ALBERT

Description: Abstract 101 Background: Treatment of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate (HD-MTX) containing chemotherapy (CT) followed by brain radiotherapy (RT). Initial CT allowed 30% to 63% of complete response (CR) in recent large series. After CT, consolidation RT can increase the CR rate up to 80%. Despite this high rate of response after initial treatment, the outcome of patients remained poor. The impact of the quality of response on outcome is not well known as well as the outcome of PR patients who converted to CR after RT. We assessed these questions in patients with newly diagnosed PCNSL treated with HD-MTX-containing CT followed by RT in the prospective LNHCP93 GELA study. Methods: 99 patients were treated in this prospective phase II study between 1995 and 2002. Patients younger than 61 years received C5R protocol (Blay et al. Blood 1995), Patients aged 61-70 years received reduced doses of C5R protocol and patients older than 70 years received a specific schedule with MTX, vepeside and cyclophosphamide. After CT, brain RT was planned: 20 Gy whole brain and a 36 Gy boost to the tumor bed. Responses after CT and after RT were evaluated by MacDonald criteria. Evaluation of response was made at time of the beginning of RT, 21-35 days after the last course of CT, and one month after the end of RT. Results: Median age of the 99 PCNSL patients was 63 years (range, 20-82), 51% were male, 51% had performance status 〉1, and 58% had involvement of deep structures of brain. Forty-five patients were younger than 61 years, 36 were aged 61-70 years and 18 older than 70 years. After a median follow-up 83 months, median overall survival (OS) and progression-free survival (PFS) were 33 and 20 months, respectively. Seventeen patients (17%) died of acute toxicity during CT; 3 patients (3%) did not receive RT; 8 patients (8%) progressed or had stable disease after CT and 3 patients (3%) had no available data. Thus, 68 patients were assessable for this exploratory study with thirty-six patients (36%) in PR and 32 patients (32%) in CR after CT. Sixteen of PR patients converted to CR after RT (44% of PR patients after CT). Median OS of patients in CR and PR after CT was 80 and 34 months with a 5-year OS probability of 65% and 29%, respectively (p=0.02). Median PFS of patients in CR and PR after CT was 60 and 21 months with a 5-year PFS probability of 56% and 17%, respectively (p=0.03). In univariate and multivariate analysis, age and response were the two prognostic factors for OS but not performance status, number of tumors at diagnosis, site of tumor (involvement of deep structures). Only response to CT was predictive of PFS in multivariate analysis but not age, performance status, number of tumors, site of tumor at diagnosis. 5-year OS was 65% for CR patients before RT compared to 31% and 28% for PR patients who converted to CR after RT and for patients not in CR after RT, respectively (p=0.06). The 5-year PFS probability was 56% for CR patients before RT compared to 13% and 20% for patients who converted to CR after RT and those not in CR after RT, respectively (p=0.09). Conclusion: Despite the inherent bias of response analysis as a prognostic factor, this analysis of a prospective study of PCNSL patients showed that only patients achieving CR after CT may experience long term survival. This study also showed that PR patients who converted to CR after RT had a poor outcome, similar to patients that did not reach a CR after chemoradiotherapy. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: There is strong evidence that the cytopenia(s) in MDS might be caused by excessive, cytokine induced, intramedullary apoptotic death of progenitor hematopoietic cells. TNFα is a key cytokine that may trigger and sustain the excessive apoptosis processes in early disease. Infliximab is a chimeric human-murine monoclonal antibody with high affinity for human TNFα. Infliximab effectively prevents TNFα specific signaling in immune mediated inflammatory diseases. The therapeutic potential of suppressing TNFα mediated apoptosis in MDS was investigated. Patients and methods: The EORTC LG conducted an open label 2-arm randomized, Simon 2-stage design, phase II study, with the primary objective of assessing the activity of two different dose levels of Infliximab, as single agent, in patients (pts) with low-/intermediate-risk MDS according to IPSS. Activity was assessed by response rate, using the International Working Group criteria: Complete Response (CR) + Partial Response (PR) + Hematological Improvement (HI). Toxicity was assessed as a secondary objective. Results: Between February 2004 and March 2006, 37 eligible/evaluable pts (targeted sample size for the analysis of first stage) were randomly assigned to receive Infliximab, 3 mg/kg (18 pts) vs 5 mg/kg (19 pts), intravenously on days 1 and 15, thereafter every 4 weeks, for a total of 8 courses. Baseline characteristics by treatment arm (3 mg/kg vs 5 mg/kg) were: median age (65 vs 69 years); IPSS risk score: low (2 vs 6 pts), Intermediate-1 (14 vs 10 pts), Intermediate-2 (2 vs 3 pts); cytogenetic risk group: good (9 vs 12 pts), intermediate (5 vs 4 pts), unknown (4 vs 3 pts). Treatment applicability (3 mg/kg vs 5 mg/kg): 20 pts (10 vs 10) completed the 8 cycles of therapy, and 17 pts (8 vs 9) stopped earlier due to: progressive disease (2 vs 4), excessive toxicity (3 vs 0), patient’s refusal (2 vs 2), death due to an unrelated cause (1 vs 1), other reasons (0 vs 2). Activity (3 mg/kg vs 5 mg/kg): 3 pts responded to treatment in the 3 mg/kg arm: 1 CR, 1 PR and 1 HI (neutrophils), while no patient responded in the 5 mg/kg arm. A total of 21 pts (7 vs 14) had stable disease, 11 pts (7 vs 4) had documented disease progression and 2 pts were inevaluable for response (1 vs 1). After a median follow-up of 1.5 years, 8 pts (6 vs 2) died. Adverse events: 3 out of 18 patients died due to infections in the 3 mg/kg arm vs 0/19 in the 5 mg/kg arm. Two of the lethal infections were considered likely related to protocol treatment: one patient developed a fatal mucormycosis during treatment and one patient developed a fatal sepsis shortly after the eighth Infliximab infusion and thereafter also had documented progression to AML. There were few other AE/toxicities. Conclusion: Infliximab in the 3 mg/kg dose/schedule showed some activity in this study. Infliximab has limited activity as single agent but may warrant further investigation in combination with other active agents. Patients must be monitored closely for occurrence of severe infections.

