of the patients assigned to the ESHAP/HDT arm underwent HDT and PBPCT. As compared with CHOP, the corporate regimen of CHOP/ESHAP/HDT seems to improve the FFS in patients with newly diagnosed, poor-prognosis aggressive NHL.

BACKGROUND Nodal peripheral T-cell lymphomas (PTCLs), except ALK-positive anaplastic large cell lymphoma (ALCL) have inferior outcomes compared with their B-cell counterparts. CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) is considered the standard therapy despite consistent results showing its ineffectiveness. The addition of etoposide (E) to chemotherapy showed encouraging results in selected subgroups of patients. We performed a matched-pair analysis comparing the efficacy of EPOCH to CHOP for untreated patients with nodal PTCLs, excluding ALK-positive ALCL. PATIENTS AND METHODS According to the Thai Lymphoma Study Group uniform treatment project, 58 patients with nodal PTCLs including angioimmunoblastic lymphoma, ALK-negative ALCL and PTCL, not otherwise specified received conventional EPOCH regimen as frontline therapy between January 2009 and December 2015. These patients were matched to 58 patients receiving CHOP (1:1) in multicenter registry of lymphoma in Thailand between 2007-2014 by center, International Prognostic Index (IPI) and age. Patients who underwent upfront autologous stem cell transplantation (ASCT) were censored at the time of transplantation. RESULTS The baseline characteristics were well balanced between the two groups except a higher proportion of patients with ALK-negative ALCL in EPOCH group (24.1% vs 5.2%) (Table 1). The median cycle of chemotherapy was 6 (range, 1-8) in both groups. Four patients (6.9%) underwent upfront ASCT after EPOCH induction. The overall response rate for evaluable patients were 75.4% (complete response [CR] 57%) and 58% (CR 39%) in EPOCH and CHOP groups, respectively (P CONCLUSION EPOCH provided superior outcomes than CHOP regimen as frontline therapy for patients with nodal PTCLS, excluding ALK-positive ALCL. The promising efficacy of EPOCH warrants further evaluation in prospective randomized controlled study. Table 1 Baseline characteristics of patients with nodal PTCLs treated with EPOCH or CHOP regimens Table 1. Baseline characteristics of patients with nodal PTCLs treated with EPOCH or CHOP regimens Figure 1 Kaplan Meier progression free survival of patients with untreated nodal PTCLs according to chemotherapy regimens Figure 1. Kaplan Meier progression free survival of patients with untreated nodal PTCLs according to chemotherapy regimens Figure 2 Kaplan Meier overall survival of patients with untreated nodal PTCLs according to chemotherapy regimens Figure 2. Kaplan Meier overall survival of patients with untreated nodal PTCLs according to chemotherapy regimens Disclosures No relevant conflicts of interest to declare.

The impact of health insurance with inequitable rituximab coverage on the survival of patients with diffuse large B-cell lymphoma (DLBCL) has never been reported. We conducted a nationwide multicenter analysis on the outcome of 553 adult patients consecutively diagnosed with DLBCL between July 2003 and June 2006, in whom treatment cost was reimbursed under the Civil Servant Medical Benefit Scheme (CSMBS) (n =201) or the Universal Coverage Scheme (UCS) (n =352). The international prognostic index was comparable between the two payment groups. Rituximab-based therapy was administered in 45.3% and 3.1% of CSMBS and UCS patients, respectively (p0.001). With a median follow-up of 24.6 months, the 6-year progression-free survival (PFS) was superior for CSMBS patients (34.2 vs. 23.2%, p =0.005). "Not treated with rituximab-based therapy" was the strongest adverse prognostic feature indicating a short PFS (hazard ratio 2.1, p0.001). It is concluded that lack of access to rituximab is the principal factor accounting for the inferior PFS observed in Thai patients with DLBCL who are treated under the UCS.

Patients with advanced-stage follicular lymphoma (FL) are considered to be incurable and eventually relapse after conventional chemotherapy. High-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) can unequivocally prolong the disease-free survival (DFS) but not overall survival (OS) in the first complete remission and in a salvage setting. Recently, the incorporation of rituximab and radioimmunoconjugates in HDT with AHSCT seems to be promising and widely accepted. Although allogeneic hematopoietic stem cell transplantation (alloHSCT) consistently demonstrates longer DFS compared with historical controls of HDT followed by AHSCT, this approach cannot be considered as a standard of care due to its unacceptably high treatment-related mortality (TRM) and the lack of improving OS. With highly encouraging results and less TRM, the role of nonmyeloablative hematopoietic stem cell transplantation (NMHSCT), especially after AHSCT needs to be validated in randomized controlled trials with a long-term follow-up.

