ALBERT

Description: Introduction: Mantle cell lymphoma (MCL) is considered to be an incurable disease with a poor prognosis, but the prognosis can be significantly different among the patients. The new prognostic index MIPI (MCL International Prognostic Index) has been proposed recently (Hoster ASH 2006, Blood 2008). Three prognostic groups with different survival (low-risk, intermediate-risk and high-risk) can been identified, based on four variables: WBC count, ECOG performance status, LDH and age. Aim: To validate MIPI on an independent unselected cohort of newly diagnosed patients with MCL in the Czech Lymphoma Study Group (CLSG) registry. Methods and patients: Out of 293 patients with MCL diagnosed and registered in the period 1999–2007, 149 patients had central pathology review and confirmation of MCL diagnosis and were eligible for the analysis. The age median was 65 year (24–86), 63% were male (M:F ratio 1,7:1). Most of patients were diagnosed in advanced Ann Arbor stage IV (82%), limited stages I+II formed only 10,5%. The bone marrow was involved in 75% of cases. B-symptoms were present in 45% patients, LDH level elevated in 51%, poor performance status (ECOG 2–4) in 21% and the median leukocyte count was 7,9 ×109/L. A chemotherapy was used as a first line treatment in 144 patients, the combination with rituximab (R) in 106 ones (73%). The most used regimens were hyperCVAD/MTX-HDaraC (30x), R-CHOP (30x), CHOP (19x), R-FC (13x), then R-maxiCHOP/HDaraC (12x), R-CHOP/HDaraC (9x), COP (8x) and others. A consolidation of the first remission with high-dose chemotherapy and autologous stem cell transplantation was used in 12 patients, and an allogeneic transplantation in 2 patients. A first-line radiotherapy was used in 14 patients. Median follow-up is 31 months. Results: Median overall survival (OS) in the whole group of confirmed MCL patients was 58 months, median progression-free survival (PFS) was 24 months. The MIPI index can be calculated for 148 patients, 28% of them belong to low-risk (LR), 35% to intermediate-risk (IR) and 37% to high risk (HR) group. All clinical stages were included. Our comparison of survival curves according to MIPI risk groups confirms a different prognosis – the median OS in the LR group was not reached, in the IR group is the median OS 58 months, and in the HR group 25 months (p 〈 0,0001). The 3-year OS probability for LR, IR and HR group is 82%, 62% and 31%, resp. Similarly, median PFS in the LR, IR and HR group is 45, 24 and 13 months, resp. (p 〈 0,0001). The analysis of rituximab-treated subgroup was performed as well, with a significant difference between the three groups regarding to OS and PFS. The 3y OS probability for LR, IR and HR group is 82%, 63% and 37%, the median OS for LR and IR was not reached, for HR is 31 months (p

Description: [§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p

Description: Background: MCL is a distinct lymphoma entity with improved outcome achieved by the introduction of rituximab, high dose Ara-C and autologous stem cell transplantation (ASCT) into the first line therapy. The outcome of the relapsed patients (pts) remain however poor and there is little data on the outcome after subsequent relapses and there is no information on secondary MIPI prognostic value. Aim: To analyze the outcome of the MCL patients after first line treatment failure and to evaluate the prognostic role of the sec MIPI which is MIPI calculated at the time of relapse/progression. Methods: This analysis is a part of the Lymphoma project in which consecutive lymphoma patients are registered since the year 1999. Altogether 519 newly diagnosed MCL patients were registered in 5 university centers and 9 regional departments between 1999 and 2011. Patients who were treated with rituximab as part of the first line treatment (n=388) were included into the analysis. The diagnoses were confirmed according to WHO classification in the reference pathology centers. The median follow up is 4.5 years. Results: The whole cohort consists of 261 males and 127 females (2.1:1) with median age 65 y (28-87), the majority of pts had advanced disease (CS IV in 81.6% pts), PS ECOG ≥ 2 in 23.6% pts, elevated LDH in 52.5% of pts. The MIPI risk profile was as follows: low risk 21.7%, intermediate risk 27.2% and high risk in 51.1%. All pts received rituximab as part of the induction, 48.7% pts received CHOP, 5.7% alternation of CHOP and HD Ara-C, 26.2% intensive induction with HD Ara-C, 10.3% CVP, 6.4% FC. High dose therapy with ASCT was performed in 23.9% of pts. The ORR was 89.0% with 63.8 CR/CRu, 6.3% had stable disease and 4.9% were primary progressive. The PFS and OS were 2.9 y and 5.5 y with significant impact of MIPI risk (p