Description: Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.

Description: Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735.

Description: Abstract 2813 Background: Myelodysplastic syndroms (MDS) are an heterogenous diseases. In order to define prognosis of differents subgroups, several scoring are elaborated. The most used was IPSS score including pourcentage of blasts, number of cytopenia and cytogenetics. Recently, IPSS was revised. IPSS-R includes new cytogenetics subgroups, anemia, thrombocytopenia, neutropenia and pourcentage of blasts. These score were defined in untreated MDS and Acute Myeloid Leukemia (AML) with less 30% of blasts patients. IPSS-R score was evaluated in MDS untreated population included AML with 20–29% of blasts. Only 16% of patients were higher-risk IPSS MDS in this study (Greenberg et al., Blood 2012). Azacitidine (AZA) prolongs survival when used as first line treatment of higher-risk MDS and AML with 20–29% bone marrow (BM) blasts (Fenaux et al., Lancet Oncology 2009). The aim of this study is to evaluate efficacy of AZA in higher IPSS-R MDS and AML with 20–99% BM blasts. Methods: We analyzed retrospectively MDS and AML patients treated by AZA in 6 centers. Patients having received ≥ 1 cycle of AZA and who had BM evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered évaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. Results: The study population included 149 patients: F/M: 65/84; median age 70 (range 35–88). Median number of cycle of AZA treatment was 6 (range 1–42). Diagnosis at AZA was (RAEB-1 n=1, RAEB-2 n=69, AML n=79). Median overall survival (OS) was 11 months. For MDS population excluding AML with 20–29% of blasts, IPSS score was intermediate-1 in 16 patients, intermediate-2 in 29 patients and high in 25 patients. In using IPSS-R score, we observed IPSS-R good in 2 patients, IPSS-R intermediate in 20 patients, IPSS-R poor in 29 patients and IPSS-R very poor in 19 patients. If we applied IPSS-R score in WHO-AML population, we observed IPSS-R intermediate in 11 patients, IPSS-R poor in 39 patients and IPSS-R very poor in 29 patients. In all cohort population, we observed a significant difference in median OS between « intermediate + poor » group versus very poor group (12 months vs 9 months respectively, p=0.01). In MDS sub group analysis excluding AML with 20–30% of blasts, we observed no significant difference in median OS between these 2 groups (13 months vs 9 mois respectively, p=0.39). Nevertheless, we still observed a significant difference in median OS between these 2 groups in AML population (12 months vs 6 months respectively, p=0.02). Conclusion: Our results suggest that AZA cancels prognostic impact of IPSS-R score in MDS patients treated by AZA. IPSS-R score could be applied in AML population and keep his prognostic impact in AML patients treated by AZA. IPSS-R score should be evaluated in larger cohort of MDS and AML patients treated by AZA in order to confirm these results. Disclosures: No relevant conflicts of interest to declare.