Introduction: Mantle cell lymphoma (MCL) is a relatively rare and aggressive mature B-cell non-Hodgkin lymphoma (NHL) entity, encounting for 3-10% of newly diagnosed patients. The purpose of the study is to analyse the incidence, clinical features and outcomes of Thai patients with MCL and compare data with those of Western countries. Patients and methods: From the nationwide multicenter registry of 4,056 newly diagnosed NHL patients in Thailand between 2007-2014, patients with MCL were identified according to the criteria of diagnosis by WHO classification of lymphoid disorders, 2008. The incidence, baseline clinical characteristics and outcomes were then analysed. Results: Ninety-nine patients (2.4%) were found to have MCL. The median age was 59.8 years (range 33-86). Seventy-nine percent of patients were men. The primary sites of disease were lymph nodes (60%), bone marrow (19%), GI tract (9%), Waldeyer's ring (4%), sinonasal area (2%) and miscellaneous (6%). (Figure 1). Eighty-three percent of the patients had stage III/IV. Eighty-one patients (82%) received chemotherapy (60.5% with CHOP or CHOP-like chemotherapy, 30.9% with HyperCVAD, and 26% with rituximab-based). Other received palliative chemotherapy or did not receive any. At a median follow-up time of 42 months, the median survival was 30 months (range, 1-94 months). By using Cox analysis, only Ann Arbor stage had impact on overall survival. Conclusion: MCL is less frequent in Thailand compare to the Western countries. The long-term survival is also much inferior reflecting the limited access to rituximab as well as the high intensity therapy in treating MCL in Thailand. Table 1. Comparison of MCL patients according to treatment modalities Clinical characteristics (Total 81 cases) CHOP-like (n=49 ) High intensity CMT (n = 25 ) CVP or palliative CMT (n = 7 ) p-value No R 33 19 4 - Age > 60 19 (67%) 6 (24%) 5 (71%) - Stage III-IV 42 (85.7%) 21 (84%) 7 (100%) - Response Overall response Complete response 26 (53.1%) 19 (38.8%) 17 (68%) 11 (44%) 6 (85.7%) 3 (42.8%) - Survival Mean OS (months) (Min-Max) 3yr-OS 5yr-OS 26.8 (0.1-83) 52.2% 52.2% 38.8 (0.8-93.9) 51% 38.1% 34.3 (10.7-70.5) 51% 30.2% 0.44 0.44 Figure 1. Biopsy sites Figure 1. Biopsy sites Figure 2. The Kaplan-Meier plots of OS according to treatment groups Figure 2. The Kaplan-Meier plots of OS according to treatment groups Figure 3. The Kaplan-Meier plots of OS according to tretment with rituximab Figure 3. The Kaplan-Meier plots of OS according to tretment with rituximab Disclosures Khuhapinant: Roche: Honoraria.

Introduction In pre-rituximab era, the IPI has been developed and widely used to predict the prognosis of aggressive lymphoma while Miller's stage modified IPI1 was reported as a better prognostic model for limited stage DLBCL. Recently, NCCN-IPI2 was stated to be a better predictor of prognosis for DLBCL in rituximab era. We aim to compare the prognostic significance between IPI, Miller's stage modified IPI, NCCN-IPI and the new proposed stage adjusted IPI (St-IPI) in limited stage DLBCL patients treated with rituximab based regimens. Methods From the 4,371 patients in a multi-institutional registry of newly diagnosed lymphoma in Thailand between 2007-2014, there were a total of 2,399 patients with DLBCL. We included patients with limited stage DLBCL receiving R-CHOP or R-CHOP-liked chemotherapy. The clinical outcomes were analyzed according to IPI, Miller's stage modified IPI, NCCN-IPI and St-IPI. To generate the St-IPI, we used 3 predictors from IPI namely, age > 60, elevated LDH and ECOG ≥ 2, classified patients into 3 risk cohorts, i.e., the low (score 0), intermediate (score 1-2), and high risk (score 3) group. Results A total of 274 patients with a median age of 58 years (range, 15-91) were included. Seventy-four percent of the cohort had stage II disease, 44% and 32% of them had elevated LDH and ECOG ≥ 2, respectively. According to St-IPI, 77, 183 and 14 patients were categorized as low (score 0), intermediate (score 1-2) and high risk groups (score 3), respectively. Most of the patients (96%) received R-CHOP regimen and one fifth of them underwent consolidation radiotherapy, contributing to a complete response rate of 76%. With a median follow up of 52 months, the 5-year progression free survival (PFS) according to St-IPI among low, intermediate and high risk groups were 79%, 66% and 22%, respectively (HR 2.48, 95%CI: 1.55-3.86). The corresponding figures for 5-year overall survival (OS) were 84%, 73% and 49%, respectively (HR 2.95, 95%CI: 1.54-4.37). The 5-year PFS and OS according to IPI, NCCN-IPI and Miller's stage modified IPI were described in Table 1. When comparing between risk models, St-IPI was able to discriminate more accurately low risk PFS than IPI, distinguished more precisely high risk PFS than NCCN-IPI and Miller's stage modified IPI (Figure 1). All risk models had no differences in predicting OS at 5 years, nevertheless, there was a trend of inferior survivals after 5 years among limited stage DLBCL patients with high risk St-IPI (Figure 2). Conclusion St-IPI is a simple and better model in predicting PFS for limited stage DLBCL treated with R-CHOP. The model is able to predict the lower risk disease more discriminately than the IPI which would suggest the tailor therapy approach to avoid unnecessary treatment related toxicities. Moreover, the St-IPI is better in predicting patients with high risk of relapses in whom more aggressive treatment is warranted to improve the cure rate of the patients. 1 Miller, et al. N Engl J Med 1998; 339: 21-6 2 Zhou, et al. Blood. 2014;123: 837-842 Table 1. 5-year PFS and OS according to risk groups categorized by St-IPI, IPI, NCCN-IPI and Miller's stage modified IPI Risk model 5-year PFS (%) HR (95%CI) P -value 5-year OS (%) HR (95%CI) P -value St-IPI (Age > 60, elevated serum LDH, ECOG ≥ 2) 2.48 (1.55-3.86) 60, elevated LDH, ECOG ≥ 2, Stage ≥ III, extranodal involvement >1) 1.99 (1.43-2.78) 40-60, 60-75, >75; elevated serum LDH 1-3X, > 3X; ECOG ≥ 2, Stage ≥ III, extranodal disease in bone marrow, liver/GI tract or lung) 1.83 (1.30-2.57) 60, elevated serum LDH, ECOG ≥ 2, Stage II) 1.71 (1.28-2.28) Figure 1. PFS according to risk groups categorized by St-IPI (Figure 1A), IPI (Figure 1B), NCCN-IPI (Figure 1C) and Miller's stage modified IPI (Figure 1D) Figure 1. PFS according to risk groups categorized by St-IPI (Figure 1A), IPI (Figure 1B), NCCN-IPI (Figure 1C) and Miller's stage modified IPI (Figure 1D) Figure 2. OS according to risk groups categorized by St-IPI (Figure 2A), IPI (Figure 2B), NCCN-IPI (Figure 2C) and Miller's stage modified IPI (Figure 2D) Figure 2. OS according to risk groups categorized by St-IPI (Figure 2A), IPI (Figure 2B), NCCN-IPI (Figure 2C) and Miller's stage modified IPI (Figure 2D) Disclosures Khuhapinant: Roche: Honoraria.

