ALBERT

Description: The addition of Rituximab (R) to front-line combination chemotherapy has substantially improved the long term perspectives of patients with advanced stage follicular lymphoma (FL) resulting in median progression free survival (PFS) times of more than 36 months. In this situation the potential role of myeloablative herapy with subsequent autologous stem cell transplantation (ASCT) in 1st remission needs to be critically reassessed. For this purpose two consecutive studies of the GLSG were analyzed both randomizing in 1st remission for Interferon alpha (IFN) maintenance therapy versus ASCT. In the GLSG trial ‘96 initial therapy comprised a randomized comparison of CHOP versus Mitoxantrone, Chlorambucil and Prednisone (MCP) (total patient number 312) while in GLSG study ‘00 CHOP was randomly compared to R-CHOP (total patient number 268). Hence, both studies had an identical treatment arm of CHOP followed by either IFN maintenance or ASCT. In both studies, the identical treatments revealed superimposable results with a 5 years PFS of 27% after CHOP and IFN maintenance and 66% after CHOP followed by ASCT. Taking these data as internal control R-CHOP followed by IFN maintenance achieved a 5 year PFS of 67% which is hence comparable to CHOP followed by ASCT. R-CHOP followed by ASCT, however, revealed a 5 year PFS of 79% with only one relapse after 24 months. Figure Figure Although the difference between R-CHOP followed by IFN maintenance or ASCT is currently not yet significant it strongly suggests a beneficial effect of ASCT in the era of R-CHOP front-line therapy particularly for intermediate of high risk patients with advanced stage FL.

Description: Introduction Mantle-cell lymphoma (MCL) is of poor prognosis, with a median survival of about 5 years. Besides the t(11;14) translocation, several secondary genetic abnormalities have been shown to correlate with prognosis. However, most studies have analysed patients with heterogeneous treatment, mostly with anthracyclin-based regimens. In 2004, the European MCL Network started the randomized MCL Younger trial comparing R-CHOP followed by high-dose radiochemotherapy and autologous stem cell transplantation (ASCT) versus alternating R-CHOP/R-DHAP followed by a high-dose cytarabine conditioning regimen and ASCT in previously untreated MCL stage II-IV patients up to the age of 65y. The R-CHOP/R-DHAP arm showed improved time to treatment failure (TTF) and, potentially, overall survival (OS) (Hermine et al., ASH 2010, ASH 2012). Our aim was to revisit the prognostic value of some gene copy number alterations (GCNA) in this randomized trial and to determine whether high-dose cytarabine could counteract some of those factors. Methods The inclusion criteria for this biological study were: confirmed histological diagnosis of MCL, the availability of diagnostic tumor DNA and complete clinical data. When no frozen biopsy was available, peripheral samples with more than 50% tumor cells were considered eligible for GCNA analysis. CDKN1B, CDK2, and MDM2 were analyzed using quantitative multiplex PCR of short fluorescent fragments (QMPSF) (Jardin et al., BJH 2009), 6q25-q26, CDK4, and the 13q14 locus were analyzed by multiplex ligation-dependent probe amplification (MLPA) (MRC-Holland CLL kit), and MYC, CDKN2A, ATM, RB1 and TP53 were assessed by both methods. The analyses of the prognostic value of GCNA was adjusted for clinical prognostic factors summarized in the quantitative MIPI score (age, performance status, LDH, and WBC). The rate of proliferating tumor cells (Ki-67 index) was centrally assessed by the reference pathologists of the European MCL Pathology Panel according to published guidelines (Klapper et al., J Hematopathol 2009). Outcome variables were TTF from treatment start to stable disease, progression, or death from any cause, and OS from trial registration to death from any cause. Results Of 135 patients fulfilling the inclusion criteria (median age 56 years), 49%, 26%, and 25% of patients were of low, intermediate, and high MIPI risk . The most frequent amplification involved MYC (18%), whereas the most frequent deletion involved the 13q14 locus (36%), including RB1 in 26%. As expected, CDKN2A and TP53 deletions were frequently found (25% and 22%, respectively). ATM alterations mostly consist of deletion (25%), but amplification was found in 3 of 129patients. The frequencies of GCNA did not differ according to the type of sample analyzed i.e. tumor biopsies (n=79) vs. high tumor load peripheral blood or bone marrow samples (n=56). The Ki-67 index was higher in patients with CDKN2A or RB1 deletion compared to patients without, but was not different between patients with or without TP53 deletion. Only TP53 gene status was associated with MCL cytology, with more frequent deletion in blastoid forms (4/8) than in classic MCL (11/81, 14%). In univariable analyses, deletions of CDKN2A, 13q14, RB1, CDKN1B, and TP53 were associated with shorter TTF and OS, whereas GCNA of 6q25-q26, MYC, ATM, CDK2, CDK4, and MDM2 were not prognostic. In multivariable analyses, adjusting for MIPI score, CDKN2A and TP53 deletions showed independent prognostic impact with hazard ratios of 2.4 (p=0.001) and 2.3 (p=0.004) for TTF and 2.3 (p=0.007) and 2.4 (p=0.007) for OS. This effect was observed in both treatment arms (Figure 1). In addition, there was an interacting effect of CDKN2A (p16) deletion and TP53 deletion on TTF (p=0.004). Conclusions The introduction of high-dose cytarabine in first-line treatment of younger MCL patients did not erase the adverse prognostic value of TP53 and CDKN2A deletions observed with previous regimens. Moreover, our study identified a small patient group of very bad prognosis which could benefit of more aggressive regimens or new targeted drugs combination. Figure 1: TTF (left) and OS (right) according to CDKN2A/TP53 deletion status in patients of the R-CHOP/R-DHAP study arm; nom=not deleted, del=deleted Figure 1:. TTF (left) and OS (right) according to CDKN2A/TP53 deletion status in patients of the R-CHOP/R-DHAP study arm; nom=not deleted, del=deleted Figure 2 Figure 2. Disclosures Feugier: Roche: Honoraria. Haioun:Roche, Celgene, Takeda, Pfizer, Janssen,: Honoraria.