Description: Management of Acute Myeloid Leukemia (AML) in the elderly is particularly difficult as life expectancy is highly variable and the benefit-risk ratio of treatment depends on comorbidities and age-related pharmacological specificities. Objective : To define the prognostic factors for overall survival (OS) and complete remission (CR) and establish a feasible and efficient new prognostic scoring system to assist clinicians in an age-adapted treatment strategy. Methods : From January 2000 to December 2014, 163 patients (pts) presenting an AML in a French regional cancer center in Nice were retrospectively analyzed. According to functional status, patients were treated with induction chemotherapy, azacitidine or palliative care. Complete remission rate (CR) and early-death rate were calculated. Six-month, 1-year and 2-year overall survival (OS) were analyzed with the Kaplan-Meier method and log-rank test. Univariate and multivariate logistic regression analyses were done and a p-value

Description: Abstract 2731 Background: Survivin is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin is overexpressed in the majority of aggressive B-cell lymphomas and thus is an attractive target in subjects with relapsed lymphoma. YM155 is a survivin suppressant that in vitro, when combined with rituximab, synergistically enhances the induction of apoptosis in lymphoma cells. In human DLBCL xenograft models, this combination significantly inhibits tumor growth and prolongs survival. Based on these preclinical combination data and single agent clinical data, a Phase 2 study utilizing YM155 rituximab was initiated. Methods: The study employs a two-stage group sequential method, designed to enroll a total of 40 subjects with an interim futility assessment (Stage I). Eligible patients have histologically confirmed relapsed CD20-positive primary or transformed diffuse large B cell lymphoma (DLBCL) or grade 3 follicular lymphoma (FL) and are either not candidates or previously had an autologous stem cell transplant (ASCT). Subjects had received ≥ 1 prior anthracycline containing regimen with a documented response to the last regimen prior to study entry. Induction, ASCT and maintenance therapy were considered as one regimen. The dosing regimen was YM155 5 mg/m2/day as a 168 hour (7-day) continuous infusion in a 14 day cycle and rituximab 375 mg/m22 Days 1 and 8 cycles 1 – 4 and then repeated every 10 cycles. The primary endpoint of the study is objective response rate (ORR) per modified IWG 2007. Imaging studies are performed every 8 weeks (4 cycles) after initiation of therapy. In order to continue enrolling in the study, an overall response rate of 4/16 (25%) must be achieved. Results from the completed Stage I are reported here. Results: Sixteen subjects, the majority of whom were male 13/16 (81%), were enrolled in Stage I. The median age was 62.9 (range: 32 – 78) with a majority of subjects 15/16 (93.8%) with DLBCL. IPI/FLIPI scores were intermediate in 10 subjects (62.5%) and high in 3 subjects (18.8%). The median number of prior therapies was 2 (range: 1 – 5), 16/16 (100%) of patients received rituximab in 1st or subsequent lines of therapy. Seven patients (43.7%) had prior ASCT. The median number of cycles of YM155 administered was 11 (1–37). The overall response rate was 9/16 (56.3%) with 2/16 (12.5%) CR, 7/16 (43.8%) PR and 4/16 (25%) SD. The median time to response was 53 days (range: 52 – 109). Median duration of response and median PFS has not been achieved. Clinical benefit rate was 13/16 (81.3%). The most common adverse events reported, regardless of relationship, were pyrexia 8/16 (50%), cough 7/16 (43.8%), asthenia 5/16 (31%) and fatigue, back pain, vomiting, neutropenia and thrombocytopenia each 4/16 (25%). Five subjects (31.3%) experience Grade 4 adverse events and 2 (12.5%) had Grade 5 adverse events (disease progression and respiratory failure), neither of which was considered related to therapy. The most common Grade 4 event was neutropenia 4/16 (25%), with all other Grade 4 events occurring in only 1 subject (febrile neutropenia, thrombocytopenia, general physical health deterioration, infusion site extravasation, central line infection, infective thrombosis, mediastinitis, dyspnoea, pleural effusion). Conclusion: In subjects with relapsed aggressive NHL receiving combination YM155 and rituximab, the ORR for Stage I was 56.3%, which exceeds the requirement to continue to Stage II. Overall the combination regimen was well tolerated with limited hematologic toxicities. Stage II enrollment is ongoing. Disclosures: Papadopoulos: Astellas: Consultancy, Research Funding. Steinberg:Astellas Pharma: Employment. Papa:Astellas Pharma: Employment. Keating:Astellas Pharma: Employment.

