ALBERT

Description: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous in clinical presentation, histopathological and biological findings, and outcome. Today, risk-adapted treatment decisions are mainly based on the International Prognostic Index (IPI). Recently, molecular profiling has been shown to correlate with survival in DLBCL patients treated with conventional chemotherapy. Immunohistochemistry (IHC) has been proposed as a surrogate of molecular profiling (« phenotypic profiling»). Besides, we and others have shown that early response evaluation (after 2 cycles) with 18FDG-PET scanning is predictive of patient outcome in DLBCL, independently of IPI (Haioun & al, Blood2005; 106: 1376). We retrospectively investigated the phenotypic profile of 81 patients (pts) from our recently published series with a confirmed diagnosis of DLBCL and available material for extensive IHC analyses. Diagnosis was based on a nodal (n=45), extranodal (n=25) or mediastinal (n=11) specimen. IHC was performed with the markers bcl2, CD10, bcl6 and MUM1, and scored by two observers. Pts were classified as having a germinal center (GC) or non germinal center (nGC) profile using the following algorithm: GC pts were to be CD10+ or bcl6+ and MUM1−, and all others were nGC (Hans & al, Blood2004; 103: 275). Bcl2 was positive in 53%, CD10 in 36%, bcl6 in 58% and MUM1 in 45% of interpretable cases. Seventy-four pts (91%) had an interpretable profile, 39 (52%) were in the GC group, 35 (48%) in the nGC group. All pts received a doxorubicin-containing regimen as induction treatment, with rituximab for 46% of them. Pretreatment characteristics and early response by 18FDG-PET according to phenotypic profile are shown in the table below. With a median follow-up of 33 months, estimated 2-y OS and EFS were 75% and 67%. Survival analysis confirmed the poor prognostic value of a positive early 18FDG-PET scan: 2-y EFS was 46% in the PET-positive group and 80% in the PET-negative group (p = 0.0003). Two-year EFS was 61% and 73% in the bcl2-positive and negative groups, respectively (p = 0.08). We could not observe any prognostic influence of the GC vs nGC profile: Two-year EFS was 72% in the GC and 64% in the nGC group (p=0.62). In this limited series, we confirm the high predictive value of early response evaluation with 18FDG-PET scanning, but did not observe any significative influence of phenotypic profile, contrarily to several published reports. The reasons for this discrepancy, be they related to treatment type (including rituximab), disease presentation (many pts with extranodal disease) or IHC evaluation (fixation, scoring), remain to be understood. Meanwhile, 18FDG-PET should be an early guide for first-line strategies in DLBCL. Characteristics according to phenotypic profile GC (n=39) nGC (n=35) p Age

Description: Abstract 1750 Poster Board I-776 Chronic myelomonocytic leukemia (CMML) is a clonal disorder sharing features of both myelodysplastic syndromes (MDS) and chronic myeloproliferative disorders (MPD). The natural course of CMML is highly variable. Several small series have suggested the prognostic importance of different characteristics but a widely accepted prognostic scoring system for CMML is not available. The main aims of the study were to identify prognostic factors, including cytogenetic findings, for overall survival (OS) and acute leukemic (AL) transformation in a large series of patients with CMML and to develop an easily applicable prognostic scoring index for estimating outcome and planning treatment in the individual patient. Five hundred and seventy-two patients diagnosed of CMML according to FAB and WHO criteria in 25 centers belonging to the Spanish Registry of MDS were included in the study. Actuarial curves of OS and risk of AL evolution were built by Kaplan-Meier method and differences between curves compared with log-rank tests. Multivariate analyses of OS and risk of AL evolution were performed by Cox proportional hazards regression method. The weights assigned to the variables included in the final prognostic scoring system were based on the regression coefficients from the proportional hazards models. Median age was 73 yr and 397 (69%) were males. According to FAB criteria 61% of the patients had MDS-CMML (absolute WBC count '13 × 109/L) and 39% MPD-CMML and by WHO classification 86% were CMML-1 (blasts

Description: CD8+ T cell-numbers rapidly expand and then contract after exposure to their cognate antigen. Here we show that the sustained frequencies of transgene product-specific CD8+ T cells elicited by replication-defective adenovirus vectors are linked to persistence of low levels of transcriptionally active adenovirus vector genomes at the site of inoculation, in liver, and lymphatic tissues. Continuously produced small amounts of antigen maintain fully active effector CD8+ T cells, while also allowing for their differentiation into central memory cells. The long-term persistence of adenoviral vectors may be highly advantageous for their use as vaccines against pathogens for which T-cell–mediated protection requires both fully activated T cells for immediate control of virus-infected cells and central memory CD8+ T cells that, because of their higher proliferative capacity, may be suited best to eliminate cells infected by pathogens that escaped the initial wave of effector T cells.

Description: Chemoradiotherapy is standard treatment for localized aggressive lymphoma (Miller et al., NEJM, 1998). Because previously published series were heterogeneous with regard to prognostic factors such as age, we aimed to determine the optimal therapy for elderly patients with low risk localized lymphoma. From March 1993 to June 2002, 576 patients (pts) over 60y of age with aggressive lymphoma (WF histology: F, G, H or Kiel anaplastic) and without any adverse factor of the age-adjusted International Pronostic Index were randomly assigned to a chemoradiotherapy arm (299 pts) consisting of 4 cycles of CHOP (doxorubicin 50 mg/m2 d1, cyclophosphamide 750 mg/m2 d1, vincristine 1.4 mg/m2 [up to 2 mg] d1, prednisone 60 mg/m2 d1-5) given every 3 weeks followed by 40 Gy involved-field radiotherapy or to a chemotherapy-alone arm (277 pts) consisting of 4 cycles of CHOP given every 3 weeks. Randomization was stratified according to center and the presence of bulky disease (≥ 10 cm). Principal characteristics were: median age, 68y; male gender, 52%; stage I, 63%; bulky disease, 8%; extranodal involvement, 56%; diffuse large B-cell histology, 80%. Complete response at the end of treatment was similar in both groups (89% and 90 % respectively). Treatment-related death occurred in 1% of pts in each group. On an intent-to-treat basis and with a median follow-up of 6.8y, event-free survival (EFS) and overall survival (OS) did not differ significantly between the two treatment groups (p= 0.7 and p = 0.6, respectively). 5y-EFS rates were 68% for pts treated with chemotherapy alone as compared to 66% for those receiving chemoradiotherapy; 5y-OS rates were 72% and 68% respectively. 66%, of deaths resulted from lymphoma progression. In the subgroup of 247 pts over 70y of age, the 5y-OS was higher in those treated by chemotherapy alone (70% as compared to 58%) but this trend did not reach significance (p=0.1). In a multivariate analysis of the 576 pts, EFS and OS were affected by stage II (p

Description: Background: Nilotinib, a potent and highly selective BCR-ABL inhibitor, has been approved in more than 50 countries including Mexico. Nilotinib is indicated for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) patients (pts) in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib (IM). Before the approval of nilotinib by FDA or EMEA a Compassionate Use Program (CUP) of nilotinib was initiated in Mexico. Methods: The pts included in this program were adults pts with Ph+ CML, IM-resistant or –intolerant in all phases of the disease. IM resistance and intolerance were defined according to current guidelines (NCCN and ELN). Physical examination, EKG, bone marrow aspiration, karyotyping and BCR-ABL mutation screening were performed in all pts before starting nilotinib. All pts signed an informed consent. Nilotinib was administered orally at a dose of 400 mg twice daily (BID). No dose escalation was allowed. All pts were monitored with karyotyping. Patients that achieved CCyR were evaluated with quantitative RT-PCR for molecular evaluation. The results of CUP of nilotinib in Mexico are reported in this abstract including the cytogenetic, qRT-PCR and mutational analysis in a highly-resistant CML patient population. Results: Between October 2006 and June 2007, 47 pts were included in the nilotinib CUP in Mexico. The median age was 41.7 years (range 22–68) and 20 (44%) were men. Of the 47 pts, 28 (59.6%) had advanced phase CML which includes 7 (14.9%) blastic phase (BP) and 21 (44.7%) accelerated phase (AP) pts. 19/47 pts (40%) were in chronic phase (CP) of CML. Most patients were resistant to IM (86%) and 14% were IM-intolerant/resistant. The median duration since CML diagnosis was 73.8 months (range 14–183). The median duration of prior IM use was 27.6 months. All pts had been treated with hydroxiurea, interferon, and/or cytarabine prior to IM. At the time of starting nilotinib 17/47 pts (36.12%) had BCR-ABL mutations (P-loop mutations in 3 pts, IM binding mutations in 5 pts, catalytic domain mutations in 5 pts, and A-loop mutations in 4 pts). Only 3/47 pts (6.38%) had T315I mutation. The median duration of exposure to nilotinib was 304 days (range 19–632). Most pts tolerated nilotinib well and only one severe adverse event (AE) was reported (long-term myelosupression). At the time of data cut-off (July 31, 2008), 25 pts (53.2%) remain on therapy. Reasons for discontinuation of therapy were: lack of efficacy in 7/47 pts (14.9%) including 3 pts with T315I mutation; disease progression in 13/47 (27.5%); adverse events in 1/47 (2.1%); lost of follow-up in 1/47 (2.1%). The cytogenetic and molecular evaluation was performed after 12 and 18 months of treatment with nilotinib, respectively. The rate of overall hematological response (HR) was 79%. The major cytogenetic response (MCyR) according the phase of the disease were as follows: 57% in CP, 40% in AP and no MCyR was observed in BP. Of the 47 pts, 11 (23.4%) achieved CCyR, 5 (10.63%) achieved molecular responses including 2 (4%) with complete molecular response (CMR) and 3 (6%) with major molecular response (MMR). The current status of pts according baseline mutational analysis was: mutation detected/alive (8/47, 17%); no mutation detectable/alive (22/47, 46.8%); mutation detected/deceased (9/47, 19.2%); no mutation detectable/deceased (8/47, 17%). Conclusions: Nilotinib showed efficacy in IM-resistant or -intolerant CML pts in Mexico regardless of the presence or absence of BCR-ABL mutations. Nilotinib induced complete cytogenetic and molecular responses in some of the advanced and resistant CML patient population.

Description: Purpose: To evaluate efficacy, safety, Disease-Free Survival (DFS) and Overall Survival (OS) in patients with indolent non-Hodgkin’s lymphoma (NHL) treated with chemotherapy vs. immunotherapy vs immunochemotherapy as first-line therapy, an up-date report. Methods: Patients with indolent NHL were randomized to receive: (A) Rituximab x 6/w, (B) CNOP (cyclophosphamide, mitoxantrone, vincristine and prednisone) x 6 or (C) R-CNOP x 6, at standard doses. Results: 195 patients were included, 183 are evaluable for OS and toxicity (A:62, B:55 and C:66), 144 are evaluable for overall response rate (ORR) and DFS (A:53, B:41 and C:50). Clinical characteristics: 89 male (45.6%), mean age 59±14 (±SD), 148 (75.9%) in stage (III/IV), without significant differences between groups. Overall Response Rate (CR+PR) was: A: 84.9%, B:83.4% and C:90% (P=0.545). Neutropenia grade 3/4 was more frequent in the chemotherapy groups: A: 4.8%, B: 23.6% and C:18.2% (P=0.001) as it was the infectious toxicity (grade 2/4): A:4.8%, B:5.5% and C:15.2% (P=0.07). DFS at 24 months was: A 68%, B:65% and C:70%, (P=0.93) and the OS was A:87%, B:84% and C:78%. P=0.89. Conclusions: We did not find any important differences, between groups, regarding the Overall Response Rate, Disease Free Survival and Overall Survival at 24 months. However, single agent rituximab was better tolerated, with less toxicity in comparison with the chemotherapy containing groups. Based on these findings, it maybe reasonable to use immunotherapy only, as first-line therapy for patients with indolent NHL.

Description: Myeloablative transplant has been investigated in poor prognosis indolent lymphoma; although recurrence rate is low it is associated with high mortality; the use of non-myeloablative conditioning regimens could reduce TRM maintaining the GVH effect. Up to May 2006, 35 patients with follicular NHL received a Non Myeloablative related allogeneic according to two prospective multicenter trials; conditioning regimen consisted of Fludarabine 150 mg and Melphalan 70–140 mg. GVHD prophylaxis consisted of CSA plus short-course MTX. All patients received filgrastim-stimulated peripheral blood stem cells from a HLA related identical donor. Median age at transplant was 50 years (34–62) and 16 (46%) had received a previous autologous transplant. At transplant, 5 patients (14%) were in CR1 (after several lines of chemotherapy), 9 (25%) in 〉CR1, 12 (34%) in PR, 1 (3%) had stable disease (after 3 chemotherapy lines) and 8 (23%) progressive disease. All patients engrafted. Acute GVHD developed in patients 19 (54%) (17patients (48%) grade II-IV). Chronic GVHD developed in 18 out of 27 patients at risk (67%), being extensive in 11 (41%). Disease was evaluated at day +100 and at that moment 23 patients were in CR, (85%) 1 (4%) in PR, two (7%) had stable disease and 9 patients ( 26%) have died. With a median follow up of 60 months (range: 32–80 months), 20 patients (57%) are alive disease free, and 14 (43%) have died, 12 of them (37%) due to transplant toxicity and 2 patients (6%) due to progression. Overall Survival (OS) and Event Free Survival (EFS) are 57 and 54 % respectively. Analysing variables which influence on OS and EFS, patients 55 years have a OS significantly shorter than those

Description: Background: Nodal aggressive PTCL have a poor prognosis with conventional chemotherapy regimens for aggressive non-Hodgkin lymphomas. Therefore innovative approaches are needed. Among them, strategies including consolidation with high-dose chemotherapy and autologous stem cell transplantation in front line therapy may improve the outcome of these diseases. Aim: To report the experience of a national cooperative group in 26 patients with aggressive nodal PTCL who underwent treatment including ASCT as consolidation of front line therapy. Patients and Methods: Twenty-six patients Gallium scan positive with nodal PTCL entered into the study: 11 cases of PTCL-unspecified (42%), 8 ALCL (31%) and 7 AIL (27%). Patients received three courses of MegaCHOP and subsequently were evaluated by CT scan and Gallium scan. Those patients Gallium scan negative received another course of MegaCHOP and then the transplant. Those patients Gallium scan positive after 3 courses of MegaCHOP received 2 courses of the IFE regimen (Ifosfamide 3.3g/m2 days 1–3 and Etoposide 300 mg/m2 days 1–3) and if at least achieved a partial response received the transplant otherwise they are out of the study. Median age was 44 years, 96% of the patients presented Ann Arbor stage III or IV; 54% presented B symptoms; 31% bone marrow involvement and 72% of the patients presented 2–3 factors of the a-IPI. Results: Thirteen patients (50%) achieved a CR after 3 courses of MegaCHOP and 12 patients received IFE as salvage therapy. Twenty patients out of the 26 initial patients were able to proceed to the transplant. After the transplant 85% of patients achieved a CR. The 6 patients who did not received the transplant was due to progression of the disease in 4 cases, lethal toxicity in one case and refusal in another case. With a median follow up of 35 months for alive patients, the overall survival (OS) and progression-free survival (PFS) at 3 years were 73% and 53%, respectively. OS, PFS and disease-free survival for the 20 patients who underwent the ASCT consolidation was 84%, 53% and 63%, respectively. Conclusion: Early salvage therapy for patients not in CR after 3 courses of chemotherapy and ASCT consolidation for chemosensitive patients may improve the outcome of patients with nodal aggressive PTCL. Larger series and longer follow up are needed to confirm this promising approach.

