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To summarize the preliminary experience on Iressa for refractory non-small cell lung cancer (NSCLC).Fifty-five patients with NSCLC, who failed after surgery, radiotherapy, chemotherapy or combination of the above modalities, were registered in this clinical trail. Prior to Iressa, 50 patients were in stage IV, and 5 in stage III. Iressa was administered orally at 250 mg, once a day until cancer progressed or severe toxicity occured, which made patients intolerable. The median time for administration of Iressa was 4 months.The toxicity of Iressa was tolerable with 47% of skin toxicity (rash) and 2%-7% of diarrhea, nausea, orally mucosal ulceration and alopecia. Overall response rate was 20%. Different sites of distant metastases responded to Iressa in different ways with higher response rate for pulmonary disseminations. One quarter of patients felt improvement of their symptoms over 2 weeks. Median survival time for entire group was 5 months (1-17 months). Median time to progression (TTP) was 3.6 months. Survival at 6 months was 67%. Prognostic predictor, which could imply the outcome, was skin toxicity with higher response rate and longer survival time ( P0.05), and no relationship with sex, histological types of NSCLC and distant metastasis had been found.Iressa could be tolerated by refractory NSCLC patients with acceptable side-effects, and have palliative effects.

There is no gold standard to treat primary gastric non-Hodgkin's lymphoma (PG-NHL). Hence, the establishment of effective prognostic factors of PG-NHL is essential for its staging and management.We retrospectively analyzed the clinicopathological features of PG-NHL patients who had been diagnosed from 1990 through 2008 in a Chinese cancer center. Event-free survival (EFS) and overall survival (OS) were primary endpoints.Estimated EFS and OS rate at 5 years were 76.0% and 78.7%, respectively. Log-rank analyses revealed OS was significantly prolonged by the following factors: ageor = 60 years; histology of mucosa-associated lymphoid tissue lymphoma; performance status of 0-1; modified Ann Arbor stage IE or IIE1 disease; normal lactic dehydrogenase level; normal hemoglobin level; normal albumin level; International Prognostic Index of 0 or 1; tumor sizeor = 5 cm; and less depth of invasion. Only performance status, modified Ann Arbor stage and albumin level retained their significance for EFS and OS in the multivariate analysis.We strongly recommend including albumin level in the management of Chinese patients. Further randomized studies with a large number of cases are needed to establish the optimal management for this disease.

The purpose of the study is to evaluate the 10 years follow-up of the efficacy in Chinese patients receiving cyclophosphamide, doxorubicin/epirubicin, vincristine, and prednisone (CHOP) or rituximab plus CHOP (R-CHOP) regimen as the initial treatment for diffuse large B cell lymphoma (DLBCL). We have retrospectively analyzed 437 patients with DLBCL who were newly diagnosed and received CHOP or R-CHOP regimen in six university hospitals and closely followed up after the completion of treatment. For all patients, there were significant differences between R-CHOP and CHOP for overall survival (OS) (median follow-up 86 months, 84.1% vs 70.2%, p = 0.018) and progression-free survival (PFS) (81.5% vs 66.7%, p = 0.015), while elder patients (>60 years old) received higher OS (median follow-up 66 months, 80.7% vs 53.0%, p = 0.011). But for younger patients (≤60 years old), the treatments with rituximab did not demonstrate a significant effect on OS (85.5% vs 79.4%, p = 0.428). In the R-CHOP group, International Prognostic Index (IPI) distinguished three risk groups instead of four risk groups. But in the CHOP group, IPI still distinguished four risk groups. Furthermore, for 212 of 437 patients diagnosed with extranodal involvement DLBCL, R-CHOP regimen provided a longer OS than CHOP regimen did (OS, 89.9% vs 71.7%, p = 0.014). Moreover, patients with extranodal lymphoma had a significant longer survival in rituximab era (OS, 89.9% vs 79.2% for extranodal and nodal, respectively; p = 0.048). The results of this large-scale study suggested that R-CHOP provided a greater survival benefit in the initial treatment of DLBCL. As for the patients with extranodal lymphoma, R-CHOP was also a good choice as first-line treatment. Extranodal disease seems to be an independent good prognostic factor in rituximab era.

Reactivation of hepatitis B virus (HBV) is less common in lymphoma patients with prior resolved HBV infection [characterized by hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (HBcAb)-positive status] compared with chronic HBV infection (HBsAg positive) when receiving chemotherapy alone. The use of rituximab in chemotherapy regimen might increase the risk of HBV reactivation in patients with prior resolved HBV infection. However, the incidence of HBV reactivation is uncertain, and prophylactic antiviral treatment for this group of patients during rituximab-containing chemotherapy is controversial. The objective of this study was to determine the incidence of HBV reactivation in HBsAg-negative/HBcAb-positive patients diagnosed of diffuse large B-cell lymphoma (DLBCL) and treated with CHOP-like or RCHOP-like regimen. In addition, this study also aims to explore the relationship of HBV reactivation and HBV serology.Patients were identified using data from six university hospitals collected between January 1998 and November 2008. Four hundred and thirty-seven patients with complete data were selected based on the diagnosis of CD20+ DLBCL, availability of HBV serum markers prior to initiation of chemotherapy and during the development of hepatitis, completion of at least four cycles of chemotherapy using CHOP-like or RCHOP-like regimen, and follow-up for at least 6 months after completion of treatment. The characteristics of the HBsAg-negative/HBcAb-positive patients treated with CHOP-like regimen were compared to those treated with RCHOP-like regimen.Eighty-eight patients of the total 437 patients had pretreatment serology of prior resolved hepatitis B, with a prevalence of 20.1%. Among them, 45 patients received CHOP-like regimen while 43 patients received RCHOP-like regimen. Five patients developed hepatitis during treatment, two from CHOP group and three from RCHOP group. Only one patient treated with RCHOP had hepatitis associated with HBV reactivation, while the other four patients did not have evidence of HBV reactivation. Those four patients also demonstrated positive HBsAb at baseline, while the only patient who suffered from HBV reactivation had negative HBsAb status. This patient was successfully treated with antiviral medications. There were no statistically significant risk factors predictive of HBV reactivation.The present study revealed a low HBV reactivation rate of 2.3% in prior resolved hepatitis B among DLBCL patients undergoing RCHOP-like therapy.

Malignant perivascular epithelioid cell tumor (PEComa) was a kind of rare disease with malignant behavior and poor prognosis. Nearly all PEComas show immunoactivity for HMB45. The treatment strategy for malignant PEComa is still of controversy, especially in advanced or unresectable disease. We reported a 14-year-old patient of unresectable malignant PEComa, who was treated with multiple combined chemotherapies. The patient died of tumor 9 months after surgery, although 3 different combined chemotherapeutic regimens and antiangiogenic drug were used. Our case suggested that empirical chemotherapeutic regimens for soft tissue sarcomas might not be suitable for PEComa.

To evaluate the outcome of CHOP chemotherapy and radiotherapy in Stage IE and IIE nasal natural killer (NK)/T-cell lymphoma, 53 patients with stage IE and IIE nasal NK/T-cell lymphoma were studied. By the Ann Arbor Lymphoma Staging Classification, 41 patients (77%) had Stage IE disease and 12 patients (23%) had Stage IIE disease. All patients were treated curatively using chemotherapy, followed by radiotherapy. Chemotherapy consisted of up to six cycles of the standard CHOP based regimen. The median radiation dose to the tumor bed was 45 Gy for all patients. The median follow-up for all 39 surviving patients was 30.2 months (range, 6 - 104 months). Twenty-six patients had complete response after chemotherapy, and all patients who completed first line chemotherapy achieved complete response after radiotherapy. The 2-year overall survival and progression-free survival rates were 75.6% and 61.8%, respectively. Multivariate analysis revealed that perforation as a presenting symptom, elevated pretreatment serum lactate dehydrogenase level, and ECOG performance statusor=2 were significant independent prognostic factors for this group of patients. Combined chemotherapy followed by involved field radiation produced suboptimal outcome for patients with early stage nasal NK/T-cell lymphoma. Further investigations, preferably prospective clinical trials, for more efficacious treatment strategies are needed to improve the treatment outcome of this malignancy.

Background Chidamide (CS055) is a new oral benzamide type of histone deacetylase (HDAC) inhibitor with subtype selective activity against HDAC1, 2, 3 and 10, and it has been approved for relapsed or refractory peripheral T-cell lymphoma (PTCL) in China. This phase II study (ChiCTR-TNC-00000806) was to evaluate the efficacy and safety of chidamide in different dosing regimens in patients with relapsed or refractory cutaneous T-cell Lymphoma (CTCL). Methods Fifty-two patients, all were mycosis fungoides or Sezary syndrome, were enrolled in this study. In the first stage of the study, 26 patients were randomly assigned to receive chidamide 30 mg twice per week for 2 weeks out of a 3-week-cycle (13 patients), or 4 weeks out of a 6-week-cycle (13 patients). Another 26 patients were enrolled in the second stage, and were treated by chidamide of 30 mg twice per week without drug-free holiday. The primary endpoint was objective response rate (ORR). Responses were evaluated based on the overall skin lesions, lymph nodes, blood cells and pruritis. Results The ORRs were 33% (4/12 PRs) for the 3-week-cycle arm, 23% (3/13 PRs) for the 6-week-cycle arm, and 36% (1/25 CR + 8/25 PRs) for the successive dosing arm, respectively. Median duration of response (DOR) was 50, 92, and 169 days for the indicated 3 arms, respectively. Twelve (92%), 11 (85%) and 20 (77%) patients experienced adverse event (AE) in the three arms. Most AEs were in Grade 1 or 2. Thrombocytopenia, leucopenia, fatigue, nausea and diarrhea were most frequently seen. Two serious adverse events (SAE) were reported in the study. One patient in the 3-week-cycle arm was hospitalized for fever and lung infection, and the other in the successive dosing arm was hospitalized for hyperglycemia. Conclusions Chidamide was active and tolerable to relapsed or refractory CTCL. The ORR of chidamide was comparable with the marketed drugs for CTCL. The major toxicities of chidamide were hematologic and gastrointestinal reactions which were controllable. Based on the overall profiles of the three different dosing regimens, 30 mg twice per week successively was clinically recommended. Table 1. Efficacy 3-week-cycle arm(N=12) * 6-week-cycle arm (N=13) Successive dosing arm(N=25) * CR 0 0 1 PR 4 3 8 ORR (%) 4 (33) 3 (23) 9 (36) Median DOR (days) 50 92 169 Median PFS (days) 84 81 88 *patients with ineligible entrance of the study were excluded for the efficacy analysis Table 2. Safety 3-week-cycle arm (N=13) 6-week-cycle arm (N=13) Successive dosing arm (N=26) Patients with AE (%) 12 (92) 11(85) 20 (77) Patients with AE ≥grade 3 (%) 3 (23) 5 (38) 4 (15) Patients with SAE (%) 1 (8) 0 1 (4) AEs in ≥10% of patients (%) Thrombocytopenia 5 (39) 3 (23) 9 (35) Leucopenia 7 (54) 4 (31) 4 (15) Fatigue 3 (23) 3 (23) 3 (12) Nausea 3 (23) 1 (8) 3 (12) Diarrhea 1(8) 1 (8) 3 (12) Fever 0 2 (15) 2 (8) Anemia 1 (8) 2 (15) 1 (4) Disclosures No relevant conflicts of interest to declare.

Supplemental Digital Content is available in the text, Patients with advanced soft tissue sarcoma (aSTS) typically have a poor prognosis. Patients progressing to doxorubicin-based regimen have limited therapeutic options. Monotherapy with cytotoxic drugs appears to have only modest activity in the second-line setting. The purpose of this phase II study was to prospectively evaluate the safety and efficacy of combination regimen with gemcitabine, vincristine, and cisplatin (GVP) as a salvage treatment for patients with aSTS. Eligible patients were female with 18∼75 years old, and had aSTS that had progressed after 1 prior anthracyclines-based chemotherapy regimen. Patients were treated with 1,000 mg/m2 gemcitabine intravenously (IV) on days 1 and 8, 1.4 mg/m2 (max 2 mg) vincristine IV on day 1 and 25 mg/m2 cisplatin IV on days 1 through 3 every 21 days until disease progression, unacceptable toxicity or up to 6 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), over response rate (ORR) and safety. This trial was registered with www.clinicaltrials.gov (no. NCT01192633). A total of 26 patients with a median age 47 years (21–72) were recruited. ORR was 23.1% [1 complete response and 5 partial responses]. The median PFS and OS were 4.8 (95% CI, 0.1–9.5) months and 15.0 (95% CI, 6.1–23.9) months, respectively. Grade 3/4 hematologic toxicities included neutropenia (34.6%), leukopenia (23.1%), thrombocytopenia (11.5%) and anemia (3.8%). No febrile neutropenia and grade 3/4 non-hematologic toxicities occurred. The most frequent non-hematologic toxicities were nausea/vomiting (50.0%), fatigue (30.8%), and fever (11.5%). We conclude that GVP regimen is effective with a favorable safety profile as the second-line chemotherapy in aSTS patients, which warrants further investigation in a phase III study.

e19503 Background: The incidence of hepatitis B virus (HBV) reactivation in lymphoma patients with prior resolved hepatitis B who receive immunochemotherapy varies in different reports, thus leads ...

The objective of this analysis was to evaluate the efficacy and treatment outcome of CHOP and CHOP combined with nitrosourea chemotherapy in natural killer (NK)/T-cell lymphoma of the nasal cavity. Sixty-three patients with NK/T-cell lymphoma of the nasal cavity were treated with CHOP or CHOP combined with oral nitrosourea chemotherapy between January 1997 and June 2005. By the Ann Arbor Lymphoma Staging Classification, 57 patients (90%) had Stage IE or IIE disease and six patients (10%) had Stage III or IV disease. All patients with Stage IE or IIE disease were intended to be treated curatively with combined chemoradiation; and patients who had Stage III or IV disease were treated with chemotherapy alone with curative intention. Chemotherapy consisted of: (1) up to six cycles of the standard CHOP based regimen, or (2) up to six cycles of the standard CHOP based regimen with oral Semustine dosed at 120 mg (or Lomustine dosed at 100mg) on day 1 of each chemotherapy cycle. External beam radiation therapy was delivered by daily conventional fractionation by Co-60 or 6MVx linear accelerator for patients with Stage IE or IIE disease. The radiation dose to the tumor bed was between 36 and 50 Gy with a median dose of 45 Gy. Fifty-three patients received chemotherapy prior to radiation, and four patients were treated with involved field radiation before chemotherapy. The median follow up for all 44 surviving patients was 31 months (range: 6-104 months). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 60% and 70%, respectively. The PFS and OS of patients who were treated with or without oral nitrosourea in addition to CHOP were 73% vs. 44% (P=0.035) and 75% vs. 64% (P=0.276), respectively. Nine patients with Stage IE or IIE diseases developed disease progression during their planned treatment and died within 10 months after the initiation of treatment; Six patients who achieved complete response (CR) after planned chemoradiation developed systemic recurrence and died at 13-48 months despite salvage treatment; one patient died of Hemophagocytic Syndrome during radiotherapy after achieving CR from chemotherapy. Three patients with Stage III or IV disease died during chemotherapy or during salvage treatment at 2, 4, and 19 months, respectively. Among the 59 patients who received chemotherapy as their initial treatment, 29, 6, 12, and 12 patients had complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) respectively after chemotherapy. The 2-year overall survival rates for these four groups of patients were 100%, 75%, 60%, and 17%, respectively (P

Background: The phase 3, randomized LYM-3002 study compared VR-CAP (n=243) vs R-CHOP (n=244) as frontline therapy in newly diagnosed MCL pts who were ineligible or not considered for bone marrow transplantation (NCT00722137). In the primary analysis after a median follow-up of 40 mos, progression-free survival (PFS) as assessed by independent radiology review committee (IRC) (median 24.7 vs 14.4 mos; hazard ratio [HR] 0.63; p Methods: In the VR-CAP arm, pts with measurable stage II–IV MCL and an ECOG performance status (ECOG PS) of 0–2 received 6–8 × 21-d cycles of Btz 1.3 mg/m2 IV on d 1, 4, 8, and 11, plus rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, all IV on d 1, and prednisone 100 mg/m2 PO on d 1–5. Btz dose adjustments for toxicities were permitted using established dose modification guidelines per the drug prescribing information. OS was estimated by Kaplan-Meier methodology. For this analysis, Btz dose intensity (total Btz dose received per cycle) during cycles 1–6 was calculated. The median value was selected as a cut-off for dichotomization of pts to be included in lower or higher ( Results: From the landmark, OS was found to be significantly longer in the higher (n=93) vs lower (n=88) Btz dose intensity group in univariate analysis (HR 0.43 [0.23, 0.80]; p=0.0059; Figure). 4-yr OS rates were 79.5% and 57.1%. In multivariate analysis adjusted for potential confounding baseline patient/disease characteristics that may have been imbalanced between the dose groups (age [≤65 vs >65 yrs], sex, race [white vs non-white], ECOG PS [≤1 vs >1], disease stage [II/III vs IV], extranodal involvement [≤1 vs >1], LDH level, white blood cell count, bone marrow involvement, albumin level, platelet count), Btz dose intensity remained the most significant predictor of OS (HR 0.40 [0.20, 0.79]; p=0.009). After selection for the most significant covariates (Btz dose intensity, ECOG PS, LDH level), dose intensity remained the strongest predictor of OS of all variables considered in the model (HR 0.38 [0.20, 0.71]; p=0.003). Dose intensities of other drugs in the VR-CAP regimen showed no association with OS due to infrequent dose modification. After adjusting for achievement of complete response (CR)/unconfirmed CR (CR/CRu) by investigator assessment (per International Lymphoma Workshop Criteria) by the end of cycle 6 (yes [n=28] vs no [n=151]), which showed no impact on OS (HR 0.36 [0.11, 1.17]; p=0.09), the impact of Btz dose intensity on OS remained highly significant (HR 0.43 [0.23, 0.80]; p=0.007). Similar findings were observed after adjusting for achievement of CR/CRu by IRC. Adjusting for change from baseline to landmark in ECOG PS (worsening [n=26] vs non-worsening [n=153]; HR 0.88 [0.40, 1.95]; p=0.76), and worst on-treatment platelet count (≥25 [n=120] vs Conclusions: Higher Btz dose intensity was the strongest predictor of OS in newly diagnosed MCL pts receiving frontline VR-CAP. The association was independent of baseline characteristics, dose intensity of co-administered drugs, or on-treatment changes in response status or hematologic parameters. Figure 1 Figure 1. Disclosures Robak: Janssen Research & Development: Consultancy, Research Funding. Off Label Use: The proteasome inhibitor bortezomib is approved in the US for the treatment of multiple myeloma and for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. In the present study, bortezomib is being investigated in combination with immunochemotherapy for previously untreated patients with mantle cell lymphoma, an indication for which it is currently not approved.. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Pei:Janssen: Employment. Rooney:Johnson & Johnson: Equity Ownership; Janssen: Employment. van de Velde:Johnson & Johnson: Equity Ownership; Janssen: Employment. Cavalli:Roche: Research Funding; Takeda: Consultancy; Pfizer: Research Funding; Mundipharma: Research Funding; Novartis: Consultancy.

Anthracycline associated cardiomyopathy (AAC) is a rare but real complication that negatively influence the clinical outcome and quality of life in B-cell lymphoma patients. Guidelines for cardiac monitoring during chemotherapy had been formulated but are primarily based on cardiac imaging. On the other hand, current available cardiac imaging studies only detect changes once significant myocardial damage has occurred. Thus, there is a need to identify, test and validate novel biomarkers that may predict early cardiac injury in cancer patients receiving cardio-toxic agents. Recently introduced into the clinical practice, high sensitivity troponin T (HsTnT) assay has allowed unparalleled sensitivity and precision to detect early myocardial injury. To this end, we prospectively evaluated changes in HsTnT levels during chemotherapy and correlated it with changes in left ventricular ejection fraction (LVEF) and/or incidence of AAC in previously untreated diffuse large B-cell lymphoma (DLBCL) patients enrolled in a phase III clinical trial comparing two chemotherapy regimens CHOP+/-R vs. CEpOP+/-R, (NCT00854568). A total of 348 DLBCL (N=315) or follicular lymphoma grade 3 (FLG3) (N=33) were randomized to receive either 6 cycles of CHOP+/-R or CEpOP+/-R administered on a 21 day cycles. Demographic, clinical and pathological characteristics were collected for each patient. In addition, baseline and after 4 cycles of the planned therapy were completed, cardiac multi gated acquisition [MUGA] scan and HsTnT using one-step electrochemiluminescence immunoassay (Roche cobase 411) were performed. Treatment groups were well balanced in terms of clinical and demographic characteristics. After 27.1 month follow up, there was no difference in terms of overall response rate (ORR) and progression free survival (PFS) between CHOP+/-R or CEpOP+/-R (Estimated 3-year PFS: 79.7±3.3 % vs. 80.0±3.4%, P = 0.958). Cardiac biomarkers were collected in 324 patients. Elevated HsTnT values after 4 cycles of therapy were observed in 30.9% and changes in LVEF were detected only in 16.0 % of the patients. In detail, elevated levels of HsTnT were observed in 100/324 patients, 66/157 in the CHOP+/-R group and 34/167 in the CEpOP+/-R group (42.0% vs. 20.4%, P = 0.001) (Figure 1). All these patients were asymptomatic, clinically and hemodynamically stable. Moreover, there was no difference between these two groups in terms of incidence of decreased LVEF (27/168, 16.1% vs. 27/180, 15.0%, P = 0.783). Patients with an elevated HsTnT after 4 cycles of their planned treatment exhibited a more pronounced decrease in the absolute LVEF than patients with stable HsTnT levels (P = 0.009) (Figure 2). Our data suggest that while CHOP+/-R or CEpOP+/-R are equivalent in terms of clinical activity; CEpOP+/-R is associated with a lower incidence of HsTnT elevation. Subclinical decrease in LVEF was associated with elevations on HsTnT in the patient population studied suggesting that HsTnT can potentially be applied as a serum biomarker to identify patients at risk for AAC. Longer follow up is required to further define if the differences observed on HsTnT changes between CHOP+/-R and CEpOP+/-R treated patients will translate in differences in the incidence of clinically relevant AAC. Figure 1. Incidence of adverse cardiac event defined as decrease in LVEF by ≥ 10% or elevated HsTnT levels in DLBCL patients treated with either CHOP+/-R or CEpOP+/-R. While changes in LVEF were similar between treatment arms, a significantly higher number of patients in the CHOP+/-R group exhibited elevation of HsTnT levels after 4 cycles of planed therapy. *P = 0.001 Figure 1. Incidence of adverse cardiac event defined as decrease in LVEF by ≥ 10% or elevated HsTnT levels in DLBCL patients treated with either CHOP+/-R or CEpOP+/-R. While changes in LVEF were similar between treatment arms, a significantly higher number of patients in the CHOP+/-R group exhibited elevation of HsTnT levels after 4 cycles of planed therapy. *P = 0.001 Figure 2. Correlation between changes in HsTnT levels and LVEF. In the combined treatment groups (CHOP+/-R and CEpOP+/-R ), DLBCL patients with elevated HsTnT levels after 4 cycles of therapy had a more pronounced decline in LVEF than patients with normal HsTnT levels.*P = 0.009 Figure 2. Correlation between changes in HsTnT levels and LVEF. In the combined treatment groups (CHOP+/-R and CEpOP+/-R ), DLBCL patients with elevated HsTnT levels after 4 cycles of therapy had a more pronounced decline in LVEF than patients with normal HsTnT levels.*P = 0.009 Disclosures No relevant conflicts of interest to declare.

Anthracylcine based regimens (i.e. cyclophosphamide, doxorubicin/epirubincin, vincristine and prednisone [CHOP/CEOP]) are standard chemotherapy in DLBCL and FL. On the other hand, the risk of anthracycline-induced cardiac toxicity (5%-26%) influences physician-treatment selection in certain patient populations (i.e. elderly, multiple co-morbid conditions, etc) and may affect negatively clinical outcomes especially in DLBCL patients. Previous research incicated that eprirubicin induced less cardiac toxicity compared to doxorubicin at the same dosage in breast cancer. However, higher dosage of eprirubicin is required in lymphoma regimen. Therefore, there is a need to study the cardiac toxicity differences between anthracycline-based regimens in the lymphoma treatment. To this end, we prospectively randomized previously untreated DLBCL (Stage I-IV, N = 359) or FLG3 patients (Stage I-IV, N=38) to receive (ratio 1:1): cyclophosphamide at 750mg/m2 on day (D) 2, vincristine at 1.4mg/m2 on D2 (Cap at 2mg/dose), prednisone 100mg on D2-6 and epirubicin at 70mg/m2 on D2 (CEOP) or cyclophosphamide at 750mg/m2 on D2, vincristine 1.4mg/m2 (Cap at 2mg/dose) on D2, prednisone 100mg on D2-6 and doxorubicin at 50mg/m2 on D1(CHOP) with or without rituximab (based on antibody availability) at 375mg/m2on day 1. Cycles were repeated every 21 days for a total of 6-8 cycles. Demographic, clinical and pharmacological characteristics were recorded for each patient. Baseline and post-4 cycles of therapy assessment of left ventricular ejection fraction (LVEF) by multi gated acquisition (MUGA) scan was performed in each patient and as needed thereafter. Primary and secondary endpoints were: differences in the incidence of cardiac toxicity (as defined by grade 2 or higher cardiac dysfunction according to New York Heart Association Functional Classification or an LVEF A total of 398 patients were randomly assigned to either CHOP/R+CHOP (N= 198, 56/142) or CEOP/R+CEOP (N=199, 67/132). Analysis was performed in evaluable patients (i.e. those patients completed at least 4 cycles of the planned therapy, N=348). Baseline demographic and clinical characteristics (i.e. stage, histology, IPI score, LVEF, etc.) were equally distributed among treatment groups. Surprisingly, CEOP/R+CEOP did not have lower cardiac toxicity incidence than CHOP/R+CHOP (15.6% vs. 16.7% P=0.778). The risk of cardiac toxicity was similar across treatment groups after adjustments for age (≤65vs. >65yr), histology subtype (DLBCL vs. FL), co-morbid conditions, rituximab combination condition and/or cumulative anthracycline dose. The overall response rate (ORR) CHOP/R+CHOP vs. CEOP/R+CEOP (95.8% vs. 96.1%, P=0.895) and complete remission rate (CR) (70.0% vs. 72.6%, P=0.695) was similar between CHOP/R+CHOP and CEOP/R+CEOP treated patients. The ORR and CR were similar across treatment groups after adjustment for histology subtype (DLBCL vs. FL) and rituximab combination condition. Although more CHOP/R+CHOP treated patients exhibited febrile neutropenia when compared to CEOP/R+CEOP (27.4% vs. 17.2%, P=0.023), the difference of neutropenia and thrombocytopenia was not statistically different. Our data suggests that CEOP/R+CEOP are not superior to CHOP/ R+CHOP in terms of cardiac toxicity. So CHOP/ R+CHOP are well tolerable and effective chemotherapy regimens for previously untreated DLBCL and FLG3. Moreover, CHOP regimen is more economic, especially in developing countries. However, CEOP/R+CEOP appear to induce less myeloid suppression than CHOP/R+CHOP. Longer follow up is necessary to determine differences in PFS, OS and delayed cardiac toxicity between these two anthracycline-based chemotherapy regimens. Disclosures: No relevant conflicts of interest to declare.

8525 Background: Chidamide (CS055) is a new benzamide type of histone deacetylase (HDAC) inhibitor with subtype selective activity against HDAC1, 2, 3 and 10. Chidamide has shown well-tolerated and favorable PK profiles in patients (pts) with advanced solid tumors and lymphomas. This phase II study was to evaluate the efficacy and safety of chidamide in relapsed or refractory peripheral T-cell lymphoma (PTCL). Methods: 102 PTCL pts were enrolled. In the exploratory trial, pts were randomized to receive chidamide 30mg or 50mg twice per week for 2 weeks, followed by 1 week of rest. In the pivotal trial, chidamide was administered 30mg twice per week w/o drug-free holiday. The primary endpoint was overall response rate (ORR). Responses were assessed using IWC criteria. Results: In the exploratory trial, 19 pts were enrolled with 9 and 10 to the 30mg and 50mg arms, respectively. ORR was 11.1% (1 CR) in the 30mg arm and 40.0% (1 CR, 1 CRu, 2 PR) in the 50mg arm. One pt in the 50mg arm experienced drug-related grade 4 thrombocytopenia. In the pivotal trial, 83 pts were enrolled. Most pts were stage III (35.2%) or IV (45.9%). 23 pts (29.1%) had confirmed responses out of 79 evaluable pts in the pivotal trial (8 CR, 3 CRu, and 12 PR). Responses of 19 pts (24.1%) maintained for ≥12 weeks. ORR with 27.8% was obtained by the Independent Review Committee. 68 pts (81.9%) experienced at least 1 AE in the pivotal trial, with 52.9% of AEs ≤ grade 2. The most common AEs were thrombocytopenia (50.6%), leucocytopenia (39.8%), neutropenia(21.7%), and fatigue (9.6%). 1 pt had a grade 3 QTc prolongation. 7 pts (8.4%) experienced at least one SAE, in which a grade 4 thrombocytopenia was considered to be drug-related. 2 pts with responses (CR) have received chidamide for > 43 months w/o evidence of cumulative toxicity. Conclusions: Chidamide as an oral single agent had significant and durable activity in pts with relapsed or refractory PTCL. Toxicities with the therapy were generally tolerable and manageable. The overall differences in pathological subtypes of pts enrolled and clinical profiles between chidamide and the two existing drugs, pralatrexate and romidepsin, will be discussed. Clinical trial information: ChiCTR-TNC-10000811.

Abstract 2730 Introduction: Recently, L-asparaginase-based combination chemotherapy was found to be effective in salvage treatment in patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type. To explore the single-agent activity of L-asparaginase, we conducted a single-institute, prospective phase II study. Methods: Patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type were eligible for enrollment regardless of prior treatment. L-asparaginase monotherapy (6000 U/m2 on days 1 to 7) was administered as the protocol treatment and repeated every 3 weeks for at most 8 cycles. For responding patients, the decision to proceed with hematopoietic stem-cell transplantation was made at the discretion of treating physicians. The primary endpoint was the best objective response after L-asparaginase. Results: A total of 40 patients were enrolled and treated with L-asparaginase for a median of 5 cycles (range, 1 – 8). The patient characteristics were shown in Table 1. Half of the patients had stage IV disease at enrollment and the vast majority (18 patients) presented with disseminated cutaneous and soft-tissue involvement. Thirty-seven patients (92.5%) had prior exposure to systemic chemotherapy and 14 of them (37.8%) received more than 1 line. The overall response rate was 82.5%. The complete response (CR) and partial response (PR) rates were 40% and 42.5%, respectively. The incidence of adverse events was shown in Table 2. In short, anemia, neutropenia, hypoalbuminemia, nausea and liver-related disorders were common toxicities, which were usually mild and manageable. No grade 4 adverse events and treatment-related mortality were observed. Five patients (12.5%) developed allergic reaction to L-asparaginase and 3 of them had to withdraw from the study since L-asparaginase re-challenge with prophylactic antiallergic agents was unsuccessful. After a median follow-up time of 31.6 months (range, 21.9 – 41.3), the median progression-free survival (PFS) was 12.8 months and median overall survival (OS) was not reached. Response status (CR, PR or no response) after L-asparaginase had a significant impact on either PFS (Figure 1) or OS (Figure 2). Moreover, its prognostic value was confirmed in the multivariate analysis. Conclusions: L-asparaginase demonstrated a high single-agent activity in salvage setting for patients with extranodal NK/T-cell lymphoma, nasal type. The first-line L-asparaginase-containing chemotherapy regimen warrants urgent investigation. Disclosures: Off Label Use: L-asparaginase, which was used in our study for NK/T-cell lymphoma, is approved to treat acute lymphocytic leukemia by US and Chinese FDA.

Abstract 5211 Introduction: Meta-analysis demonstrated that B cell lymphoma appears to be at high risk of infection by Hepatitis B Virus (HBV). Recently, cohort study showed HBV infection is associated with the increasing risk of B cell type lymphoma. Retrospective studies demonstrated high prevalence of HBV infection in Chinese lymphoma patients, with HBsAg-positive rates ranging from 23.5% to 30.5%. HBsAg-positive Diffuse Large B Cell Lymphoma (DLBCL) patients are associated with younger age and more advanced stage. However, the relation between HBV infection and poor prognosis in DLBCL remains uncertain. Molecular markers based on Immunohistochemical (IHC) expression were widely used as prognostic markers in DLBCL. Our study aimed to investigate the prevalence of HBVinfection in the different subtypes of lymphoma, and the molecular prognostic profiles in HBsAg-positive DLBCL. Patient and Methods: From Jan 2008 to Dec 2010, a total of 672 patients diagnosed as lymphoma were tested for HBsAg. Of these, 399 were male and 273 were female; 426 were B-NHL, 216 were T-NHL and 30 were HL. The expressions of BCL-2, BCL-6, CD10, MUM-1 were tested in patients diagnosed with DLBCL. Results: We found the overall HBsAg-positive rate was 15.9% (107/672) in total lymphoma patients. The positive rate of HBsAg was higher in B-NHL patients (20%,85/426) than T-NHL(9.7%,21/216) and HL (3.3%,1/30) (P Conclusion: Our date demonstrated that the infection rate of HBV was higher in DLBCL, whereas lower in the subtypes of mantle cell lymphoma, burkitt's lymphoma and HL. Based on IHC analysis, non-GCB subtype accounted of two-third of DLBCL in our series. Patients with HBsAg-positive DLBCL had lower positive rate of BCL-6. However, the expression of Bcl-2, CD10, MUM-1 seems no significant difference between patients with HBsAg-positive and negative DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract 265 Background: Treatment goals in patients with relapsed FL are to prolong PFS and improve overall survival (OS). To optimize treatment for individual patients, identification of subgroups most likely to benefit from a specific therapy is important. The international, randomized, phase 3 LYM3001 study in patients with relapsed or refractory FL demonstrated improved PFS with bortezomib-rituximab vs rituximab alone (median 12.8 vs 11.0 months, HR 0.822, p=0.039), plus increased overall response rate (ORR; 63% vs 49%, p=0.0004), complete response rate (CR/CRu; 25% vs 18%, p=0.035), and durable (≥6 months) response rate (50% vs 38%, p=0.002) in an unselected patient population. Here we present exploratory biomarker analyses aimed at identifying patient subgroups deriving a longer PFS benefit with bortezomib-rituximab and showing a trend for better OS. Methods: Patients received five 5-week cycles of bortezomib-rituximab (N=336) or rituximab (N=340). Response was assessed using modified International Working Group response criteria. Archived tumor tissue was collected at baseline from 502 (74%) patients; whole blood samples for germ-line DNA were collected on day 1 of cycle 1 from 619 (92%) patients. Protocol-specified candidate biomarkers were based on associations with bortezomib (NF-κB p65, PSMA5, p27, PSMB1/5/8/9) or rituximab (CD68, FCGR2A/3A) activity. Immunohistochemistry assays were used for protein analysis. Taqman SNP assays and PCR/LDR were used for genotyping. Statistical analyses included single-marker analyses, pair-wise combination analyses (n=1140 comparisons), and multiple comparison analyses of all evaluable patients in LYM3001. Clinical covariates included in the analysis were baseline FLIPI score, prior rituximab, time since last anti-lymphoma therapy, region, age, gender, race, Ann Arbor stage, high tumor burden, and number of prior lines of therapy. Results: Single markers and biomarker pairs (n=102) highlighted patient subsets that had significantly improved outcomes with bortezomib-rituximab vs rituximab. For 14 of the pairs, the PFS benefit was ≥6 months. Using false discovery rate (FDR) to control for multiple comparison corrections, one biomarker pair was significant. This pair (presence of the PSMB1 P11A C/G heterozygote, and low CD68 expression [0–50 CD68-positive macrophages in the follicular space]) was associated with significantly improved PFS in patients receiving bortezomib-rituximab vs rituximab (median 16.6 vs 9.1 months, HR 0.407, p2 prior lines of therapy). There was also a trend towards an OS benefit (medians not reached, HR 0.426, p=0.0550), as well as a significantly higher ORR (73.7% vs 47.5%, p=0.0077), a higher CR rate (33.3% vs 23%, p=0.3044), and a significantly longer time to next therapy (median 33.1 vs 14.8 months, p=0.0013). In patients lacking this biomarker pair (N=238) no significant efficacy differences were seen. No other similar studies were available to confirm the reproducibility of these analyses. Therefore, we split the LYM3001 dataset into discovery and confirmation cohorts (7:3 ratio of biomarker-evaluable patients) to enable evaluation and confirmation in independent cohorts of patients The significant biomarker pair of PSMB1 P11A C/G heterozygote and low CD68 was identified in the discovery cohort (N=198) with a PFS advantage with bortezomib-rituximab vs rituximab of 5.7 months (median 14.2 vs 8.4 months, p=0.0003) and an indication of longer OS (HR 0.47, p=0.1291). This biomarker pair also showed a clear PFS advantage in the confirmation cohort (N=108, 8.7-month PFS benefit; median 18.2 vs 9.5 months, HR 0.44, p=0.0817). Other significant biomarker combinations, including combinations of molecular and clinical variables (e.g. high tumor burden) were identified and will be presented. Conclusions: Analyses of the phase 3 LYM3001 trial identified biomarker combinations present in a third of patients offering a significant PFS benefit with bortezomib-rituximab vs rituximab. Use of such biomarker assays in patients with relapsed or refractory FL may aid identification of subgroups deriving maximal benefit from the addition of bortezomib to rituximab therapy. Disclosures: Coiffier: Janssen-Cilag: Consultancy; Roche: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; MedImmune: Consultancy; CTI: Consultancy. Off Label Use: Bortezomib used in combination with rituximab in patients with relapsed/refractory follicular lymphoma. Li:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Henitz:Janssen Research & Development: Employment. Karkera:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Favis:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Gaffney:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Shapiro:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Theocharous:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Elsayed:Janssen Research & Development: Employment; Johson & Johnson: Equity Ownership. de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Rule:Johnson & Johnson: Advisory Board, Institutional grant, meeting attendance expenses, Honoraria. Walewski:Janssen-Cilag: Institutional/personal grants, advisory board; Hoffman La Roche: Honoraria, Institutional/personal grants, travel/accommodation expenses; Mundipharma: Honoraria; Celgene: Honoraria. de Vos:Millennium Pharmaceuticals, Inc: Consultancy. Crump:Janssen/Ortho-Biotech: Consultancy. Shpilberg:Janssen-Cilag: Consultancy, Honoraria. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc: Employment; Johnson & Johnson: Equity Ownership. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Ricci:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.

e18549 Background: Patients with refractory or relapsed diffuse large B-cell lymphoma (DLBCL) are usually managed by salvage chemotherapy. However, standard regimen remains uncertain. Moreover, the benefit of adding rituximab is not well established. The aim of this study was to determine the efficacy and the safety of R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine and cisplatin) as salvage therapy in patients with relapsed or refractory DLBCL. Methods: Patients received at least 2 cycles of R-ESHAP. For patients with chemo-sensitive disease after R-ESHAP, high dose therapy and autologous stem cell transplantation (ASCT) were recommended. Results: A total of 31 patients were enrolled. Eight patients (26%) were diagnosed with refractory disease which was defined as lack of complete response on previous chemotherapy. All patients received CHOP regimen as their initial chemotherapy and 8 patients had rituximab combination. The median cycle of R-ESHAP salvage chemotherapy was four. Thirty patie...