Description: Abstract 2929 Background: Azacitidine (AZA) has changed the outcome of patients (pts) with myelodysplastic syndromes (MDS) or acute myeloid leukemia with multi-lineage dysplasia (AML-MLD) unfit for intensive chemotherapy. AZA is a hypomethylating agent providing about 50% of responses in MDS and AML with low blast count (Fenaux et al., Lancet Oncol 2009, JCO 2010). To date, no consensus genetic predictor of response has been reported. Methods: In MDS (including RAEB-t) and AML-MLD (〉30% blasts) patients treated by AZA in 5 centers, we performed genomewide single nucleotide polymorphism (SNP) analysis using SNP 6.0 arrays (Affymetrix, High Wycombe, U.K.) on bone marrow (BM) samples. Patients having received ≥ 1 cycle of AZA and who had bone marrow evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered evaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. DNA were prepared for hybridization according to the manufacturers' recommendations. Affymetrix CEL files for each sample were analyzed using the Genotyping Console software (v3.0.2). Genotyping was performed using Birdseed V2 algorithm. Unpaired Copy Number and LOH analysis was performed with Regional GC correction. Copy number and UPD were also analyzed using the Copy Number Analyzer for GeneChip (CNAG version 3.3.0.1) algorithm (http://www.genome.umin.jp/CNAGtop2.html). Results: The study population included 92 pts: F/M: 41/51; median age 72 (range 35–88). Diagnosis at AZA onset was MDS in 54 (RAEB-1 n=6, RAEB-2 n=37, RAEB-t=11, IPSS int-1 in 7, int-2 in 15, high in 32, undetermined in 2) and AML-MLD in 38 pts. Cytogenetic according to IPSS was favorable in 33, intermediate in 19, unfavorable in 28, unknown in 11. Median number of cycles was 6 (range 1–41). All pts received the approved (75 mg/m2 for 7 days every 4 weeks) or a reduced AZA schedule (75 mg/m2 for 5 days every 4 weeks). Median overall survival (OS) of our cohort was 22 months. DNA samples from 52 patients were available for SNP analysis. There were no significant differences between the SNP and no SNP subgroups in term of median age, sex ratio, disease status at AZA onset, cytogenetic according to IPSS, median number of cycles, responses and OS. We listed aneuploidies (CNA) and uniparental disomies (UPD) detected by SNP analysis in the samples, and focused on 18 chromosomal bands (1p13.2, 2q34, 3p14.2, 3q26, 4q24, 5q33.1, 5q35, 6p21.3, 7q36.1, 9p21.3, 11p13, 11q23.3, 13q12.2, 15q21, 15q26.2, 20q11.21, 21q22.1) containing genes implicated in MDS or AML. Preliminary results show correlations between some CNA/UPD and response to AZA and OS, such as 1/a UPD at 9p21 (6% of patients) associated to a better hematologic improvement (X2, p=0.037), 2/an amplification at 20q11.21 (8% of patients) correlated with a poorer response (X2, p=0.048) and a trend toward poorer OS (Log-Rank, p=0.091), and 3/deletion and UPD at 15q21 (6% of patients) strongly correlated to poorer OS (Log-Rank, p=0.001). Several additional CNA and UPD of potential interest are presently under investigation. Conclusion: SNP analysis using SNP 6.0 is a powerful tool to decipher genome complexity in BM samples of MDS and AML patients treated with AZA. