ALBERT

Description: BACKGROUND: Epstein Barr Virus (EBV) positive status is associated with poor survival in Hodgkin lymphoma and T cell NHL. AIM: In order to define the prognostic impact of Epstein Barr Virus (EBV) infection in newly diagnostic nodal diffuse large B cell lymphoma (DLBCL), we investigated the EBV status in Peruvian DLBCL patients. PATIENTS AND METHODS: Between January 2002 and December 2004, seventy-four patients, diagnosed with nodal DLBCL, were included in the analysis. Tissues from patients were analyzed for the presence of EBV encoded RNA (EBER) using the in situ hybridization (ISH) RESULTS: Of the 74 cases, 53 cases (71.6%) were of the non Germinal Center DLBCL type (non GC). This group had a higher IPI than the Germinal Center DLBCL type (GC). Also the non GC DLBCL type had an inferior overall survival compared with GC DLBCL type, but the difference was not significant (p=0.171). Eleven cases (14.9%) were identified as EBER-positive. EBER positive was associated with an advanced age (〉 60 years), poorer performance status, more advanced stage, higher IPI and poorer outcome to initial treatment. The EBER+ DLBCL patients demonstrated substantially poorer overall survival (EBER+ vs. EBER−): 1.1 months (95% CI, 0.0–2.6 months) vs. 15.5 months (1.0–30.0 months) respectively, (p=0.001). Most of the cases EBER (+) were of the non GC group. At the multivariable level, EBER status is an independent variable compared with the International Prognostic Index (IPI) (p=0.001) with a 3.2-fold (95% CI, 1.5–7.2) risk for death for positive cases. CONCLUSION: EBV positive status in de novo, nodal DLBCL was present in 11/74 cases and is a powerful prognostic factor in this Peruvian population. EBV positive status correlated with advanced age, poor performance status, more advanced stage, non-GC group and short survival. New therapeutic strategies should be investigated in this poor prognostic subgroup. Figure Figure

Description: Abstract 2833 Introduction: No therapy with reliable, durable efficacy exists for patients with aggressive non-Hodgkin lymphoma (aNHL) who relapse following at least two lines of therapy. Pixantrone dimaleate (PIX) is a novel aza-anthracenedione, structurally similar to anthracyclines and mitoxantrone, and forms stable DNA adducts. Unlike anthracyclines and mitoxantrone, PIX does not bind iron, minimally promotes reactive oxygen species formation, and is substantially less cardiotoxic in preclinical models. On the basis of promising early clinical activity and acceptable safety, we conducted a phase 3 trial with PIX in patients with aNHL and ≥2 relapses. Patients and Methods: This randomized, multicenter, controlled, open-label study enrolled patients with aNHL (de novo or transformed) with ≥1 prior anthracycline-containing regimen and ≥2 relapses. Patients were randomized to PIX 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle, for up to 6 cycles, or to investigator's choice of single-agent comparator (COMP): vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, or, in the US only, gemcitabine or rituximab. Both groups were followed for 18 months after last treatment. The primary endpoint, CR/CRu rate in ITT population, was assessed by an independent assessment panel. Other efficacy endpoints were overall response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Final end-of-study results are reported here. Results: Planned enrollment was set at 320 patients; however, due to slow accrual, a total of 140 patients were randomized (n=70 per group) to this study. Median number of treatment cycles for PIX group was 4 vs 3 for COMP. Median duration of treatment for patients in the PIX group was about one month longer than in the COMP group (3.8 vs 2.6 months). The end-of-study CR/CRu rate was 24% (16% CR, 8%CRu) for PIX vs 7% (no CRs, 7% CRu only) for COMP (P = 0.009); ORR (CR/CRu/PR) was 40% vs 14% (P = 0.001). After treatment ended, 3 patients in the PIX group achieved CR with no subsequent therapy. Two of the 3 patients converted from SD to CR and 1 from PR to CRu. Median CR/CRu duration was 9.6 months for PIX vs 4.0 months for COMP (P = 0.081). For survival endpoints, there was a 40% improvement in PFS with a median of 5.3 months vs 2.6 months (HR = 0.60, log-rank P = 0.005) and a 21% improvement in OS with a median of 10.2 months for PIX vs 7.6 months for COMP (HR = 0.79, log-rank P = 0.251). Exploratory subgroup analyses of CR/CRu and ORR were consistently higher for PIX patients and suggest stronger efficacy with the subgroups sex (female),