Abstract 857 Background: Follicular lymphoma (FL) is an incurable B-cell non-Hodgkin's lymphoma (NHL) representing ∼20% of all NHL. Rituximab (R) is approved for the treatment of CD20+ relapsed/refractory FL, and single-agent bortezomib (Vc; VELCADE®) has shown activity in heavily pretreated patients. Vc and R show additive activity in preclinical models, and the combination was active and well tolerated in a phase 2 study. This randomized, open-label, multi-center, international, phase 3 clinical trial (LYM3001) compared the efficacy and safety of Vc plus R (Vc-R) vs R alone in patients with relapsed or refractory, R-naive or R-sensitive FL. Methods: Patients with grade 1/2 measurable FL who had relapsed/progressed following prior therapy (time to progression [TTP] ≥6 months if prior R-containing therapy), ECOG performance status ≤2, and no peripheral neuropathy grade ≥2 were randomized (1:1) to receive 5-week cycles of Vc-R (Vc 1.6 mg/m2, d 1, 8, 15, 22, cycles 1–5, plus R 375 mg/m2, d 1, 8, 15, 22 in cycle 1 and d 1 only in cycles 2–5) or R alone (administered according to the same schedule as for the Vc-R arm). In both groups, treatment was administered for five cycles or until progression or unacceptable treatment-related toxicity. Randomization was stratified by FLIPI score (0–1 vs 2 vs ≥3), prior R therapy (yes vs no), time since last dose of anti-FL therapy (≤1 vs >1 year), and region (US vs EU vs rest of world). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR) rate, TTP, and safety/tolerability. Response and progression were assessed by independent radiology committee (IRC) using the modified International Workshop Response Criteria. Planned sample size was 670 patients to provide 90% power (α=0.05, 2-sided) to detect a 33% improvement in median PFS with Vc-R vs R (i.e. 13.3 vs 10 months). Results: Between April 2006 and August 2008, 676 patients (intent-to-treat [ITT] population) were enrolled from 164 centers in 29 countries across Europe, the Americas, and Asia. Baseline characteristics were well balanced between the two arms; median age was 57 years (range 21–84), 54% were female, 75% were Caucasian and 21% were Asian. The majority of patients (93%) had an ECOG performance status of 0 or 1, 51% and 48% had grade 1 and 2 FL, respectively, and 41%, 35%, and 23% had high, intermediate, and low FLIPI score, respectively; 83% had Ann Arbor Stage III or IV, and 38% had bone marrow involvement at baseline. 33% of patients had received 3 or more prior lines of therapy (range 1–6+); 44% had received prior R therapy. The most common prior regimens were CHOP (38%), CVP (25%), single-agent R (17%), R-CHOP (12%), and R-CVP (11%). At a median follow-up of 33.9 months, a total of 440 PFS events were observed by IRC in the ITT population, 212 in the Vc-R arm and 228 events in the R arm. Median PFS improved from 334 days (95% CI: 278, 365) with R alone to 389 days (95% CI: 351, 456) with Vc-R; the hazard ratio was 0.822 (95% CI: 0.681, 0.991). This improvement is statistically significant with a 2-sided P-value of 0.039. The ORR was 63% with Vc-R vs 49% with R (P6 months) was 50% with Vc-R vs 38% with R (P=0.002). The median time to subsequent antilymphoma treatment was significantly improved in the Vc-R vs R arm (700 vs 537 days, P=0.027). Median OS was not reached in either group. Patients received a median 25 weeks treatment in both the Vc-R and R groups (range 5–40 and 5–35 in the Vc-R and R groups, respectively). Adverse events (AEs) were reported for 95% of Vc-R and 78% of R patients. The most common AEs were diarrhea (52% Vc-R, 8% R), nausea (29% Vc-R, 7% R), and pyrexia (25% Vc-R, 10% R). Most AEs were grade 1 or 2. Grade ≥3 AEs were reported in 46% of Vc-R and 21% of R patients; the most common grade ≥3 AEs were neutropenia (11% vs 4%) and diarrhea (7% vs 0%). Peripheral sensory neuropathy was reported in 17% of patients in the Vc-R arm vs 1% in the R arm; 3% vs 0% grade ≥3. 18% and 11% of Vc-R and R patients, respectively, had serious AEs, only 4% and 1% of patients discontinued due to drug-related AEs, and there were 9 and 4 on-treatment deaths, respectively. Conclusion: The addition of weekly Vc to R therapy in patients with relapsed FL was associated with statistically significant improvements in PFS, response rate, and time to next antilymphoma treatment, with acceptable additional toxicity. Disclosures: Coiffier: Johnson & Johnson: Honoraria. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Mayer:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rule:Johnson & Johnson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermann:Millennium Pharmaceuticals: Research Funding. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. Zhu:Johnson & Johnson: Employment. Enny:Johnson & Johnson: Employment, Equity Ownership. Theocharous:Johnson & Johnson: Employment. van de Velde:Johnson & Johson: Employment, Equity Ownership. Elsayed:Johnson & Johnson: Employment, Equity Ownership.

Background: Recent studies showed that stress can modulate biological behavior of ovarian carcinoma through adrenergic receptors. Since both nonselective beta-adrenergic receptor antagonist propranolol and selective beta 2-adrenergic receptor (b2AR) antagonist ICI 118,551 instead of b1AR antagonist atenolol could eliminate most of the effects, b2AR is accordingly regarded as the key molecule. In this study, we investigated the role of b2AR in breast cancer. Material and Methods: Gene expression of b2AR was analyzed by RT-PCR in human breast cancer cell lines MDA-MB-231, MDA-MB-435, MDA-MB-468, MCF-7, T47D, BT-549, HCC1937, BCaP-37 and normal mammary epithelial-like cell line HBL-100. b2AR cDNA was transfected into MDA-MB-435 cells. Protein level of b2AR was analyzed by immunohistochemistry in clinical samples, including 25 normal human breast or benign disease breast tissues and 202 breast cancer tissues. Results: b2AR was detected in majority of breast cancer cell lines, except for MDA-MB-435, MCF-7 and T47D, and all of normal or benign disease breast tissues. Both nonselective beta-adrenergic receptor agonist norepinephrine (NE) and selective b2AR agonist terbutaline promoted proliferation and invasion of spontaneous b2AR-positive MDA-MB-231 cells and transfectant MDA-MB-435-b2AR cells, these effects were completely inhibited by selective b2AR antagonist ICI 118,551. In the breast cancer patients, 125 samples (61.9%) expressed b2AR weakly or moderately just as normal breast or benign diseases tissue, and 43 (21.3%) presented significantly stronger b2AR expression, while no b2AR staining was found in other 34 samples (16.8%). Higher expression or lack of b2AR were associated with axillary lymph nodes metastasis and poor disease free survival (DFS). Discussion: Based on our preliminary results, the breast cancer patients could be classified into three subgroups: b2AR “normal”, high expression and negative groups. Overexpression or lack of b2AR associated with metastasis and clinical prognosis in breast cancer. Obviously, abnormal expression of b2AR may influence the outcome of breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4165.