Description: Management of patients with refractory and relapsed AML needs optimization. We performed a prospective study in these patients aiming at 1) the definition of the anti-leukemic efficacy of the S-HAI regimen; and 2) the evaluation of the prognostic impact of cytogenetic aberrations at relapse in the context of other prognostic parameters. Treatment consisted of AraC 1 g/sqm q 12 h days 1, 2, 8, and 9 and idarubicin 10 mg/sqm days 3, 4, 10, and 11. AraC was given at 3 g/sqm in patients under age 60 with refractory AML or relapse after CR1

Description: Abstract 880 On behalf of the German Low-Grade Lymphoma Study Group (GLSG) and the European MCL Network Background: In younger patients with mantle cell lymphoma (MCL), autologous stem cell transplantation (ASCT) significantly prolonged response duration with a trend towards improved overall survival in a randomized trial of the European MCL Network (Dreyling et al., ASH 2008). A recently updated clinical trial of the German Low-Grade Lymphoma Study Group (GLSG) also reported a significantly prolonged response duration by the addition of Rituximab to first-line CHOP (Hoster et al., ASH 2008). By pooled analysis of these trials we investigated whether Rituximab and ASCT independently prolong response duration. Methods: The analysis included all advanced stage MCL patients of the trials “CHOP vs. MCP” (Nickenig et al., Cancer 2006), “CHOP vs. R-CHOP” (Lenz et al., JCO 2005) and European MCL trial 1 (Dreyling et al., Blood 2005) with complete or partial remission to either CHOP or R-CHOP first-line induction and randomization between ASCT and Interferon-α maintenance. Response duration was defined as time from the end of successful induction chemotherapy to relapse or death from any cause, overall survival from the end of successful induction chemotherapy to death from any cause. Stratified Kaplan-Meier curves for response duration and overall survival were calculated for the four treatment groups (CHOP without ASCT, CHOP with ASCT, R-CHOP without ASCT and R-CHOP with ASCT). By multiple Cox regression we tested whether the impact of Rituximab (R) and ASCT was independent and additive. Results: One-hundred and eighty patients with MCL were evaluable, 80 treated with R-CHOP, 78 with ASCT (CHOP without ASCT: 56, CHOP with ASCT: 46, R-CHOP without ASCT: 44 and R-CHOP with ASCT: 34). Median age was 55 years (range 34-65), the MIPI classified 71% as low risk, 22% as intermediate risk, and 6% as high risk, and baseline characteristics were comparable between treatment groups. With a median follow-up of 63 months, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT. In multiple Cox regression including R and ASCT, the hazard ratios of R (0.60, 95% CI 0.42-0.86, p = 0.0056) and ASCT (0.50, 95% CI 0.35-0.70, p = 0.0001) were independently significant. There was no interaction between R and ASCT (p=0.43). Median overall survival was 54 months after CHOP without ASCT, 66 months after R-CHOP without ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP with ASCT. The hazard ratios for OS were 0.70 (95% CI 0.44-1.12, p = 0.14) for R and 0.63 (95% CI 0.41-0.97, p = 0.0379) for ASCT. Conclusions: Our results indicate an additive effect of ASCT and Rituximab in combination with CHOP on response duration in advanced stage MCL patients and support strategies of several study groups to combine Rituximab-containing induction therapies with ASCT in younger MCL patients. However, even after combined treatment approaches, delayed relapses have been observed, supporting the use of maintenance therapy and the introduction of molecular targeted therapeutical strategies. Disclosures: Hoster: Roche: Travel Support. Off Label Use: Rituximab in Mantle Cell Lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees. Dührsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support. Dreyling:Roche: Honoraria, Research Funding.