Description: Background : 18Fluorodeoxyglucose-PET has been advocated as a powerful mean to evaluate response in aggressive non-Hodgkin’s lymphoma. Its relative merits compared to the widely accepted International Workshop Criteria (IWC) (Cheson, 1999. J Clin Oncol 17: 1244) have been investigated (Juweid, 2005 J Clin Oncol 23:4652), but need to be further confirmed. Materials and methods : We studied 103 patients with diffuse large B-cell lymphoma after 4 cycles of inductive CHOP or CHOP-like chemotherapy, with (n=51) or without Rituximab (n=52) using the IWC criteria and PET. The patients where also evaluated with an early PET after 2 courses, the results of which did not influence treatment decisions. PET response criteria have already been published (Haioun, Blood2005; 106). The interpretation of PET took into account the results of the early PET, in particular to define progressive disease. Results : The baseline characteristics of the patients where as follows : Median age 53y (19–78); age 〉60 : 25 (24%); LDH 〉 normal : 71 (69%); 〉 1 extranodal site : 53 (51%); poor performance status (〉=2) : 37 (36%); stage III–IV: 84 (81%). The international prognostic index (IPI) score was 0–2 in 40 pts (39%) and 3–5 in 63 (61%). The comparative response evaluation using IWC criteria or the combination of IWC criteria and PET is shown in the following table. Three years after completion of therapy, patients being in CR by PET at 4 cycles had an estimated event-free survival (EFS) of 83% if in CR/CRu by IWC criteria, and of 80% if in PR or SD by IWC. Patients not in CR by PET had an EFS of 51% when in CR/CRu by IWC criteria and of 8% when in PR, SD or PD by IWC criteria (p

Description: Introduction: Whether erythropoietin (Epo) has an impact on survival of patients (pts) with malignancies is debated. Since Dec 2003, the GELA has conducted a prospective randomized study to evaluate the safety and efficacy of Darbepoetin alfa (DA) in elderly pts with DLBCL treated by immunochemotherapy. In 2005, new recommendations about the use of Epo for patients with chemotherapy induced anemia have been published. Following these recommendations, the protocol was temporarily stopped and a first safety analysis was performed. Here we report the preliminary results on the first 130 enrolled patients. Patients and methods: pts between 66 and 80 years old with DLBCL and aaIPI ≥1 have been enrolled from Dec 2003 to Aug 2005. Pts were firstly randomised between two regimens combining Rituximab and the classical CHOP (Coiffier and al. NEJM 2002) delivered every 2 (R-CHOP14) or 3 weeks (R-CHOP21) for 8 cycles and were subsequently randomised between an investigational arm with DA (Arm 1) given in order to maintain hemoglobin (Hb) level between 13 and 15 g/dL and a conventional arm (Arm 2) with usual treatment of chemotherapy induced anemia, including transfusions and Epo according to usual practices. G-CSF was given according to physicians’decision. Results: 63 pts were randomised in Arm 1 and 67 in Arm 2. Median age is 71 y (66 – 80). Patients’characteristics were similar between arms and the percentage of patients with aaIPI 2–3 is 59%. Mean Hb level at randomisation is 12.2 g/dL (7.1 – 15.6). There rate of deaths during the treatment period is similar between arms (8% and 10%) and mainly related to treatment toxicity or lymphoma progression. The number of serious adverse events of any cause is lower in Arm 1 (96 events) compared to Arm 2 (153 events). Grade 3–4 Hb toxicity is higher in Arm 2 (39% versus 22%, p = NS). 18/63 (29%) patients received red blood cells transfusions in Arm 1 compared to 37/67 (55%) in Arm 2 (p=0.01). The number of patients with at least one episode of febrile neutropenia is lower in Arm 1 as compared to in Arm 2 (23% vs 36%, p = NS). There is no increase of cardiac and vascular events (respectively 9% and 9% in Arm 1 compared to 8% and 10% in Arm 2). The median level of Hb in Arm 1 during treatment is 12.05 g/dL and 10.65 g/dL in Arm 2. Sixteen percent of patients in Arm 1 have had at least one episode of Hb 〉 15 g/dL during treatment compared to 5% in Arm 2. The rate of thromboembolic events is similar in these patients (2/10) and in those who never have reached this Hb level (7/53). One year after completion of treatment, overall survival (OS) of the entire population is estimated at 74% and event free survival (EFS) at 67%. OS (78% in Arm 1 versus 70% in Arm 2 at 1 year) and EFS (73% in Arm 1 versus 64% in Arm 2 at 1 year) are similar between the two arms. Conclusions: these preliminary results provide encouraging results about the safety of a prophylactic use of Darbepoetin alfa and support the continuation of accrual to draw definite conclusions about safety and also efficacy.