INTRODUCTION: Hodgkin lymphoma (HL) is curable if the patients are treated early and properly. Thailand is a country where public health care resources are limited and as such, dacarbazine was not listed in the national drug list, thus, cannot be reimbursed in patients under the Universal Coverage payment scheme which comprised 60-70% of all patients. This study was aimed to compare outcome differences between patients with HL who were treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), ABV (doxorubicin, bleomycin, vinblastine) and COP/ABV (cyclophosphamide, vincristine, prednisolone, procarbazine /ABV) as happened in the real world practice in Thailand. METHODS: From the nationwide multicenter registry of 4,371 newly diagnosed lymphoma patients in Thailand from 2007 to 2014, there were 316 patients with HL. The data is part of the Thai Lymphoma Study Group Registry performed at the thirteen major medical centers in Thailand. The patients' characteristics, treatment options and outcomes were analyzed. RESULTS: The median age was 42 years (range,13-89 years). Male: female was 1.3:1. Fifteen percent of the patients were older than 60 years. Histological subtypes were classical HL, nodular sclerosis, 45.3%, mixed cellularity, 28.6%, lymphocytic rich, 3.5%, lymphocytic depletion 5.1%, nodular lymphocytic predominant, 7.5% and unclassifiable, 10.5%. Fifty percent of patients were stage III/IV and 46% had B symptoms. Clinical characteristics were not significantly different between patients treated with ABVD, ABV and COP/ABV (Table 1). Treatment options were varied according to doctors' preference, hospital strategy and the reimbursement policy. ABVD was the most common prescribed regimen (32.7%); the other options included ABV (29.2 %), COP/ABV (13.1 %), CHOP (2.8 %) and radiotherapy only (1.6%). With a median follow-up of 32 months, patients treated with ABVD had superior 5 year overall survival rate over those treated with ABV (86.6% vs 47.7%, p < 0.001) and COP/ABV (86.6% vs 62.7%, p < 0.01)(Figure 1). Discrepancies in survivals could be demonstrated both in patients with limited as well as in advanced diseases (Figure 2). CONCLUSION: ABVD yielded superior survival compared to ABV and COP/ABV. Dacarbazine is therefore an essential drug for the treatment of HL in developing countries. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Khuhapinant: Roche: Honoraria.