Description: Background: The addition of rituximab to chemotherapy (R-CHOP) has been shown to improve response rates in mantle cell lymphoma (MCL), but prolongation of response duration or overall survival was not observed (Lenz et al., JCO 2005). In a similar randomized comparison of 90 patients, again the addition of rituximab to MCP showed a tendency towards higher CR rates, but no improvement of overall response rate, progression free, or overall survival (Herold et al., ICML-10, 2008). Methods: We present an update of a previously published trial randomly comparing efficacy and safety of R-CHOP to CHOP induction in previously untreated patients with advanced stage MCL. Results: Of the 123 evaluable patients, 63 patients were randomized to R-CHOP. Median age was 62 years, and risk profiles of the two treatment arms were comparable. Overall response rates were 92% vs. 75% for R-CHOP vs. CHOP (p = 0.0139) and complete remission rates 33% vs. 8% (p = 0.0008). After a median follow-up of 65 months, median time to treatment failure was prolonged from 14 months for CHOP to 28 months for R-CHOP (p = 0.0003). Similarly, median response duration was prolonged from 18 (CHOP) to 29 months (R-CHOP, p = 0.0052). So far, no significant improvement of overall survival has been observed with median not reached vs. 59 months and 5-years OS rates of 59% and 46% (p = 0.27) after R-CHOP and CHOP, respectively. Toxicity was not significantly higher for R-CHOP treated patients. Conclusions: After longer follow-up, superior remission rates, time to treatment failure, and response duration of combined immuno-chemotherapy were confirmed. However, in contrast to other lymphoma entities, improvement of overall survival has not yet been proven in MCL patients. Therefore new therapeutic options are urgently warranted to further improve the long term outcome in this otherwise dismal disease.

Description: Two randomized intergroup trials of the European MCL Network investigating the impact of different combined immunochemotherapy protocols for patients with stage II-IV mantle cell lymphoma (MCL) followed by autologous stem cell transplantation for patients 65 yrs are currently performed. Patients and methods: 182 German patients with evidence for peripheral blood (PB) involvement as demonstrated by consensus IGH-PCR at diagnosis were analyzed for quantitative PB involvement and molecular response (MR) by Real Time Quantitative (RQ) IGH-PCR. The results were evaluated according to ESG criteria (van der Velden, Leukemia 2007) and were compared to clinical parameters at diagnosis and outcome. Results: Patients had a median age of 61 years, an elevated LDH in 37%, B-symptoms in 42% and extranodal involvement in 36%. According to the MIPI prognostic index 20% had an adverse, 37% an intermediate and 43% a good prognosis. Median level of circulating MCL cells in PB at initial diagnosis were 6×10−2 (range 2×10-4 to 8×10-1) and correlated significantly with clinical parameters as advanced stage (p=0.0016), elevated LDH (p= 0.0026), bone marrow infiltration (p= 0.0001) and MIPI prognostic index (p

Description: Dose density during early induction has been demonstrated to be one of the prime determinants for antileukemic efficacy. The German AML-CG therefore pilots a dose dense induction regimen S-HAM (sequential HD-AraC [3g/m2/12h d1,2,8,9] and Mitoxantrone 10mg/m2 [d3,4,10,11] followed by pegfilgrastim) in which two induction cycles are applied over 11 – 12 days as compared to conventional double induction, in which two cycles are applied over 25 – 29 days - thereby increasing dose density ca. two-fold in the critical first weeks of treatment. In the past 2,5 years 168 patients with de-novo AML (excluding APL) have been recruited into the trial with a median age of 53 years (range 18 – 78). Of 136 patients evaluable for response the following results were achieved: CR 62%, CRi 22%, PL 7%, ED 9% - resulting in an overall response rate (ORR) of 84%. The early death rate (ED) of 9% and the toxicity profile compared favourably with a historical control group of the AML-CG 1999 study (de-novo AML, 〈 60 years, HAM-HAM double induction) which demonstrated an ED rate of 14% (ORR 68%, persistent leukemia (PL) 18%). The high antileukemic efficacy of S-HAM was also demonstrated by the fact that 89% of patients had a blast count of 〈 10% one week after therapy as compared to less than 48% of patients of the HAM-HAM double induction group. Whereas even for patients with unfavourable cytogenetics (including complex aberrations) a median overall survival of 13,5 months was reached (23% at 2 years), for patients with favourable karyotypes overall survival at 2 years was 81%and for patients with intermediate karyotypes 74% after S-HAM treatment. Importantly the compression of the two induction cycles into the first 11 – 12 days of treatment seems actually beneficial for normal hematopoesis as demonstrated by a significantly shortened duration of critical neutropenia of 30 days as compared to 45 days after conventionally timed double induction. This shortening of critical neutropenia by more than 2 weeks was highly relevant for the duration of hospital stay and hospital costs. In conclusion S-HAM with pegfilgrastim support is a highly effective regimen in primary de-novo AML with a very favourable safety profile and significantly shortened duration of neutropenia. This regimen will therefore constitute the (dose-dense) experimental arm for a randomized comparison with standard double induction in the next generation of the German AML-CG studies.

Description: Two prospectively randomized intergroup trials of the European MCL Network investigating the impact of different combined immuno-chemotherapy protocols for patients with stage II–IV mantle cell lymphoma (MCL) 〉〈 65 yrs followed by autologous stem cell transplantation (PBSCT) for patients 65 yrs are currently performed. Patients and methods: 180 German patients with diagnostic peripheral blood (PB) involvement detectable by consensus IGH PCR were analysed for t(11;14) translocation by FISH and 4-colour Flow Cytometry (FC) at diagnosis as well as molecular response (MR) by quantitative IGH-RQ-PCR after induction. The results were compared to clinical parameters at diagnosis and PFS. Results: Patients had a median age of 61 years, an elevated LDH in 37%, B-symptoms in 41% and extranodal involvement in 37%. According to the MIPI risk factor score 26% had an adverse, 34% an intermediate and 40% a good prognosis. PB involvement by MCL was demonstrated in 67% (74/111) by t(11;14) FISH and in 97% (152/156) by FC. Detection of MCL cells by FC in PB did not correlate with clinical parameters as stage, LDH, extranodal involvement or bone marrow infiltration. However, median % of MCL cells measured by FC differed significantly with clinical stage (p