Description: Abstract 2882 Absolute lymphocyte count (ALC) at time of diagnosis has been documented as an independent predictor of survival in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The optimal cut-off values of ALC are still a matter of debate. An extensive analysis of the prognostic impact of ALC in the elderly population treated with rituximab has not yet been carried out. Thus, we assessed the prognostic significance of different ALCs in unselected, newly diagnosed elderly patients with DLBCL in the population of the Central European region (the Czech Lymphoma Project registry). We analyzed data of 651 patients with confirmed DLBCL older than 59 years. Those with CNS involvement were excluded. The median age at diagnosis was 69 years (range, 60–97); the Ann Arbor stages were as follows: I (16.5%), II (26.1%), III (15.9%), and IV (41.5%). The IPI scores were: low (L) 19.8%, low-intermediate (LI) 26.6%, intermediate-high (IH) 24.3%, and high (H) 29.3%. We analyzed the prognostic value of lymphopenia with 3 different cut-off values. Values of ALC 〈 1.0 × 109/L and ALC 〈 0.84 × 109/L were chosen according to the previously published data, the third value was the median ALC at diagnosis (ALC 1.35 × 109/L). ALC 〈 1.0 × 109/L was observed in 201 (31%) and ALC 〈 0.84 × 109/L in 159 (24%) patients. ALCs below predefined levels were associated with higher (IH, H) IPI scores: ALC 〈 0.84 × 109/L (78% vs 46%, p 〈 0.001), ALC 〈 1.0 × 109/L (77% vs 43%, p 〈 0.001), and ALC 〈 1.35 × 109/L (68% vs 38%, p 〈 0.001); advanced disease (stages III/IV): ALC 〈 0.84 × 109/L (72% vs 53%, p 〈 0.001), ALC 〈 1.0 × 109/L (72% vs 51%, p 〈 0.001), and ALC 〈 1.35 × 109/L (66% vs 48%, p 〈 0.001); and low performance status (ECOG ≥ 2): ALC 〈 0.84 × 109/L (52% vs 27%, p 〈 0.001), ALC 〈 1.0 × 109/L (50% vs 25%, p 〈 0.001), and ALC 〈 1.35 × 109/L (43% vs 22%, p 〈 0.001). In 85% of patients, treatment was initiated with an anthracycline-containing regimen (CHOP), i.e. only 15% of patients recieved a non-anthracycline-based regimen (COP). The median number of chemotherapy cycles was 6. Chemotherapy was combined with rituximab in all patients (a median of 6 doses). Generally, treatment response was assessed in 544 (83.6%) patients. Complete remission (CR) or unconfirmed CR was achieved in 79.8% and partial remission in 12.5% of patients, with 7.7% of patients being classified as having stable disease or disease progression. CR rates were significantly higher in patients with higher lymphocyte counts: ALC 〉 0.84 × 109/L (82% vs 71%, p = 0.006), ALC 〉1.0 × 109/L (83.1% vs 71.7%, p = 0.008), and ALC 〉 1.35 × 109/L (85% vs 75%, p = 0.027). The overall survival (OS) and event-free survival (EFS) rates were superior in all subgroups of patients with higher ALC levels. The 3-year OS rates stratified by lymphocyte count: ALC 〉 0.84 × 109/L (67% vs 51%, p = 0.0002), ALC 〉 1.0 × 109/L (67% vs 52%, p = 0.0017), and ALC 〉 1.35 × 109/L (71% vs 55%, p = 0.0001). The 3-year EFS rates stratified by lymphocyte count: ALC 〉 0.84 × 109/L (61% vs 44%, p = 0.0002), ALC 〉 1.0 × 109/L (62% vs 44%, p = 0.0002), and ALC 〉 1.35 × 109/L (66% vs 47%, p 〈 0.0001). Only ALC 〈 1.35 × 109/L was found to be an independent negative prognostic factor for the OS (RR = 1.53, p = 0.006) and EFS (RR = 1.43, p = 0.013) in a multivariate analysis when compared with the LDH level, clinical stage, performance status and age (above median). In summary, the data support the hypothesis that host innate immunity is critical in tumor growth control and is a limiting factor for the efficacy of immunochemotherapy in elderly patients with DLBCL. The optimal cut-off levels of ALC may be different in various populations. This fact should be taken into account when designing new ALC-based prognostic schemes. Disclosures: Prochazka: ROCHE: Honoraria. Pytlik:ROCHE: Honoraria.