Description: Adult T -cell leukaemia/lymphoma (ATL) is an aggressive disease associated with human T-cell lymphotropic virus type-I (HTLV-I) with heterogeneous clinical presentation and outcomes, described in Southern Japan, Europe, Caribbean and previously on Pacific coast of South America including Peru (EHA 2001, abst. 304). Shimoyama’s ATL classification (BHJ1991:79) includes four types: acute, lymphomatous, chronic and smoldering; recently a new clinical type cutaneous had been described (BJD2005:152). Herein we show our experience in ATL in our institution between October 1997 and May 2005 All our 55 cases shown positivity to HTLV-I Western Blot test; immune-histopathology, blood smears and flow cytometry showed mature T-cell lymphocyte. Median age at diagnosis 61 years old (range 23–84), female/male ratio: 1.2. Thirty-one (56%) patients had ECOG status performance at diagnosis ≥ 2. Clinical types: acute (n=26), lymphomatous (n=22), smouldering (n=2), cutaneous (n=5) with no chronic type observed. Median haemoglobin diagnosis was 12.1 g/dl (range 6.9–17), median albumin was 3.2 g/dl (range 1.8 – 4.9), median beta-2 microglobulin was 4.6 g/dl (range 1.5 – 16.9), median globulin was 2.7 g/dl (range 1.5 – 8.2) and DHL was 796 UI/ml (range 331 – 13000). Twenty-five per cent (9/36) debuted with hypercalemia (acute type=7, lymphomatous=2). Acute ATL showed median leukocytes of 48,900 cell/mm3 (range 6830–259,000). IPI risk score was: low (n=6), low intermediate (n=7), high intermediate (n=16) and high (n=27). Treatment for acute ATL was based on acute leukaemia and lymphoma regimens without any response but one, interestingly this patient was treated with Fludarabine 25 mg/mt2 day 1–5 each 28 day for 6 cycles and got complete remission. Twenty-one over 24 lymphomatous ATL type were evaluable for treatment response: overall response 38% (9/24) with 26% complete response. Smouldering and cutaneous ATL types received mainly topic treatments. Stratify analysis for IPI, DHL, beta-2 microglobulin, globulin and albumin for acute and non-acute ATL did not show any statistic difference. Median overall survival was: acute type (2.0 months DE 0.2), lymphomatous type (10.2 months DE 3.6), smouldering type (17.2 months) and cutaneous type (36.2 months DE 19.5) (Log Rank 30,76 p=0.0) ATL persist is a poor prognostic peripheral T-lymphocytic malignancy with bad clinical and therapeutically outcomes mainly in the acute type. Cutaneous type seems to be less aggressive. Figure Figure

Description: Abstract 1677 Poster Board I-703 Introduction Nearly half of patients with aggressive non-Hodgkin's lymphoma (NHL) relapse or are refractory to initial therapy. With each subsequent therapy, the probability of response decreases and the responses are less durable. An agent currently in development, pixantrone dimaleate (pixantrone), is a novel aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. The clinical activity and safety profile of pixantrone are promising in patients heavily pretreated for relapsed aggressive NHL and who received prior treatment with up to 450 mg/m2 of doxorubicin. Patients and Methods This phase 3, randomized, multicenter, controlled, open-label study enrolled patients who had ≥1 prior anthracycline-containing regimen and failed 2 prior treatment regimens for relapsed aggressive (de novo or transformed) NHL. Seventy patients were randomized to a treatment group administered pixantrone 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle, for up to 6 cycles. Seventy patients were randomized to the investigator's choice of a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, or mitoxantrone; in the US only, gemcitabine and rituximab were permitted). Patients in both groups were followed up to 18 months after last treatment. The primary endpoint, CR/CRu rate, was assessed by an independent assessment panel (IAP). Other efficacy endpoints were overall response rate (ORR), responses lasting ≥4 months, progression-free survival (PFS), overall survival (OS), duration of response, and time to response. This report includes the results from the treatment period and updated results from the follow-up period, which is still ongoing. Results A total of 140 patients were randomized with 70 patients in each treatment group. Of the 140 patients, 96% received treatment (n=68 for pixantrone, n=67 for comparator). The median number of treatment cycles that patients in the pixantrone group received was 4 compared with 3 for the comparator group. The percentage of patients who received all 6 treatment cycles in the pixantrone group was 32.4% compared with 28.4% for the comparator. The primary endpoint, CR/CRu rate (assessed by IAP), in the ITT population was 20.0% for the pixantrone group compared with 5.7% for the comparator (P = 0.021). The ORR for the pixantrone group was 37.1% compared with 14.3% for the comparator (P = 0.003), and the percentage of patients with objective responses lasting at least 4 months for the pixantrone group was 25.7% compared with 8.6% for the comparator (P =0.012). The median number of months of PFS in the pixantrone group was 4.7 compared with 2.6 for the comparator (HR= 0.60, log rank P = 0.007). The median number of months of OS, while not fully mature, was 8.1 for the pixantrone group compared with 6.9 for the comparator (HR=0.88, log rank P = 0.554). Subgroup assessments of the CR/CRu rate and ORR, by risk factor, were consistently higher in the pixantrone group than in the comparator group. These subgroup assessments included prior exposure to anthracyclines ('300 mg/m2 or ≥300 mg/ m2) and rituximab (treated or not treated), IPI score ('1 or ≥2), and NHL diagnosis (refractory or relapsed), and age ('65 or ≥65). In the pixantrone group, neutropenia and leukopenia were the most common (≥10%) grade 3/4 adverse events and the incidence of febrile neutropenia was 7.4%. The percentage of patients with cardiac disorder SAEs was 8.8% in the pixantrone group compared with 4.5% for the comparator. Conclusions In this phase 3, randomized, multicenter study, patients with relapsed aggressive NHL administered single-agent pixantrone achieved superior efficacy, compared with other single-agent chemotherapeutic agents, as measured by CR/CRu rate, ORR, responses lasting ≥4 months, and PFS. Positive trends were observed in OS and duration of response. Patients in the pixantrone group tended to reach CR sooner than patients in the comparator group. Pixantrone has a tolerable safety profile in heavily pretreated patients with relapsed aggressive NHL. Disclosures Cernohous: Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment.

Description: Background: Association between osteonecrosis of the jaw (ONJ) and aminobisphosphonate treatment in patients (pts.) with multiple myeloma, breast cancer and prostate cancer has been increasingly reported in the literature. Risk factors for this complication include presence of infection, recent dental extraction and any oral surgical procedure with bone exposure. Patients and Methods: All patients with myeloma multiple or prostate cancer diagnosis treated at two institutions from Lima with either IV zoledronic acid or pamidronate from 2005–2007 were evaluated using outpatient records. Patients with ONJ were identified and their characteristics were compared to all patients receiving bisphosphonate therapy. Results: One hundred eighty three patients were evaluated. One hundred three had metastatic prostate cancer, and eighty myeloma multiple. All patients with myeloma multiple received pamidronate and all patients with prostate cancer received zoledronic acid. Six patients developed ONJ (3.2%). Five pts. were male and one female; a median age of 62 (range 50–74) and 5 had metastatic prostate cancer and 1 myeloma multiple. Zoledronic acid and pamidronate were involved in 5 and 1 cases respectively. The median number of bisphosphonate infusions prior to the development of ONJ was 16 (range 12–20). No patient had dental extraction or oral surgical procedure before ONJ. Bone exposition occurred in four cases. Treatment was antibiotics in all cases and surgery in two. Conclusions: ONJ is a serious complication of bisphosphonate therapy and it affected a significant proportion of our Latino american patients.

Description: Background: The clinicopathologic characteristics of malignant lymphomas may vary according to geography. We previously described Adult T -cell leukaemia/lymphoma (ATLL) cases associated with human T-cell lymphotropic virus type-I (HTLV-I) in their different clinical presentation: acute, lymphomatous, chronic and smoldering and the recently primary cutaneous subtype in Peru (EHA2001: abstract 129). The aim of this study is to determine the relative frequency of cutaneous lymphomas and evaluate the clinical relevance of the new WHO/EORTC classification in a General Hospital in Lima-Peru Methods: We conducted a clinicopathologic retrospective study of primary cutaneous lymphomas diagnosed from 1997 to 2004 in our General Hospital. Clinical records, haematoxylin & eosin-stained slides and immunohistochemical stains from 78 patients were reviewed. HTLV-1 serology was made using ELISA and Western Blot method. The statistical method was descriptive and survival was calculated using the Kaplan-Meier method. Results: The mean age at time of presentation was 62 years and the female/male ratio 1,5:1. T-cell lymphomas were 88.6% and 11.4% were B-cell lymphomas. Eight-six percent (67/78) were primary cutaneous lymphomas and fourteen percent (11/78) were secondary cutaneous lymphomas. The most frequent primary cutaneous lymphomas was mycosis fungoides (MF): 44.7% (30/67); cutaneous / smoldering ATLL sutypes included 13/67 (19.4%) patients; unspecified peripheral T-cell lymphoma 4/67 (6%), lymphomatoid papulosis 2/67 (3%), leg-type diffuse large B-cell lymphoma 2/67 (3%), diffuse large B-cell lymphoma 2/67 (3%), subcutaneous panniculitis-like T-cell lymphoma 2/67 (3%), one case of the following lymphomas: anaplastic large cell, Sézary syndrome, nasal type extranodal NK/T-cell lymphoma, marginal zone B-cell lymphoma, follicle center lymphoma and intravascular lymphoma; finally unclassifiable lymphomas 5/67 (7.4%). Most frequent secondary cutaneous lymphomas were acute and lymphomatous subtypes of ATLL with 72% of the cases. Five-years overall survival for MF was 77%. The 5-years overall survival for primary cutaneous ATLL lymphomas was 18% and 0% for the secondary cutaneous ATLL group. Conclusions: In this retrospective analysis, both ATLL and MF are the most frequent cutaneous lymphomas in our General Hospital. ATLL has a poor overall survival.

Description: Objectives: Alemtuzumab (Campath®/Mabcampath®, a humanized anti-CD52 monoclonal antibody) has shown to be effective in the treatment of diverse hematological malignancies, including B-cell chronic lymphocytic leukemia and T-cell prolymphocytic leukemia. Mycosis fungoids (MF) is a low grade T-cell cutaneous lymphoma with indolent course and good prognosis while response to chemotherapy is achieved. We started a prospective phase II study in refractory relapse MF cases (advanced disease) treated with i.v. Alemtuzumab (ClinicalTrial.gov Identifier: NCT 00157274) Methods: From July 2005 to April 2006 a total of eight patients were recruited from 2 centers in Lima-Perú with hystopathological diagnosed of advanced refractory relapse MF. Inclusion criteria include: above 18 years old, ECOG status 0–2, no active infections, no more than 3 previous chemotherapy or radiotherapy, HTLV-1 negative, HIV negative, normal renal or hepatic function and written informed consent. Median age 64 years old (range: 36–72). Five were male. Median number of previous therapies was 2 (range: 2–3). Original treatment scheduled was planed as Alemtuzumab 30 mg i.v. tiw per 12 weeks with a gradually escalated doses during the first week (3, 10, 30 mg). Trimethoprim/sulphamethoxazole and acyclovir prophylaxis was given as regular. Median Alemtuzumab total dose was 283 mg (range: 123–706) over a median of 5 weeks of treatment (range: 3–15). The first four patients (pts.) received the programmed dosification and due toxicity the subsequent 2 pts. received Alemtuzumab 30 mg i.v. tiw for 4 weeks and then 30 mg i.v. weekly and the last 2 recruited pts. received Alemtuzumab 10 mg i.v. tiw for 4 weeks them 10 mg i.v. biw and finally 10 mg i.v. weekly. CMV monitoring with pp65 was performed in the first five pts. and qualitative PCR in the last 3 pts. Results: Seven patients were evaluated for response, overall response rate (ORR) was 57% (4/7), with two pts. achieving complete remission (CR), two pts. with partial response (PR) and three pts. progressive disease (PD) during treatment. Response duration and follow-up and CMV status is described in table 1. Median Pruritus Analogue Scale was reduced from 4 to 1. Grade 1 neutropenia in one pt. and grade 1 thrombocytopenia in one pt. One patient developed urosepsis caused by E. Coli. No cardiac toxicity was reported. Kaposi’s sarcoma was discovered in a CR pt. (pt 4, table 1) Conclusions: Alemtuzumab shows promising clinical activity in patients with advanced MF previously treated. Alemtuzumab s.c. as maintenance therapy or in combination with other agents should be explored in advanced MF. Table 1. Outcomes, follow up and CMV status Alemtuzumab TD (mg) Response Follow-up (m.) CMV status TD=total dose, NE=no evaluable, AD=active disease, m=months, R=Reactivation, F=Fever 1 123 NE AD, 14 m. R with F 2 313 PD Died, 8 m. 3 706 PD AD, 8 m. 4 403 CR Relapse at 6 m. R with F 5 253 CR Relapse at 3 m. R with F 6 493 PR PR, 5 m. 7 123 PR Relapse at 3 m. R no F 8 163 PD AD, 3 m. R no F

Description: BACKGROUND: Foxp3 is a key regulatory gene required for the development and function of: regulatory CD4+CD25high T cells (Treg) specialized in maintaining the balance between immunity and tolerance and activated conventional CD4+CD25low T cells without suppressive activity. Until now it is not yet possible to study human FOXP3+ Treg irrespective of their CD25 expression. Previous studies had reported FOXP3+ T cells in Adult T-cell Leukemia/Lymphoma cells (ATLL) related to HTLV-1 and in other lymphomas types the FOXP3 expression was only detected in the reactive T-cell background. AIM: To determine the specifity and prognostic value of the FOXP3 expression in T-cell lymphomas. METHODS: A retrospective study was performed on 46 samples collected from diverse T-cell lymphomas in our institution. A highly sensitive immunohistochemical method was used to demonstrate FOXP3 protein expression with a mouse monoclonal antibody (clone 236A/E7ABCAM) in most formalin-fixed paraffin-embedded tissue sections from lymph nodes, skin, bone marrow and extranodal sites samples as cavum and stomach. We did not co-stained with CD25 and considered a FOXP3+ tissue when positivity was 〉 80% of toumor cells. Correlation with survival was done. RESULTS: Among the 46 evaluable T-cell lymphomas collected, 33 were ATLL, 7 mycosis fungoids (MF) and 6 unspecified peripheral T-cell lymphomas (U-PTCL). Among the 33 ATLL: lymphomatous=17, acute=11, smoldering=1, chronic=1, cutaneous=1 and undefined=2. FOXP3 expression in tumour cells was detected in 24% (8/33) of ATLL cases, was negative in MF tumour cells and detected in 33% (2/6) of U-PTCL. Interestingly FOXP3 expression between 30–40% was expressed in 3 MF cases associated to Treg cells. Among the ATLL cases FOXP3 positivity were obtained in 35% (6/17) of lymphomatous type; 18% (2/11) of acute ones and none in others ATLL types studied. We failed to demonstrated any correlation between FOXP3 status and survival. CONCLUSIONS: FOXP3 is expressed in ATLL and T-cells peripheral lymphoma. Treg presence in the tumour environment plays an important immune system response role and its identification should be fundamental.