Introduction: Despite improved treatment outcome of DLBCL in the immunochemotherapy era, secondary CNS relapse remains a serious and fatal complication. Several prognostic models were reported in order to define high-risk patients for CNS relapse and provide proper prophylactic strategies. There is no standard approach for CNS prophylaxis in DLBCL with more data suggesting lack of efficacy of intrathecal chemoprophylaxis. In 2013, the DSHNHL introduced a prognostic model including each international prognostic index (IPI) factor (age, lactate dehydrogenase (LDH), stage, performance status (PS), extranodal involvement (EN) and kidney/adrenal involvement) to stratify patients into 3 groups. Herein, we applied and validated DSHNHL model to DLBCL patients treated at nationwide University hospitals in Thailand including analyzing an impact of rituximab and intrathecal chemoprophylaxis on CNS relapse. Method: From the nationwide multicenter registry of 4,371 newly diagnosed lymphoma patients in Thailand between 2007 and 2014, there were a total of 2,399 DLBCL patients. We looked at the incidence and clinical predictors of CNS relapse, the effect of immunotherapy and intrathecal chemoprophylaxis on CNS relapse in DLBCL who were treated with at least one cycle of CHOP-like or intensive chemotherapy regimens. Result: After excluding patients with CNS/ocular involvement at diagnosis, 2,034 DLBCL patients were included in the analysis. Table 1 summarizes baseline characteristics of DLBCL patients. The median follow up time for living patients was 51 months (interquartile range, 22-75 months). A total of 565 patients (27.8%) progressed or relapsed after first-line induction therapy and 61 patients (3.0%) developed CNS relapse. Median time to CNS relapse was relatively shorter than non-CNS relapse (8.4 vs 10.5 months, P=0.07). A total of 729 (35.8%), 1,024 (50.3%) and 281 (13.8%) patients were classified as low-, intermediate- and high-risk groups based on DSHNHL risk model for CNS relapse. Of high DSHNHL risk group, 45 patients (16%) received intrathecal chemotherapy for CNS prophylaxis along with induction treatments. Using the competing risk regression analysis, 2-year cumulative incidence of CNS relapse was 2.7% (1.5%, 3.1%, and 4.6% for low-, intermediate- and high-risk DSHNHL group respectively). Univariate analysis showed elevated LDH, poor PS, stage III/IV, presence of B symptoms, higher risk IPI and DSHNHL risk group as risk factors of CNS relapse (Table 2). Presence of concurrent EN involvement more than one site and elevated LDH was a significant predictor of CNS relapse (Hazard Ratio [HR] 2.39, P =0.004). Kidney/adrenal gland and gonadal involvement were not associated with higher risk of CNS relapse whereas breast involvement showed a trend toward higher incidence of CNS relapse (HR 2.46, P=0.07). Either immunochemotherapy or intrathecal chemoprophylaxis was not associated with lower risk of CNS relapse; in fact patients who received intrathecal chemotherapy had more CNS relapse though this could be due to selection bias. Median survival of patients with CNS relapse was 13.2 months which was significantly worse than patients without CNS relapse (81.8 months, P Conclusion: The 2-year cumulative incidence of CNS relapse in DLBCL in this analysis was 2.7% which was comparable to other series. Using the DSHNHL prognostic model was able to define DLBCL patients into low, intermediate and high risk for CNS relapse. The high-risk group in our series had lower incidence of CNS relapse compared to German and recently reported British Columbia cohorts. Our study confirms poor survival outcome of DLBCL patients with CNS relapse and no protective effect of immunochemotherapy or intrathecal chemoprophylaxis on the incidence of CNS relapse. Novel risk-adapted CNS prophylaxis strategies are warranted to be further investigated in prospective studies. Figure 1. Baseline characteristics of DLBCL patients based on pattern of CNS relapse IQR: Interquartile Range Figure 1. Baseline characteristics of DLBCL patients based on pattern of CNS relapse. / IQR: Interquartile Range Figure 2. Univariate analysis for factors associated with risk of CNS relapse DSHNHL: The German High Grade Non-Hodgkin's Lymphoma Study Group, R:Rituximab Figure 2. Univariate analysis for factors associated with risk of CNS relapse. / DSHNHL: The German High Grade Non-Hodgkin's Lymphoma Study Group, R:Rituximab Figure 3. 1A shows cumulative incidence (CI) of CNS relapse. 1B shows CI of CNS relapse stratified by the presence of > 1 extranodal involvement and elevated LDH. 1C shows CI of CNS relapse stratified by DSHNHL risk group. 1D shows overall survival based on relapse status. Figure 3. 1A shows cumulative incidence (CI) of CNS relapse. 1B shows CI of CNS relapse stratified by the presence of > 1 extranodal involvement and elevated LDH. 1C shows CI of CNS relapse stratified by DSHNHL risk group. 1D shows overall survival based on relapse status. Disclosures Khuhapinant: Roche: Honoraria.

Introduction The difference in origin between nodal and extranodal DLBCL may contribute to the distinct clinical outcomes and prognoses. Previous studies including patients with both limited and advanced diseases showed various clinical results. The purpose is to study the clinical characteristics, and outcomes of patients with limited stage DLBCL according to the primary site of lymphoma. Methods From the 4,371 patients in a multi-institutional registry of newly diagnosed lymphoma in Thailand between 2007-2014, there were 920 patients with limited stage DLBCL, excluding those with primary central nervous system lymphoma. The baseline patient characteristics and clinical outcomes were analyzed according to the primary site of diseases. Results Majority of patients had extranodal diseases (n= 535, 58.2%) while the other 385 cases (41.8%) had nodal DLBCL. The five most common primary sites of extranodal disease were Waldeyer ring (12.2%), stomach (7.3%), intestine (6.8%), sinonasal cavity (6.7%) and breast (2.8%) (Figure 1). Baseline characteristics, treatment and responses were well balanced between the two groups except for a slightly higher proportion of stage I disease in extranodal DLBCL (36.8% vs 28.8%, P =0.01) (Table 1). Two-third of patients received CHOP chemotherapy while the others were treated with R-CHOP. Radiotherapy (RT) was delivered to one-fifth of the patients in each group. Overall response rates were comparable between patients with nodal and extranodal diseases (68.6% vs 66.7%). With a median follow up of 52 months, there were no significant differences of progression free (PFS) (57.6 vs. 60.8%, P =0.46) and overall survival (OS) (63.1% vs. 65.6%, P =0.20) between patients with extranodal and nodal diseases. Among patients with extranodal manifestations, those with primary lymphoma at pancreas & gall bladder, pleura & lung, adrenal gland & kidney and intestine had the worst 4-year OS (33.3%, 39.3%, 53.3%, and 53.7%, respectively) (Figure 2). RT improved PFS (71.7% vs. 54.5%, P =0.03) and OS (74.7% vs. 62.9%, P =0.02) only in primary nodal DLBCL. The two prognostic factors for survivals were being treated with R-CHOP (HR for PFS 0.84, 95%CI: 0.74-0.96; HR for OS 0.70, 95%CI: 0.55-0.91) and the IPI scores (HR for PFS 1.49, 95%CI: 1.24-1.80; HR for OS 1.86, 95%CI: 1.37-2.51). Conclusion Among limited stage DLBCL in Thailand, primary extranodal disease was more common than the nodal manifestations. Primary sites of origins did not affect baseline characteristics as well as the outcomes. Patients with unusual site lymphomas, however, had an inferior survivals warranted a further investigational therapy. Table 1. The clinical characteristics of limited stage DLBCL according to disease of origin Clinical characteristics Nodal DLBCL(n = 385) Extranodal DLBCL(n = 535) p-value Male 205 (53.2%) 294 (55%) 0.60 Median age (years) 54.9 56.2 0.23 Stage Stage I Stage II 111 (28.8%) 274 (71.2%) 197 (36.8%) 338 (63.2%) 0.01 HIV seropositivity 11 (3.4%) 19 (4.3%) 0.53 Age ≥ 60 164 (42.6%) 230 (43%) 0.90 High serum LDH 183 (47.5%) 230 (43%) 0.17 ECOG ≥ 2 46 (11.9%) 60 (11.2%) 0.73 IPI Low (IPI = 0-1) Low-intermediate (IPI =2) High-intermediate (IPI = 3) 285 (74.0%) 81 (21.0%) 19 (4.9%) 406 (75.9%) 108 (20.2%) 21 (3.9%) 0.82 Chemotherapy regimens R-CHOP CHOP 98 (29.0%) 227 (67.2%) 160 (33.7%) 286 (60.2%) 0.25 Radiotherapy 94 (24.9%) 120 (22.8%) 0.46 Response Overall response Complete response 261 (68.6%) 227 (59.7%) 352 (66.7%) 322 (61%) 0.24 *IPI: International prognostic index Figure 1. Sites of origin among limited stage DLBCL Figure 1. Sites of origin among limited stage DLBCL Figure 2. Overall survival of patients with limited stage DLBCL according to primary sites of lymphoma Figure 2. Overall survival of patients with limited stage DLBCL according to primary sites of lymphoma Disclosures Khuhapinant: Roche: Honoraria.