Description: Abstract 993 Purpose: Cell of origin (COO) has a major prognostic impact in DLBCL. However this impact has never been analysed in the context of relapsed/refractory DLBCL. The purpose of this study was to evaluate the prognostic value of COO immunohistochemical markers and BCL2, BCL6 and c-MYC translocations in a well-defined cohort of patients included in the CORAL trial1. Methods: Enrolled patients had CD20+ DLBCL in first relapse or refractory after upfront therapy. Treatment was randomized to either R-ICE (rituximab, ifosfamide, etoposide, carboplatin) or R-DHAP (rituximab, dexamethasone, aracytine, cisplatin). Responding patients had high-dose chemotherapy and ASCT. Paraffin-embedded tumor samples of 249 patients were analysed by immunochemistry for CD10/MME, BCL6, MUM1/IRF4, FOXP1, BCL2 expression and for BCL2, BCL6 and c-MYC breakpoints by FISH, and were categorized according to different COO algorythms2-5. Primary biopsy at diagnosis and relapse biopsy were available for 189 and 147 patients respectively, including 87 matched pairs. Results: With a median follow-up at 27 months, there was no significant difference between R-ICE and R-DHAP for 2-year progression-free survival (PFS) (56.7%+/−5% vs 60%+/−5%, p=0.24) or overall survival (OS) (46%+/−5% vs 60%+/−5%, p=0.24). We confirmed that early relapse, prior rituximab exposure and secondary aaIPI had adverse prognostic value. In univariate analysis, absence of bcl6 expression, non-GC phenotype2, ABC phenotype4, at diagnosis were associated with an unfavourable PFS (p=0.038, p=0.0044, p=0.044, respectively), whereas only non-GC phenotype2 was associated to a worse OS (p=0.027). At relapse, expression of Foxp1 and bcl2, c-MYC breakpoint, ABC phenotype4, immunoFISH index5 was associated with an unfavourable PFS (p=0.02, p=0.027, p=0.03, p=0.032, p=0.02, respectively), and c-MYC breakpoint was associated with a worse OS (p=0.01). Tumor immunophenotype and FISH analysis at diagnosis and at relapse were statistically concordant in matched pairs (Wilcoxon's test between 0.42 and 1). In the whole group, only c-MYC breakpoint present in 13% of the patients was correlated with worse PFS (p= 0.02) and OS (p =0.04). Statistical interaction were found between GC/non-GC classification2 and the treatment R-ICE vs R-DHAP. Patients with GC B-cell like DLBCL subtype treated with R-DHAP have a better 2-year PFS (64% +/−7%) than those with GC B-cell like DLBCL treated with R-ICE (42% +/−7%), and the patients with ABC B-cell like DLBCL treated either with R-DHAP (35%+/−7%) or R-ICE (45%+/−7%) (p= 0.04). In multivariate analysis, only GC/non-GC phenotype2 interaction with the treatment, FOXP1 expression, prior rituximab exposure, secondary aaIIPI, time to relapse were statistically significant. Preliminary results of gene expression profiling seem to confirm these data and are currently under validation. Conclusion: COO remains a major factor in relapsed patients with a better response to R-DHAP salvage chemotherapy in GC-B DLBCL, underlying the importance of molecular DLBCL subtyping. Treatment of ABC subtype is still unsatisfactory. Disclosures: Schmitz: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding.

Description: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich B-cell lymphoma (T/HRBCL) are distinct tumors and are treated differently. They are linked by a morphologic and probably a biologic continuum, which renders the differential diagnosis difficult. To develop criteria to distinguish the entities along the morphologic continuum, we correlated the lymph node architecture and immunophenotype of both tumor cells and reactive components of 235 neoplasms in the spectrum of NLPHL and T/HRBCL with clinical data. Two hundred and eighteen cases fitted the World Health Organization (WHO) criteria of NLPHL (139) or T/HRBCL (79). While tumor cells in both entities were immunophenotypically similar, background composition differed: in NLPHL small B cells and CD3+CD4+CD57+ T cells were common, whereas in T/HRBCL, CD8+ cytotoxic T cells and histiocytes dominated. Follicular dendritic cells (FDCs) formed expanded meshworks in NLPHL, whereas they were absent in T/HRBCL. Seventeen cases represented a gray zone: within FDC meshworks, neoplastic B cells resided in a background depleted of small B cells but rich in T cells and histiocytes. Tumor cells either were loosely scattered or formed clusters, thus resembling areas of either T/HRBCL or inflammatory diffuse large BCL (DLBCL) within the nodules. Patients with these NLPHLs with T-cell/histiocyte-rich nodules presented at a high stage and with B symptoms, as in T/HRBCL, but had an excellent survival, as in NLPHL. This morphologic pattern suggests a biologic continuum between NLPHL and T/HRBCL. (Blood. 2003;102:3753-3758)