Description: Background: The follicular lymphoma international prognostic index (FLIPI) has become a widely accepted tool for stratification of patients with follicular lymphoma according to their risk profiles (Solal-Celigny et al., Blood 2004). Its prognostic relevance has been proven in patients treated with standard chemotherapy as well as with immunochemotherapy (Buske et al., Blood 2006). Recently, a new prognostic index, the F2 index, has been proposed as possible alternative to the FLIPI (Federico et al., ICML-10, 2008). Methods: We used the collective of patients with advanced stage follicular lymphoma treated first-line within the recent trials of the GLSG to explore the prognostic relevance of the F2 prognostic index in comparison to the FLIPI. Outcome parameters were time to treatment failure (TTF) and overall survival (OS). Statistical methods included Kaplan-Meier plots to validate the prognostic indices and multiple Cox regression to explore the relevance of the prognostic factors. Results: Of the 1562 patients, the F2 index could only be assessed in 758 patients (50%), of those 355 had had a treatment failure and 124 had died. The low number of evaluable patients was mainly due to the use of β2-microglobulin as prognostic factor, which was missing in 45% of the patients. The FLIPI could be assessed in 1424 patients (93%), of those 697 had had a treatment failure and 255 had died. The F2 index classified 7% of the patients as low risk, 58% as intermediate risk, and 35% as high risk, in comparison to 14%, 41% and 45% according to the FLIPI. Both F2 and FLIPI separated three risk groups with regard to TTF (p 6 cm and elevated β2-microglobulin showed no prognostic relevance for TTF. Furthermore, after backward elimination, all the FLIPI risk factors (age 〉 60 years, LDH 〉 ULN, hemoglobin 〉 120 g/l and more than 4 involved nodal regions) remained independently significant together with bone marrow involvement, whereas bulk 〉 6cm and b2-microglobulin were of no relevance. With regard to OS, the FLIPI separated three groups, whereas according to the F2 index low and intermediate risk groups were overlapping. Conclusion: The F2 index did not show superior relevance to the FLIPI in our evaluation and should not replace the FLIPI as prognostic index in follicular lymphoma in general. However, a simplification of the FLIPI with regard to the assessment of the number of involved nodal areas and the incorporation of the performance status would be challenging.

Description: Background: Conventional chemotherapy achieves only short term remission despite high initial response rates of 70%–80%. In the current study generation, the European MCL Network investigates the impact of various combined immuno-chemotherapy regimens. Additionally, in elderly patients the role of rituximab maintenance is being evaluated, whereas in younger patients dose-intensified regimens with implementation of high dose cytarabine are investigated based on the excellent results of the HyperCVAD regimen. Methods: In MCL elderly, patients are initially randomized between 8 cycles of R-CHOP or 6 cycles of R-FC (experimental arm). Patients who achieve either an PR or CR, receive subsequently either interferon maintenance (standard arm) or a single rituximab dose every 2 months. In MCL younger, the standard arm (R-CHOP induction followed by myeloablative consolidation: 12 Gray TBI, 2x 60mg/kg cyclophosphamide) is compared to the implementation of high dose cytarabine into induction (R-CHOP/R-DHAP) and consolidation (10 Gray TBI, 4x1,5 g/m2 Ara-C, 140mg/m2 melphalan). Results: In MCL elderly, 222 of 263 patients were evaluable based on the annual interim analysis. Median age was 70 years with 66% of patients displaying an intermediate high/high risk IPI. Induction was well tolerated with mainly hematological toxicity (grade III/IV in R-CHOP/R-FC): Leukocytopenia 62/72%, thrombocytopenia 13%/40%, but only rare febrile neutropenia (23%/7%) or infections (19%/23%). Despite the poor risk profile, combined immuno-chemotherapy (total group) achieved a remarkable 84% response rate (51% CR/CRu). Although the impact of maintenance is not yet evaluable, both progression-free and overall survival were encouraging with 77% and 86% at 12 months, respectively. In MCL younger, 247 of 271 patients were evaluable. Again, toxicity (grade III/IV in R-CHOP/alternating R-DHAP) was mainly hematological: leukocytopenia 58/77%, thrombocytopenia 14%/74%, but only rare febrile neutropenia (11%/22%) or infections (5%/7%). Combined immuno-chemotherapy achieved a 93% response rate (60% CR/CRu) before subsequent high dose consolidation. Again, both progression-free and overall survival are remarkable with both 90% at 12 months, respectively. Discussion: Combined immuno-chemotherapy results in high response rates in two prospective international trials. Further recruitment and follow-up will determine the role of rituximab maintenance and high dose cytarabine in this distinct subtype of malignant lymphoma.