CHOP-like Regimens Research Articles

B cell non-Hodgkin’s lymphoma: experience from a tertiary care cancer center

Information on presentation and outcome of B cell non-Hodgkin's lymphoma (B-NHL) is limited from developing countries. Data of newly diagnosed adult aggressive B-NHL (n = 260) patients were analyzed for clinical presentation, histological subtype, response to therapy, and survival. Univariate and multivariate Cox-regression analyses were performed for identification of prognostic factors. Diffuse large B cell lymphoma was the most common subtype (71 %). Median age was 50 years (18-78 years). The most common symptom was peripheral lymphadenopathy seen in 66 % of cases. Forty-seven percent of patients had advanced stage (stage III/IV), and 41 % had ECOG performance status of II-IV. B symptoms and bulky disease were present in 47 and 26 %, respectively. Intermediate to high risk score according to the International Prognostic Index (IPI) was seen in 67 %. Cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) and CHOP-like regimens were used in 70 % cases, while R-CHOP was used in 18 % cases. For diffuse large B cell lymphoma (DLBCL) patients, in intent-to-treat analysis, the overall response and complete remission rates were 73 and 60 %, respectively. Four-year event-free and overall survival was 54 and 64.7 %, respectively. Presence of B symptoms (p = 0.004), stage III/IV (p = 0.02/p = 0.01), performance status II-IV (p = 0.001), serum albumin (<4 g/dl; p = 0.001), hemoglobin <10 g/dl (p = 0.001), high-risk IPI score (0.001), use of <6 chemotherapy cycles (p = 0.001), and failure to attain CR (p = 0.001) were significantly associated with lower event-free and overall survival. DLBCL is the most common B cell NHL seen at our center. Intermediate to high IPI was seen in 45 % and was associated with poor survival. Majority of the patients were treated without rituximab. In comparison to western data, we observed higher proportion of DLBCL, lower median age, higher male to female ratio, and higher proportion of patients with B symptoms in our study.

Long‐term follow‐up of patients with HIV‐related diffuse large B‐cell lymphomas treated in a phase II study with rituximab and CHOP

Long‐term follow‐up of patients with <scp>HIV</scp>‐related diffuse large <scp>B</scp>‐cell lymphomas treated in a phase <scp>II</scp> study with rituximab and <scp>CHOP</scp>

Clinical characteristics and outcomes of primary bone lymphoma in Korea

BackgroundThis study evaluates the effectiveness of immunochemotherapy and radiation therapy in the treatment of patients with primary bone lymphoma (PBL).MethodsWe retrospectively reviewed the medical records of 33 patients with PBL who were treated at 6 medical centers in Korea from 1992 to 2010. Clinicopathological features and treatment outcomes were analyzed.ResultsThe median age of the patients participating in our study was 40 years. The most common sites of involvement were the pelvis (12.36%) and femur (11.33%). CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens were administered to 20 patients (61%), and R-CHOP (rituximab plus CHOP) was administered to the remaining 13 patients (39%). The overall response rate was 89% (complete response, 76%; partial response, 12%). The overall survival (OS) of patients with solitary bone lesions was longer than that of patients with multiple bone lesions (median OS: not reached vs. 166 months, respectively; P=0.089). Addition of rituximab to CHOP did not significantly affect either OS or progression-free survival (P=0.53 and P=0.23, respectively). Combining radiation therapy with chemotherapy also did not improve the OS or progression-free survival of patients with solitary bone lesions.ConclusionConventional cytotoxic chemotherapy remains an effective treatment option for patients with PBL. Additional benefits of supplementing chemotherapy with either rituximab or radiation therapy were not observed in this study. Further investigation is needed to characterize the role of immunochemotherapy in treating patients with PBL.

Detection of the Epstein-Barr virus in blood and bone marrow mononuclear cells of patients with aggressive B-cell non-Hodgkin’s lymphoma is not associated with prognosis

The Epstein-Barr virus (EBV) is associated with a large spectrum of lymphoproliferative diseases. Traditional methods of EBV detection include the immunohistochemical identification of viral proteins and DNA probes to the viral genome in tumoral tissue. The present study explored the detection of the EBV genome, using the BALF5 gene, in the bone marrow or blood mononuclear cells of patients with diffuse large B-cell lymphomas (DLBCL) and related its presence to the clinical variables and risk factors. The results show that EBV detection in 21.5% of patients is not associated with age, gender, staging, B symptoms, international prognostic index scores or any analytical parameters, including lactate dehydrogenase (LDH) or β-2 microglobulin (B2M). The majority of patients were treated with R-CHOP-like (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone or an equivalent combination) and some with CHOP-like chemotherapy. Response rates [complete response (CR) + partial response (PR)] were not significantly different between EBV-negative and -positive cases, with 93.2 and 88.9%, respectively. The survival rate was also similar in the two groups, with 5-year overall survival (OS) rates of 64.3 and 76.7%, respectively. However, when analyzing the treatment groups separately there was a trend in EBV-positive patients for a worse prognosis in patients treated with CHOP-like regimens that was not identified in patients treated with R-CHOP-like regimens. We conclude that EBV detection in the bone marrow and blood mononuclear cells of DLBC patients has the same frequency of EBV detection on tumoral lymphoma tissue but is not associated with the risk factors, response rate and survival in patients treated mainly with immunochemotherapy plus rituximab. These results also suggest that the addition of rituximab to chemotherapy improves the prognosis associated with EBV detection in DLBCL.

A Case of Anaplastic Lymphoma Kinase-Negative Primary Gastric Anaplastic Large Cell Lymphoma

Primary malignant lymphoma of the stomach comprises 1 to 7% of all gastric malignancies and is mostly B-cell type. Anaplastic large cell lymphoma (ALCL) of the stomach is very rare and regarded to have a poor prognosis. A 66-year-old man complained of dyspepsia for 3 days. A esophagogastroduodenoscopic examination revealed a flat, depressed ulcer at the distal antrum. Biopsy of the lesion showed diffuse infiltration of large pleomorphic lymphoid cells that were positive for CD3 and CD30 and negative for cytokeratin and anaplastic lymphoma kinase (ALK). We diagnosed the patient with ALK-negative primary gastric ALCL with multiple lymphadenopathies, and he received systemic chemotherapy. CHOP-like regimens followed by consolidation therapy have been widely used for ALK-negative ALCL. However, the patient maintained complete remission for 36 months with only induction chemotherapy. This case suggests that heavy treatment for ALK-negative ALCL is not required for all patients. (Korean J Med 2012;83:674-678)

Therapies for Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of disorders that, for the most part, are associated with a very poor prognosis. The standard therapy for PTCLs is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or a comparable CHOP-like regimen that incorporates anthracyclines. With the exception of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK(+) ALCL), the cure rate for PTCLs with CHOP is low, and limited evidence suggests that anthracyclines do not improve the prognosis. However, there is no compelling evidence that any other regimen or approach is superior. It remains challenging to compare alternative therapies or treatment strategies with CHOP because the majority of data are retrospective and include diverse patient populations. Recently, prospective studies have been initiated exclusively for PTCL, and in some, select histologic subtypes are evaluated in an effort to remove heterogeneity. Encouragingly, there have been several new therapies emerging with activity in PTCLs and exciting novel combinations under consideration that will hopefully move the field forward and improve outcome in this challenging group of diseases.

Comparison CHOP Like Vs Rituximab (R) + CHOP in Non Hodgkin Lymphomas (NHL): Nine Years Uruguayan University Hospital Experience

Comparison CHOP Like Vs Rituximab (R) + CHOP in Non Hodgkin Lymphomas (NHL): Nine Years Uruguayan University Hospital Experience

Re-Assessment of the Prognostic Value of International Prognostic Index (IPI) and Revised IPI (R-IPI) in Patients with Diffuse Large B-Cell Lymphoma Treated with or without Rituximab in Chinese Populations: A Retrospective Multicenter Study by Shanghai Lymphoma Research Group

Abstract 2649 Background:The International Prognostic Index (IPI) is a widely accepted prognostic factor system for diffuse large B cell lymphoma (DLBCL) patients treated with chemotherapy. However, the prognostic value of IPI has been a focal point of the debate in the era of immuno-chemotherapy. Recently, the study of British Columbia group suggested that a revised IPI (R-IPI) which redistributed the IPI factors into 3 distinct prognostic groups provided a more clinically useful prediction of outcome for patients with DLBCL. In order to reassess the value of IPI and R-IPI in unselected Chinese population, we conducted this study. Methods:A multicenter retrospective analysis of DLBCL patients treated with CHOP-like chemotherapy alone or plus rituximab was performed by Shanghai Lymphoma Research Group. In total, 438 patients of newly diagnosed DLBCL treated at 6 participated hospitals were included during the period of 1997–2008. The prognostic value of IPI and R-IPI at diagnosis with regards to overall survival (OS) and progression-free survival (PFS) was evaluated. Results:The median age at diagnosis was 50 years (range, 18–83 years), and the median follow-up was 34 months (range, 3–145 months). Among them, 241 patients received CHOP-like regimen, whereas 197 had rituximab (R)-CHOP-like regimen. While IPI remained predictive in CHOP-like group, it could not distinguish between each prognostic category in the R-CHOP-like group (Fig.1). Redistribution of the IPI factors into a R-IPI identified three distinct prognostic groups with significantly different outcomes both in the patients treated with and without rituximab. In R-CHOP-like arm, these three risk groups had distinctly different rates of 3-year progression-free survival rates of 96%, 84.3% and 67.5% (P<0.001), respectively, and 3-year overall survival rates of 96%, 87.6% and 71.1% (P<0.001), respectively (Fig.2). [Display omitted] [Display omitted] Conclusions:Our study underscores the power of R-IPI as a simplified and more clinically relevant predictor of the disease outcomes than the standard IPI in Chinese DLBCL populations in the rituximab era, and it deserves a further study in larger population-based prospective study. Disclosures:No relevant conflicts of interest to declare.

Different Clinical Features but Not Outcome in SLL Patients Compared to CLL,

Abstract 3896Chronic lymphocitytic leukaemia/Small lymphocytic lymphoma (CLL/SLL) is a neoplasm composed of monomorphic small neoplastic B cells that usually co-express CD5 and CD23. The current WHO classification considers CLL/SLL as the same entity being SLL the non-leukemic lymphoma presentation of CLL. The criteria for SLL include the presence of lymphadenopathy with less than 5×109/L peripheral blood B cells. Patients with SLL usually develop PB involvement during the evolution of the disease. The aim of this study was to analyze the main clinico-biological features and outcome of a series of SLL patients and compare them with the CLL patients diagnosed in the same period of time.Patients and methods: we have included 588 patients (353M/ 233F; median age 61 years) diagnosed with CLL or SLL according to the WHO classification criteria in the same period of time.The main clinico-biological features and the outcome were recorded and analysed according to the CLL/SLL diagnosis. Results: five hundred forty-five patients (93%) fulfil the criteria for CLL and 43 patients (7%) for SLL. The main clinico-biological variables according to the CLL/SLL criteria are detailed in the table. No differences were observed in gender distribution, age at diagnosis or ECOG. Patients with SLL had more frequently Binet C stage, low haemoglobin levels and platelet counts. 320 patients eventually received therapy, including purine analogues containing regimens (159 patients), chlorambucil (113), CHOP-like regimens (31), and other therapies (17). Sixty-nine patients received rituximab in combination. SLL patients received more frequently CHOP-like regimens than CLL patients, but this difference did not reach statistical significance. During the follow-up, 58% of the SLL patients eventually developed leukemic presentation, after a median time from diagnosis of 4.6 years (0.2–15 years). Patients with SLL not receiving treatment progressed to PB involvement sooner than treated SLL (median time, 1 year vs 6 year, respectively; p=0.06).Twenty four of the 588 patients eventually developed Richter syndrome, with this proportion being higher in the SLL than in CLL patients (13.1% vs 3.5%; p=0.001). Moreover, the proportion of second neoplasm (excluding non melanoma skin cancer) was higher for SLL patients than for CLL patients. After a median follow-up for surviving patients of 7.4 years (range, 0.1 to 28), 207 patients eventually died with no differences in overall survival between the two groups of patients. In addition, the causes of death were also similar (50% in SLL and 43% in CLL due to disease progression). In conclusion, although the outcome is similar in SLL and CLL groups, SLL patients more frequently had cytopenias as well as higher risk to develop Richter syndrome and second neoplasias. Genetic and other biological studies are warranted to elucidate the particular presentation and features of SLL.Patients (n=588)CLL (=545)SLL (n=43)pMedian age (years)6161Gender (Male/female)324/21929/14Binet C27/536 (5%)8/43 (18%)<0.001Hemoglobin <110 g/L26/526 (5%)7/39 (18%)0.001Platelets <100x109/L22/525 (4%)4/39 (10%)0.08High serum LDH (%)57/496 (11%)7/37 (18%)n.s.High B2 microglobuline191/442 (43%)17/32 (53%)n.s.High CD 38 expression135/484 (27%)18/38 (47%)0.011High ZAP 70 expression138/527 (26%)14/41 (34%)n.s.Unmutated IGHV160/335 (48%)10/15 (66%)n.s.Presence of Monoclonal Paraprotein28/545 (5%)4/43 (9%)n.s.Second Neoplasia (excluding Skin)74/545 (14%)11/43 (25%)0.03110-year risk of Richter Syndrome5.3%32.8%0.00110-year OS59%53.1%n.s. Disclosures:No relevant conflicts of interest to declare.

Fractionated Cyclophosphamide, Vinblastine with Prednisolone and Daily Oral Etoposide Based Treatment of AIDS-Related Plasmablastic Lymphomas (PBL): A Highly Active and Well Tolerated Regimen

Abstract 2690 Background:Aggressive biology, tumor re-growth on treatment and poor tolerance to chemotherapy, are the factors responsible for dismal outcomes in patients with AIDS- related PBL. Treatment with CHOP, CHOP-like regimens or more intensive protocols (HyperCVAD, CODOX-M/IVAC) has failed to improve median survival beyond 15 months. To overcome the problems of tumor re-growth secondary to cancer cell resistance and treatment related toxicity, we devised a regimen in which drugs with proven anti-lymphoma activity were given in fractionated and continuous manner. Continuous daily dosing of oral etoposide for 2–3 weeks provides an effective concentration of drug for extended time periods. Anthracyclines were omitted to reduce the incidence of myelosuppression and mucositis. This regimen was tested prospectively to assess the efficacy and tolerability Methods:Between August 2007 to February 2011, consecutive patients with untreated AIDS-related PBL and age >18 years were counseled for treatment with the proposed regimen at our center. Diagnosis of PBL required absent or weak expression of CD20, expression of MUM-1 or CD 38 or CD138 to suggest plasma cell differentiation. Paraffin blocks were evaluated for expression of EBER, HHV-8 and Ki-67. All patients who were willing for treatment and follow up and did not have CNS involvement or concurrent infections were enrolled. Anti-retroviral therapy (ART) was started concurrently with chemotherapy if not received before. The 3-weekly regimen included cyclophosphamide 375 mg/m2 and vinblastine 4mg/m2 intravenously on day 1 and 8, oral etoposide 50 mg daily for 2 weeks and prednisolone 40 mg/m2//day for the first week of each cycle. Ten weekly doses of intrathecal methotrexate were given as CNS prophylaxis. Radiation was given to the bulky and extranodal sites. Mid and end of therapy responses were evaluated clinically and radiologically (CT or PET-CT). Results:Eighteen patients (males-11, females-7) with median age of 37.5 years (range, 22–51 years) were treated with the above mentioned regimen. Two-thirds of patients were not on ART at diagnosis. Ten patients had tuberculosis as an AIDS-defining illness. Median CD4 count at diagnosis was 175/μL (range 75–407/μL). Significant proportion of patients had adverse prognostic features like B symptoms (9/18), performance status (ECOG) ≥2 (11/18), stage III/IV disease (14/18), bulky disease (15/18), multiple extranodal sites (6/18), raised serum LDH (9/18). Extranodal disease was seen in 17/18 patients commonest being bone followed by anal canal. All except one patient received treatment with chemotherapy (median cycles-6, range 4–8). This patient did not follow up after the initial staging evaluation. Complete responses were seen in 15/17 patients after chemotherapy and 2 patients had partial response. Sixteen patients received radiation. All patients except one had complete response after RT. Patient who continued to have partial response at the end of radiation progressed after 7 months and died. At median follow up of 19 months (range, 3–48 months) both overall survival and event free survival are 87.7%. Median overall survival has not yet been achieved. Treatment was well tolerated with 6 episode of febrile neutropenia which were managed on outpatient basis. One patient was hospitalized for pneumonitis for 7 days. There were no treatment related deaths. On paraffin blocks expression of EBER was seen in 55%. None of them were positive for HHV-8. Six patients had Ki-67 of >90%. Conclusion:This is the first reported series from a single center which has shown improved response rates and survival for AIDS related PBL with a novel regimen as compared to available data till date. However the study has limitations of small size and short follow up. Disclosures:No relevant conflicts of interest to declare.

Evaluation of Therapy in Symptomatic Patients with Lymphoproliferative Disorders of Large Granular Lymphocytes in Italy

Abstract 4607 Background.Chronic proliferations of large granular lymphocyte (LGL) are characterized by the expansion of cytotoxic T or NK cells. Relevant clinical features include neutropenia and anemia, either symptomatic or asymptomatic. The immunological and biological features of patients'LGL and the frequent association with autoimmune conditions represent the rationale for the immunosuppressive therapy frequently used in these conditions. However, no common criteria for starting therapy have been defined nor standard therapy has been established. We herein present data on 30 symptomatic patients treated in different Italian Centers, in the context of a collaborative study sponsored by the GIMEMA group. Methods.Diagnosis of lymphoproliferative disorder of LGL was made according to published criteria (Blood 1997, 1:89) and WHO classification 2008. Twentyseven patients were diagnosed as LGL leukemia and 3 as NK chronic lymphoproliferative disorder (NK-CLPD). Patients required treatment for symptomatic neutropenia, more frequently represented by recurrent bacterial infections (23/30), transfusion dependent anemia (4/30), other reasons (5/30; n: 2 pulmonary hypertension, n:2 aggressive disease and n:1 neurologic involvement). Treatments.First line therapy consisted of methotrexate (MTX) at 7,5 mg/m2/week in 13/30 patients; cyclosporin A (CyA, (2-3 mg/Kg/die) in 10/30 patients; cyclophosphamide (CY, 50–100mg/die) in 5/30 patients; (immuno)-chemotherapy (Campath-fludarabine, CVP, CHOP-like regimens) in 2 patients characterized by aggressive clinical presentation of disease with B symptoms. Steroid was generally given for short period (1 mg/kg p.o. prednisone) and then tapered off in all but 2 patients. Growth factors (G-CSF and EPO) were also used for short period of times. Before considering failure, each treatment was continued for at least 4 months. Response criteria were defined according to Lamy and Loughran (Blood 2011, 10:117).Second line therapy with MTX, CyA and CY was used in 2, 4 and 3 patients, respectively. Results.Time to response to MTX therapy ranged from 1 to 12 months. The overall response rate were 60% (9/15), with 3 CR and 6 PR. The duration of response ranged from 5 to 48 months. The 5 patients failing MTX as first line therapy were treated with CY (n:2, 1 CR, 1 PD), with CyA (n:2, 2 PR) and 1 rapidly progressed and died.Time to response to CyA ranged from 2 to 12 months. The overall response rate were 50% (7/14) with 2 CR and 5 PR. The duration of response ranged from 1 year to 10 year. The 5 patients failing first line CyA therapy were treated with MTX (n:1, with PR), with CY (n:2, with failure, but one case was rescued using the combination of CyA/CY), 1 patient with chemotherapy with failure; for 1 patient the follow up is too short.Time to response to CY ranged from 3 to 9 months. The overall response rate were 37.5% (3/8):2 CR, 1 PR. The duration of response ranged from 5 months to 5 years. The 3 patients failing CY at first line were treated with bendamustine (n:1), with alemtuzumab (n:1), with MTX (n:1) with failure in each casesTwo patients with very aggressive presentation were treated with chemotherapy: 1 case rapidly progressed and died; 1 case, who failed CT, was treated first with CyA and then with MTX with failure. This patient underwent allotransplant. Conclusions.Immunosuppressive therapy with MTX or CyA or CY represents the common initial approach to patients with symptomatic LGL proliferation. Patient failing one therapy can be efficiently rescued by one of the other immunosuppressive drugs. Although any conclusive evaluation is difficult due to the low number of patients, our data are likely to indicate that the duration of response after treatment with CY and CyA is longer than the response obtained with MTX. The aggressive initial presentation of disease correlates with a very dismal prognosis. A prospective randomized clinical trial comparing these three different clinical approaches is going to start in Italy. Disclosures:No relevant conflicts of interest to declare.

Phase I Study of mTOR Inhibitor Everolimus Plus CHOP in Patients with Advanced, Aggressive T-Cell lymphomas

Abstract 1642 Background:Advanced stage T-cell lymphomas usually follow aggressive clinical course and their treatment outcomes are worse than B-cell non-Hodgkin lymphoma. Furthermore, the optimal treatment regimen is still not established for these disease entities. Thus, cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens are still used as a primary treatment even though their efficacy is not satisfactory. This unmet need of T-cell lymphomas has required the development of more effective regimen. Thus, we incorporated an oral mTOR inhibitor, everolimus (RAD001, Afinitor®) into CHOP regimen to improve its efficacy. The mTOR complex is one of emerging targets in the lymphoma treatment because mTOR signal pathway is used by malignant cells to promote growth and survival. Previous studies demonstrated a single agent activity of mTOR inhibitor against relapsed or refractory lymphomas. Furthermore, several animal study results suggested that the mTOR inhibitor might enhance the effects of vincristine and cyclophosphamide when it was tried in combination with these drugs. Thus, we performed the phase I study to evaluate the feasibility and safety of everolimus plus CHOP chemotherapy for advanced stage, aggressive T-cell lymphomas. Methods:We enrolled patients with newly diagnosed T cell lymphomas including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALCL) and cutaneous T-cell lymphoma (CTCL). Extranodal NK/T-cell lymphoma was excluded because it is resistant to anthracycline-based chemotherapy, and mycosis fungoides was also excluded due to its indolent nature. All patients were Ann Arbor stage III/IV and had adequate organ function. Patients received everolimus from day 1 to day 15 (once daily schedule of four dose levels, 2.5, 5, 7.5, and 10mg/dose) in addition to 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5. Six cycles of therapy administered every 21 days were planned. As a pharmacokinetic study, steady state trough concentrations of everolimus were measured at the end of cycle 1 and 2. All patients provided written informed consents and this trial was registered at www.ClinicalTrials.gov (NCT01198665). Results:Fifteen patients were enrolled between October 2010 and April 2011 including PTCL-NOS (n = 8), AITL (n = 4), ALCL (n = 1) and CTCL (n = 2). Ten patients presented as stage IV (66.7%) and the majority of patients showed serum LDH elevation (n = 13, 86.7%). Thus, the International Prognostic Index risk was dominantly high or high-intermediate (n = 9, 60.0%). There was no dose-limiting toxicity (DLT) at the level I (2.5mg/dose of everolimus) while one patient experienced hematologic DLT (grade IV thrombocytopenia) at the level II (5mg/dose). Thus, after patients were enrolled up to six at the level II, dose of everolimus was escalated to 7.5mg (level III). At the level III, two patients experienced DLT (grade IV thrombocytopenia and febrile neutropenia) among six patients enrolled. Therefore, the maximum tolerated dose for everolimus was determined as 5mg. In the evaluation of pharmacokinetic profile, there were no differences in the trough concentrations of everolimus between cycle 1 and 2 for all of these three dose groups. There was no dose-limiting non-hematologic toxicity in the all three dose levels. Although the main toxicity of everolimus was hematologic toxicity and it was overlapped with the toxicity of CHOP regimen, these hematologic toxicities were manageable. Among 15 patients, 14 patients responded to the treatment including 7 complete responses and 7 partial responses. However, five patients relapsed or progressed during follow-up. Conclusions:Everolimus can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II study of everolimus plus CHOP is 5 mg/dose of everolimus once daily for 15 days as first-line treatment. Disclosures:No relevant conflicts of interest to declare.

Characterizing Canine Lymphoma As a Potential Large Animal Model of Human Diffuse Large B-Cell Lymphoma

Abstract 5193Diffuse large B-cell lymphoma (DLBCL) affects ∼25,000 people in the U.S. each year, and fewer than half of them are cured with standard therapy. DLBCL can be divided into two subtypes by gene expression profiling, germinal center B-cell (GCB) type and activated B-cell (ABC) type. ABC-type DLBCL patients have significantly poorer outcomes. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL is one of the most common cancers in veterinary oncology. Similar to human DLBCL patients, dogs with lymphoma are treated with both CHOP-like regimens and autologous stem cell transplants. Morphologically, canine lymphomas are similar to hDLBCL, with shared histologic markers, such as CD20 and PAX5. With recent technologies based on knowledge of the canine genome sequence, it is now possible to evaluate dogs as a potential large-animal model for hDLBCL.We evaluated 58 canine B-cell lymphomas by generating comprehensive gene expression profiles and comparing them to previously published hDLBCL expression profiles. Canine B-cell lymphoma expression profiles were similar in some ways to hDLBCLs. For instance, increased expression of NF-kB pathway genes was noted in a subset of lymphomas, mirroring NF-kB pathway activation in human ABC-type DLBCL. Furthermore, immunoglobulin heavy chain (IGH) mutation status, which is correlated with ABC/GCB cell of origin in hDLBCL, separated canine DLBCL into two groups with statistically different progression-free and overall survival times. However, canine DLBCL differed from hDLBCL in other aspects, including rare immunohistochemical positivity for BCL6 and MUM1/IRF4. Collectively, these results define aspects of canine B-cell lymphomas that resemble hDLBCL, identifying molecular similarities that could allow dogs to be used as a representative model of hDLBCL. Further comparative studies, including therapeutic trials, could potentially improve outcomes in both species. Disclosures:No relevant conflicts of interest to declare.

A Restrospective Review of Peripheral T-Cell Lymphoma in a Single Institution Between 2000 and 2010

Abstract 1623 Background:Peripheral T-cell non-hodgkin lymphomas (NHL) comprise a heterogeneous group of malignancies, characterized by an aggressive disease course and a poor clinical outcome. T-cell lymphomas present in lymph nodes and they also frequently involve extra nodal sites. The first line treatment consists in CHOP-like regimen. Consolidation treatment in first line or in relapse is autologous stem cell transplantation (ASCT) or allogenic stem cell transplantation (SCT).Patients and methods: We retrospectively analysed the data of 189 adults who had received chemotherapy in our institution between 2000 and 2010. Results:Median age at time of presentation was 55 (range 17–89) years, 76% were <65 years. 50% had B symptoms and 50% serum elevated LDH. ECOG was 0–1 in 60% and 2–4 in 40%. According to the Ann Arbor classification, 15% were stage I-II and 85% were stage III-IV. 50% had low IPI (0-1-2) and 50% had elevated IPI (3-4-5). The histologic subtypes were 42% peripheral T-cell NHL unspecified (PTCL-U), anaplastic large cell lymphoma (ALCL), 8% had ALK+ and 10% had ALK-, 24% angioimmunoblastic lymphoma (AILT), 3% transformed mycosis fungoide, 2% instestinal T-cell lymphoma, 2% hepatosplenic γδ T-cell lymphoma and 1% adult T-cell lymphoma/leukemia. Primary extranodal lymphoma represented 17% and 8% were diagnosed with hemophagocytosis.Five-year overall survival (OS) was 28.3% (21.8–36.8%), and five-year progression free survival (PFS) was 18.4% (13.1–25.7%). On multivariate analysis, ALCL-ALK+ (p=0.008), AILT (p<0.001), extranodal involvement (p=0.01), PS>1 (p<0.001), LDH>N (p=0.003) were independent adverse factors for OS. Moreover B symptoms (p<0.01) was a significant factor for PFS.86% received CHOP-like induction treatment. The median number of chemotherapy was 2 (1–7). 59% experienced a complete response during the therapeutic procedure, while 22% were primary refractory. 44% had ASCT and 14% allogenic SCT. Only 28% of patients referred for allogenic SCT received this treatment. Conclusions:This 10-year review of patients treated in a single institution with initial conventional chemotherapy followed by more intensive treatments confirms the poor OS and PFS in the case of T-cell lymphoma. Despite a low incidence, T-cell lymphoma could be a priority area of research for new treatments with a potential to improve OS and PFS. Disclosures:No relevant conflicts of interest to declare.

Biweekly Gemcitabine-Oxaliplatin and Dexamethasone for Relapsed/Refractory Malignant Lymphoma

Abstract 4952Gemcitabine (GEM) and oxaliplatin (OX) are commonly used as weekly or biweekly therapy. In this regard, dose dense biweekly schedule seems of reasonable investigational value in GEM and OX combination for non-Hodgkin lymphoma (NHL). We conducted phase II study to evaluate the efficacy of the combination chemotherapy consisting of GEM, OX and dexamethasone (GemDOx) as a biweekly regimen in patients with relapsed or refractory NHL. Primary end point was objective response rate and secondary end points were toxicities, progression-free survival, overall survival, ASCC efficacy, rate for proceeding to ASCT. The inclusion criteria were relapsed or refractory malignant aggressive NHL of any histological subtypes: Patients who have refractory to first-line CHOP-like regimen; Patients who have first relapsed after first-line CHOP-like regimen or upfront autologous or allogeneic hematopoietic stem cell transplantation Chemotherapy was repeated every 4 weeks. Gemcitabine 1000 mg/m2 in NS 500 mL was administered IV as a fixed dose rate infusion (FDRI, 10 mg/m2/min) on days 1 and 15. OX 85 mg/m2/d in 5DW 500 mL was administered IV over 6 hour on day 1 and 15. Dexamethasone 40 mg was admistered orally on day 1 through 4. All 29 patients were enrolled in this phase II study. Patients were male in 18 (62.1%), DLBCL in 16 (55.2%), stage III/IV in 25 (79.3%) and relapsed NHL in 23 (79.3) patients. Five (17.2%) patients had relapsed after upfront autologous/allogeneic stem cell transplantation. The most common prior chemotherapy was R-CHOP (n=16, 55.2%) and 17 (58.6%) were exposed to rituximab as prior chemotherapy. The median age and median prior chemotherapy were 53 (range 26–74) years old and 1 (range 1–4) cycle, respectively. IPI at relapse were 3/4 in 11 (37.9%). Only 17 (58.6%) and 9 (31.0%) patients could finish 2 or more and 4 or more cycles, respectively, and median received cycle was 2 (range 0.5–8). Four patients completed planned all 6 or more cycles, and 4 patients stopped GemDOx after 4 cycles for ASCT, and 1 patient lost initial response and progressed after 4 cycles. The reasons of drop-out were progressed disease in 15 (51.7%), lost to follow-up in 4 (13.8%), discrete of attending physician in 1 (3.4%) and withdraw of consent in 1 (3.4%). Maximal response rate was 27.9% (CR in 13.8%; PR in 13.8%) in intent-to-treat basis and 47.0% (CR in 23.5% and PR in 23.5%) among patients who had received at least 2 cycles of GemDOx. Stable disease was observed in 6 (20.7%) in intent-to-treat basis and 5 (29.4%) among patients who had received at least 2 cycles of GemDOx. Among patients who received 2 or more cycles, ORR was 53.4% (CR in 26.7% and PR in 26.7%) in relapsed NHL and 0% (SD in 50% and PD in 50%) in refractory NHL. Median survival and median progression-free survival were 20.526 (95% CI, 8.945–32.108) and 3.947 (95% CI, 0–10.358), respectively in all patients (Figure 1). Among patients who had completed 2 or more cycles, median survival and median progression-free survival were not reached and 10.625 (95% CI, 0–21.575), respectively. In conclusion, dose-dense biweekly GemDOx showed activity against highly unfavorable relapsed NHL, but failed to show superior overall response rate especially against refractory NHL. The main cause of failure was progressive disease although considering high drop-out rate. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Second-Line Therapies After Treatment with Fludarabine, Cyclophosphamide, and Rituximab (FCR) or Fludarabine and Cyclophosphamid Alone (FC) for Chronic Lymphocytic Leukemia (CLL) within the CLL8-Protocol of the German CLL Study Group (GCLLSG)

Abstract 2863 Introduction:The CLL8-trial is the first study that has shown not only an increase in complete remission rates and progression-free survival, but also an improved overall survival (OS) in physically fit, treatment-naúve CLL-patients (pts) with FCR-chemoimmunotherapy in comparison to FC alone [Hallek et al., Lancet 2010]. Despite this remarkable progress, CLL remains an incurable disease and virtually all pts will eventually relapse. So far, little is known about the efficacy of 2nd-line therapies of these pts. Patients and Methods:Between July 2003 and March 2006 817 pts in good physical fitness as defined by a cumulative illness rating scale (CIRS) score of ≤6 and creatinine clearance 70 ml/min were randomized within the trial and received 6 courses FC (n=409; F: 25mg/m2 i.v. d1–3 and C: 250 mg/m2 i.v. d1–3; q 28 days) without or with rituximab (n=408; 375 mg/m2 i.v. d0 cycle 1, 500 mg/m2 d1 of all subsequent cycles; q 28 days) for 1st-line treatment. Results:As of March 2009, 65% of the patients who had received FCR were free of progression compared to 45% of those who were treated with FC (p<0, 0001) [Hallek et al, Lancet, 2010]. Until July 2010, 232 pts were treated for relapsed CLL, among them 91 of 408 (22%) initially treated with FCR and 141 of 409 (35%) initially treated with FC. In 2nd-line treatment after FCR and FC, the drugs most frequently used either alone or in combination were rituximab (R, 52% of all 2nd-line therapies), fludarabine (F) and bendamustine (B) (21% each), as well as alemtuzumab (A, 12%). The combination of cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab (CHOP-R) was the most common treatment (35 pts, 15% of all 2nd-line therapies), applied mainly in cases with a relapse ≤24 months after FC/FCR, whereas FCR or BR were administered predominantly in case of relapse >24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent A (20 pts) or B (17 pts), CHOP and FC (11 pts respectively), chlorambucil (9 pts) as well as R monotherapy (7 pts). 9 pts underwent stem cell transplantations. Second-line therapies with FC+/−R and B+/−R were found to be more effective with regard to treatment-free survival (TFS, time to 2nd relapse) and OS when compared to A or CHOP-R and CHOP-like chemotherapies. However, the outcome of 2nd-line therapies seemed to be influenced by the 1st-line treatment. In pts initially treated with FC, FCR was found to be the most effective 2nd-line therapy (TFS: 23 months, OS: not reached), whereas in pts initially treated with FCR, a substitution of the chemotherapeutic agents FC by B seemed justified, as TFS was superior after 2nd-line treatment with B+/−R (16 and 18 months respectively) when compared to FC+/−R (11 and 8 months). Furthermore, in pts who had received FCR for 1st-line treatment, chemotherapy with FC or B was found to be at least equally or even more effective in prolonging OS than FCR or BR (OS calculated from beginning of 2nd-line therapy: FC: not reached, B: 45, FCR: 19, and BR 18 months). Conclusion:Second-line treatments of pts with a relapse after FC or FCR were found to be surprisingly heterogeneous even though the patient collective examined is comparatively homogenous due to the inclusion/exclusion criteria of a clinical trial. As the majority of CLL8-patients is still in remission and has not yet received a 2nd-line treatment, the therapies captured in this analysis are predominantly 2nd-line therapies for earlier relapses. Therefore and because of the short follow-up time, the results ought to be considered as preliminary and descriptive trends. The worse outcome of CHOP-like regimen and A-based therapies in comparison to more established CLL-therapies such as FC+/−R and B+/−R might be related to the fact, that these therapies were administered more often in case of an early relapse after FC/FCR, which is known to be related to other poor prognostic factors [Fink et al, ASH 2010]. Nevertheless, the observation of favorable TFS and OS times after 2nd-line treatment with FC+/−R and B+/−R supports the recommendation to repeat chemoimmunotherapy in case of a relapse >24 months after 1st-line treatment. Further analyses are needed to confirm the observation that chemotherapy (FC or B) without rituximab might be sufficient for for 2nd-line treatment after FCR. Disclosures:Cramer:Mundipharma: Travel Grants. Fink:F. Hoffmann La Roche:. Eichhorst:Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Wendtner:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Pflug:Hoffmann La Roche:. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria. Fischer:Hoffmann La Roche:.

Cyclosporine, prednisone, and high-dose immunoglobulin treatment of angioimmunoblastic T-cell lymphoma refractory to prior CHOP or CHOP-like regimen

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, distinct subtype of peripheral T-cell lymphoma, possessing an aggressive course and poor prognosis with no standard therapy. Twelve patients who have failed at least two initial CHOP or CHOP-like regimens were enrolled in this study and treated with individualized cyclosporine (CsA), prednisone (PDN), and monthly, high-dose intravenous immunoglobulin (HDIVIG). The dose of CsA was adjusted individually based on the blood trough concentration of CsA and renal function. All patients were examined for response, toxicity and survival. The most significant toxicities (≥ grade 2) were infection (16.7%), renal insufficiency (8.3%), hypertension (8.3%), diabetes (8.3%) and insomnia (16.7%). Discontinuation of treatment occurred in one patient (8.3%) due to grade 3 renal toxicity and subsequent grade 4 pulmonary infection. Treatment-related death was not observed. The overall response rate was 75.0% (complete response, 33.3%; partial response, 41.7%). With a median follow-up of 25.5 months, the median duration of response was 20 months (range, 12 to 49 months) and the median progression-free survival (PFS) was 25.5 months (range, 10 to 56 months). The 2-year PFS rate was 81.5%. Our findings indicate the combination of CsA, PDN and HDIVIG is an effective salvage regimen for refractory or relapsed AITL with predictable and manageable toxicity.

Interim positron emission tomography scan associated with international prognostic index and germinal center B cell-like signature as prognostic index in diffuse large B-cell lymphoma

[18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is essential to optimize the initial staging and to predict the prognosis of diffuse large B-cell lymphoma (DLBCL). To assess the relationship between the germinal center B cell-like/activated B cell-like (GCB/ABC) classification and PET scan features in DLBCL, 57 cases treated with rituximab and a cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)/CHOP-like regimen were analyzed. The expression profile of 18 GCB/ABC related genes and five genes coding for glucose transporters (GLUTs) was determined from frozen tissues using DASL (cDNA-mediated Annealing, Selection, Ligation and extension) technology. According to the gene expression profile (GEP), 30 cases of DLBCL were classified as GCB subtype (2-year progression-free survival [PFS] 76%) and 27 cases as ABC subtype (2-year PFS 51%, p = 0.03). Using a semiquantitative assessment of the decrease in standard uptake value (SUV) at interim PET performed after 3–4 cycles of chemotherapy, we defined fast (n = 36) and slow (n = 9) metabolic responders. In multivariate analysis, GCB/ABC subtype, age-adjusted international prognostic index (aaIPI) and slow/fast metabolic response were independent variables that predicted outcome. A score incorporating aaIPI, fast/slow metabolic response and GCB/ABC classification was used to define two groups with highly significantly distinct outcomes. Our study suggests that the combination of GEP, aaIPI and interim PET more accurately predicts DLBCL prognosis and is therefore suitable for tailoring therapeutic strategies.

Long-term outcomes of patients with newly diagnosed extranodal natural killer/T-cell lymphoma treated by etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen: a single-institution experience

One possible reason for the relapse and refractoriness of extranodal natural killer/T-cell (NK/T) lymphoma (ENKL) is resistance to a CHOP-like regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). To evaluate the outcome of first-line EPOCH chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for ENKL, 34 patients, including 30 with nasal ENKL (88.2%) and four with extranasal ENKL (11.8%), were studied. Involved-field radiation therapy (IFRT) was administered to patients with localized nasal focus after chemotherapy. Thirty-three cases were eligible for response evaluation. The response rate (RR) was 60.6% (20/33) with a complete remission (CR) rate of 45.5% (15/33). For patients with localized nasal ENKL, the CR rate was 57.7% (15/26). The 3-year progression-free survival and overall survival rates were 53.6% and 69.0%, respectively. After initial EPOCH chemotherapy followed by IFRT, the CR rate was 75.0% and the 3-year overall survival rate was 75.0%. However, patients with disseminated and extranasal disease responded poorly. These results indicate that EPOCH followed by IFRT yields promising outcomes for patients with localized nasal ENKL.

First-line gemcitabine, oxaliplatin, and l-asparaginase chemotherapy followed by involved field radiation in stage IE/IIE extranodal NK/T-cell lymphoma.

e18540 Background: Now, there is lack of consensus on treatment of Extranodal NK/T cell lymphoma (ENKTL), and no therapy is considered standard. ENKTL shows a poor response to anthracycline-based chemotherapy, such as CHOP or CHOP-like regimens, because of the frequent expression of a multidrug-resistant P-glycoprotein. Thus, we designed an induce chemotherapy regimen consisted of gemcitabine, oxaliplatin and l-asparaginase(GELOX), which are not affected by P-glycoprotein. In addition, we added involved field radiation. The objective of this study is to investigate the efficacy and safety of GELOX followed by involved field radiation. Methods: From January 2008 to April 2010, 17 newly diagnosed patients with stage IE/IIE ENKTL were frontline treated with GELOX chemotherapy (gemcitabine 1000 mg/m2 intravenous drip on day 1,8; oxaliplatin 130mg/m2 intravenous drip on day 1; and l-asparaginase 5000IU/ m2 intravenous drip on days 1-7) followed by involved field radiation ( radiation 46 Gy to 56 Gy) in Sun Yat-sen University Cancer Center. Results: After treatment of GELOX regimen, there were 12 CRs (70.5%, 12/17) and 5 PRs (29.5%, 5/17), which is a 100% response rate. No patient was disease progression or stable during chemotherapy. All patients achieved CRs after involved field radiation, which is a 100% CR rate. At a median follow-up of 18.6 months (range 5–31), 2 (11.8%) of 17 patients experienced disease progression. the estimated median disease-free survival (DFS) is 30.0 months (95% CI, 26.2 to 38.9). Grades 1 to 2 toxicities were frequent during GELOX, but grades 3 to 4 toxicities were rare (5.9%). Conclusions: In conclusion, GELOX followed by involved field radiation can be a feasible and effective treatment strategy for stages IE to IIE ENKTL.