OBJECTIVE: To analyze clinical features, outcome of treatment and prognosis of Thai patients with oropharyngeal diffuse large B cell lymphoma (DLBCL). METHODS: From the nationwide multicenter registry of 4,371 newly diagnosed lymphoma patients in Thailand between 2007 and 2014, there were a total of 2,399 DLBCL patients. The patients who have oropharyngeal lesions were collected. Clinical profiles and response to treatment and outcome were analyzed. RESULTS: Among 2,399 DLBCL patients, 1664 cases(69.4%) had extranodal lesions. The five most common site of extranodal involvement were oropharyngeal, stomach, intestine, sinonasal cavity and breast. There were 193 cases with oropharyngeal lesions accounted to 11.6% of DLBCL with extranodal lesions. The median age was 58 years (range17-91).Fifty percent of patients were male. B symptoms were presented in 39.9%. Most common sites of involvement were tonsils (81.8%) and base of tongue (15.0%) Majority of patients presented with stage I-II ( 21.2%, 43.0%) , 38.8% presented with advanced stage. Eighty three percent of the patients had ECOG score 0-1. Majority of the patients have IPI< 2 (74.6%). Ninety four percent of the patients received chemotherapy, the most common regimen was CHOP (96.0%), Rituximab was given in 29.1%. Intrathecal methotrexate was given in 8.9% Radiation therapy combine with chemotherapy was used in 16.0%, 2.7% received only local radiation therapy and 2.7% received only palliative care . Among those who received curative aim treatment,the overall response rate was 87.1% (CR 78.4 %). With a median follow-up time of 46 months (range 4-91 months) , median overall survival (OS) was 50.3 months and median progression free survival(PFS) was 31.5 months. The multivariate analysis revealed IPI>2, age>60 years and stage >2 associated with poor OS (HR 2.98, CI: 1.93-4.61, p=0.000, HR 2.79, CI:1.67-4.68, p=0.000 and HR 1.79,CI:1.09-2.97, p=0.002) but only age and IPI was significantly associated with PFS (HR 2.79,CI: 1.28-6.06, p=0.10, HR 2.86, CI:1.37-5.97, p=0.005). Advanced stage trended to associated with poor PFS but did not reach statistical significant (HR 1.90,CI:0.95-3.79, p=0.07). Rituximab significantly improved both OS and PFS (HR 0.58, CI;0.33-0.99, p=0.046 and HR 0.44, CI; 0.19-1.0, p=0.05) but radiotherapy did not improved outcomes(HR1.05,CI:0.56-1.99, p=0.87). The patient who received intrathecal methotrexate had poor outcome (HR 3.43,CI: 1.57-7.50, p=0.004) CONCLUSION: Comparing to other Thai patients with DLBCL , those with orpharyngeal lesion have similar prognosis. Receiving Rituximab improved outcomes. Different from international data, combination chemo-radiotherapy and intrathecal chemotherapy were not routinely practice and did not relate with good outcomes. This may be caused by limited resource of radiotherapy in Thailand so it was reserved for only patients with bulky mass or impending airway obstruction. Table 1. Clinical characteristics No. of patients % Median age in year (range)58 (17-91) < 60 >60 108 85 55.96 44.04 Male: female ratio 1:1Male Female 98 95 50.78 49.22 Stage1-2 3-4 124 69 64.25 35.75 ECOG0-1 2-4 159 34 82.3. 17.62 B symptom 77 39.9 LDHNormal High 111 82 57.51 42.49 IPI groupLow Intermediate-Low Intermediate high High 77 67 32 17 39.90 34.72 16.58 8.81 TreatmentPalliative Chemotherapy alone XRT alone Combine chemo-XRT 5 145 5 28 2.73 79.23 2.73 15.30 Response to treatment Overall response Complete response Partial response 121 109 12 87.1 78.4 8.7 Disclosures Khuhapinant: Roche: Honoraria.

OBJECTIVES: To analyze clinical features, treatment outcomes in Thai patients with angioimmunoblastic T cell lymphoma (AITL). PATIENTS AND METHODS: From a nationwide multicenter registry of 4,056 NHL patients in Thailand between 2007 and 2014, there were a total of 54 angioimmunoblastic T cell lymphoma (AITL) patients. The clinical features and treatment outcomes were analyzed. RESULTS: There were a total of 54 cases accounted to the prevalence of 1.2 % of NHL and 12% of peripheral T cell lymphoma. The median age was 59 years (range 35-81). Male: female was 1.5:1. Seventy-eight percent of patients had advanced disease (stage III, IV), 69% had B symptoms, 28% had poor performance status (ECOG > 2) and 61% had elevated serum LDH level. Extranodal involvement was 56 %; the most common sites of which were bone marrow (30%) and liver (19 %). Thirty-five percent of the patients had IPI score > 2 and 7% had PIT >2. Eighty-one percent of patients were treated with chemotherapy of which CHOP/CHOP-like was the main regimen. Of the 43 evaluable patients receiving chemotherapy, complete remission was achieved in 41.9%. Forty-four percent of patients with complete remission had disease progression. With the median follow-up time of 65 months, the 5-year overall survival was comparable to peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), (28% vs. 37%, p=0.7). On multivariate analysis, response to treatment (at least PR) was associated with better outcome (HR 0.13, 95%CI 0.05-0.33, p= 0.000). Patients with PIT > 2 or B symptoms trended to have inferior survival outcome, although statistical significant was not achieve (HR 3.2, 95%CI 0.36-27.95, p=0.3; HR 2.3, 95%CI 0.78-7.31, p=0.13). CONCLUSIONS: The prevalence of Thai patients with AITL was much less than data reported from the international T-cell lymphoma project (18% of T-NHLs) (Vose et al, JCO2008;26:4124-30). The long-term survival was not inferior to patients with PTCL, NOS. Disclosures Khuhapinant: Roche: Honoraria.

Introduction The additional benefit of consolidation radiotherapy (RT) following chemotherapy in limited stage DLBCL remains controversial. Previous 5 randomized trials, 4 trials before rituximab era (SWOG 8736, ECOG 1484, GELA 93-1 and 93-4 studies) and 1 trial with R-CHOP combination (Lysa/Goelams 02-03), could not demonstrate a remarkable benefit of RT. The purpose of this study is to explore the benefit of combined modality treatment including the combination of RT and rituximab (R)-based chemotherapy in limited stage DLBCL. Methods From the 4,371 patients in a multi-institutional registry of newly diagnosed lymphoma in Thailand between 2007-2014, there were a total of 2,399 patients with DLBCL. We included patients with limited stage DLBCL receiving CHOP/CHOP-liked chemotherapy +/- R and +/- RT. The baseline patient characteristics and clinical outcomes were analyzed according to treatment modalities. Results A total of 816 patients with a median age of 56 years (range, 15-91) were included in the study. Male:female was 1:1.1. Majority of patients had primary extranodal diseases (58%), stage II (68%), good performance status (89%), normal LDH (55%) and no B-symptoms (59%). The IPI scores were 0 (30.6%), 1(45%), 2 (20%) and 3 (3.9%), respectively. The modalities of treatment were CHOP alone (48.5%), R-CHOP (26.5%), CHOP+RT (17.9%) and R-CHOP+RT (7.1%). Patients in R-CHOP group were older than in other groups ( P =0.001) (Table 1).There was a higher proportion of patients in stage II disease in R-CHOP (74.1%) and R-CHOP+RT (74.1%) groups than in CHOP (66.9%) and CHOP+RT (57.5%) groups ( P =0.007), whereas the patients were relatively equally distributed between the IPI scores. Complete response (CR) rate was higher in R-CHOP+RT group (82.8%) than in R-CHOP (75%), CHOP+RT (70%) and CHOP groups (58%) ( P

mo (range 2.9-178.1) for the 190 survivors. Median age was 58. 61% were male. 38% had ISS stage I and 18% stage III. 10% had high risk cytogenetics. 51% started therapy using 1⁄4 3-druginduction-regimens. There appeared to be no statistically significant difference in age, cytogenetic risk, and ISS between pts in both groups (p1⁄40.128, 0.362, 0.302, respectively) but time from induction to ASCT was statistically different (6.1 vs 6.5 mo, p1⁄40.012). Best response prior to ASCT was >1⁄4VGPR 52% and >1⁄4PR 88% while post ASCT >1⁄4VGPR 82% and >1⁄4PR 98%. Median PFS from ASCT for the entire cohort was 32.3 mo, and median OS 84.2 mo. By multivariate analysis, cytogenetic risk (p1⁄40.002) and response prior to ASCT (p 1⁄43 groups, we could not show a statistical difference in median PFS (29.5 mo vs 33.4 mo; p1⁄40.26) and OS (78.6 mo vs 94.4 mo; p1⁄40.54), respectively. Conclusion: This retrospective study suggests that a response adapted approach to MM therapy may yield good outcome and guide the choice of induction. With emerging data suggesting the importance of MRD in predicting outcome, response-driven study designs should be prospectively explored.

Characterization of an artificial antigen-presenting cell to propagate cytolytic CD19-specific T cells

Objective Preclinical and clinical trials are investigating the potential of T cells genetically modified to express a first-generation CD19-specific chimeric antigen receptor (CAR), designated CD19R, for adoptive immunotherapy of B-lineage leukemias and lymphomas. Currently, our genetically modified CD19-specific CD8 + (CD19R + CD8 + ) T cells are expanded ex vivo using a rapid expansion protocol (REP) to clinically meaningful numbers after antigen-independent activation with anti-CD3ɛ and recombinant human interleukin-2 on a double-cell feeder-layer of γ-irradiated allogeneic peripheral blood mononuclear cells and a lymphoblastoid cell line. We now compare the ability of the REP with CD19-dependent numerical expansion using CD19 + artificial antigen-presenting cells to propagate CD19R + CD8 + T cells. Materials and Methods We evaluated long-term (28 days) propagation, CD19R CAR expression, and cytolytic activity of CD19R + CD8 + T cells expanded by either a REP or an antigen expansion protocol (AEP) using K562-derived artificial antigen-presenting cells coexpressing CD19 antigen and two T-cell costimulatory molecules (4-1BB ligand and major histocompatibility class I–related chains A) in the presence of exogenous recombinant human interleukin-2 and recombinant human interleukin-15. Results Populations of CD19R + CD8 + T cells could be numerically expanded on AEP to meet anticipated clinical need. The AEP was superior to REP, as this method selected for an outgrowth of T cells with increased CD19R CAR expression and improved redirected cytolytic activity. Conclusion Robust propagation of CD19R + CD8 + T cells achieved by AEP supports qualifying this cell line for use in current good manufacturing practices for CAR + T cells as an alternative to REP for adoptive immunotherapy clinical trials.

Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)–derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.

Standard-dose (2 mg/day) oral granisetron seems to have more antiemetic efficacy than that of high-dose (0.5-1 mg/kg/dose) metoclopramide in moderately emetogenic chemotherapy. However, the cost of oral granisetron is much higher than that of metoclopramide so the authors tried to overcome this disadvantage by dose reduction and adding dexamethasone to enhance the antiemetic effect of oral granisetron. Twenty four young patients (aged50 years), with non-Hodgkin's lymphoma receiving CHOP-therapy were enrolled and evaluated in a randomized, double-blind, crossover study comparing the antiemetic efficacy, toxicity and patients' preference of a combination of low-dose oral granisetron plus intravenous dexamethasone (gran/dex) with a combination of high-dose metoclopramide plus intravenous dexamethasone (met/dex) on days 1-5 after chemotherapy. The acute, delayed (day 2-5) and 5-day total control of nausea and vomiting in the gran/dex group were significantly higher than those of the met/dex group (75.0% vs 25.0%; p-value = 0.004, 79.2% vs 33.3%; p-value = 0.007 and 75.0% vs 25.0%; p-value = 0.004, respectively). Except for extrapyramidal reactions in the met/dex group, the side effects in both groups were comparable. The mean total score of antiemetic preference in the gran/dex group was also significantly higher than that of the met/dex group (9.0 vs 7.5; p-value = 0.004). In conclusion, low-dose oral granisetron combined with intravenous dexamethasone had significantly higher protective effects against both acute and delayed nausea and vomiting induced by CHOP-therapy. Thus, this regimen may be considered as an alternative outpatient antiemetic treatment for young patients with non-Hodgkin's lymphoma.

Abstract 2064 OBJECTIVE: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in Thailand. The objective of the study was to evaluate clinical features, histopathology, treatment outcomes and prognostic factors in Thai adult patients with NHL. METHODS: Using web-based registry system, we prospectively collected clinical information of newly diagnosed NHL patients from eleven major medical centers situated in various geographic regions of Thailand. All histopathological diagnoses were reviewed by consensus meeting of panels of 6 expert hematopathologists and classified according to the 2008 WHO classification of the lymphoid neoplasms. Clinical features and treatment outcomes were analyzed using STATA program. RESULTS: Between January 2007 and May 2009, there were a total of 939 NHL patients whose clinical information including follow-up data and tissue samples were readily available for analysis. The median age was 58 years (range, 15–99). Forty six percent of the patients were ≥60 years of age. Male:female was 1.18:1. The six leading subtypes were diffuse large B-cell lymphoma (67%), extranodal marginal zone lymphoma of MALT type (7%), follicular lymphoma (6%), mantle cell lymphoma (4%), peripheral T-cell lymphoma, not otherwise specified (NOS) (3%) and extranodal NK/T-cell lymphoma, nasal type (3%). T-cell lymphoma constituted 10% of all NHL. The three most common subtypes in T-cell lymphomas were peripheral T-cell lymphoma, NOS (26%), extranodal NK/T-cell lymphoma, nasal type (25%) and angioimmunoblastic T-cell lymphoma (15%). Fifty-eight percent of all patients had advanced disease (stage III, IV), 42% had B symptoms and 54% had elevated serum LDH. The IPI risk groups were 23% low, 30% low-intermediate, 30% high-intermediate and 17% high-risk. HIV-associated NHL was seen in 4.4% of the patients. Of the 801 patients who received chemotherapy, 90% were treated with anthracycline-containing regimen. Twenty-five percent of the patients received rituximab. Of the 663 evaluable patients, the rate of objective tumor response was 75% (CR+CRu, 59%). At a median follow-up time of 13 months, the 4-year projected overall survival (OS) was 73% (95% CI 69–77%). The OS of patients with T-cell lymphoma was inferior to B-cell lymphoma (58% vs. 74%, p = 0.04). With multivariate analysis, the independent adverse prognostic factors for OS in B-cell lymphoma were poor performance status (HR 2.4, 95% CI 1.7–3.5), elevated serum LDH (HR 2.1, 95% CI 1.4–3.1), stage III/IV (HR 1.6, 95% CI 1.1–2.3), WHO subtype (HR 1.1, 95% CI 1.0–1.2), no chemotherapy (HR 3.1, 95% CI 1.9–5.1) and no rituximab treatment (HR 1.7, 95% CI 1.1–2.6). The independent adverse factors for OS in T-cell lymphoma were elevated serum LDH (HR 3.7, 95% CI 1.2–11.1) and male sex (HR 3.4, 95% CI 1.3–8.8). CONCLUSIONS: This study confirmed the characteristic features of NHL among Thai population, i.e., a preponderance of diffuse large B-cell lymphoma and a low incidence of follicular lymphoma within B-cell lymphoma; a relatively high incidence of nasal NK/T-cell lymphoma within T-cell lymphoma. The IPI risk-groups and survival outcomes were comparable to most previously published reports. Disclosures: Bunworasate: Novartis Pharmaceutical: Research Funding. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. Chuncharunee:Novartis: Research Funding.

First line combination chemotherapy can result in long-term disease-free survival (DFS) in 65–90% of patients with Burkitt lymphoma (BL) depending on prognostic factors at presentation. However, only a small number of patients with relapsed/refractory diseases can achieve long-term DFS after the high-dose therapy and hematopoietic stem cell rescue. Irinotecan (CPT-11) and topotecan, two analogues of campthothecin (CPT), have been successfully used alone or in combination with other cytotoxic agents as salvage treatments for patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) other than BL. A disadvantage of CPT-11 and topotecan observed in early clinical trials was a high incidence of treatment-related toxicity (TRT). IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclodextrin-based polymer, has recently been developed to minimize TRT and increase anti-tumor activity. To evaluate preclinical efficacy and toxicity of IT-101, we conducted an in vivo study in nude mice bearing subcutaneous xenografts from human BL-derived Daudi cell line stably transfected with plasmid DNA containing firefly luciferase (ffluc) reporter gene. The tumor-derived ffluc activity was evaluated in vivo using an IVIS 100 imaging system (Xenogen); background ffluc luminescence was defined as ≤106 p/sec/cm2/sr. Ten days after subcutaneous tumor injection, 42 nude mice with tumor-derived ffluc activity of >108 p/sec/cm2/sr were allocated into six different treatment groups as followings: Group 1 (no therapy); Group 2 (CPT-11 100mg/kg, ip, qwk × 3); Group 3 (IT-101 5mg/kg, iv, qwk × 3); Group 4 (IT-101 10mg/kg, iv, qwk × 3); Group 5 (IT-101 15mg/kg, iv, qwk × 2); and Group 6 (IT-101 single dose of 15mg/kg, iv). The average tumor-derived ffluc activity among all of the treatment groups was equally distributed. Tumor burden was monitored weekly by tumor-derived ffluc activity and physical tumor measurements. After completion of the treatment, there were two treatment-related deaths (TRDs; body weight loss >20%) and one non-TRD in group 5 and 6, respectively. At the 3rd week after starting therapy, all treatment groups that received two or three weekly doses of IT-101 (Groups 3, 4, and 5) had 100% complete tumor regression (CTR), determined by ffluc activity (

The safety and feasibility of adoptive immunotherapy, using CD19-specific T cells that have been genetically modified to express a chimeric antigen receptor (CAR) and numerically expanded ex vivo, need to be addressed. Second-generation trials are being developed incorporating improvements into the design of the CAR as well as the manufacturing processes. Here we describe a platform for propagating CD19-specific T cells through an artificial antigen presenting cell (aAPC) which co-expresses CD19 and T-cell co-stimulatory molecules to provide a fully-competent T-cell activation signal leading to T-cell proliferation. K562 cells were selected as the platform for the aAPCs since (i) they have previously been used in compliance with current good manufacturing practice (cGMP), (ii) they express the desired endogenous T-cell adhesion molecules, and (iii) they fail to express classical HLA class I/II molecules and thus are not targets for a T-cell mediated allogeneic immune response. Therefore, K562 cells were genetically modified to co-express CD19 and both of the T-cell co-stimulatory molecules 4-1BBL (CD137L) and MICA. We then tested the ability of these K562 aAPCs to expand T cells expressing a new CD19-specific CAR designated CD19RCD28. This CAR utilizes a CD19-specific scFv to bind to CD19 independent of MHC and confers an activation signal to genetically modified T cells through both CD28 and CD3-ζ. The CD19RCD28+ T cells could be rapidly expanded (50-fold in 14 days) when cultured in the presence of recombinant human IL-2 and irradiated K562 aAPCs (1:50 ratio, T cell to aAPC). The use of freshly thawed aAPCs improved the practicality of using this antigen-driven expansion method in compliance with cGMP. The numerical expansion of the genetically modified T cells was associated with an increased CAR cell-surface expression, from 17 ± 11% (mean ± SD) before co-culture compared with 44 ± 8% (mean ± SD) after co-culture with the aAPCs, which is consistent with T-cell activation through the CAR. A 3H-thymidine incorporation assay was used to demonstrate that CD19 on the K562 aAPC was necessary, but not sufficient, to proliferate CD19RCD28+ T cells. Furthermore, this proliferation assay demonstrated that co-expression of both 4-1BBL (CD137L) and MICA along with CD19 resulted in the most efficient proliferation of the genetically modified T cells. The propagation of CAR+ T cells on antigen+ aAPCs may thus (i) avoid the need for allogeneic peripheral blood mononuclear feeder cells, which are expensive and time-consuming to prepare in compliance with cGMP, (ii) select in vitro for genetically modified T cells with proven CAR-dependent replicative capacity, and (iii) provide conditions for the outgrowth of subpopulations of T cells within a bulk culture that have increased transgene expression. The feasibility of this new T-cell propagation method using aAPC will be tested in the upcoming clinical trials.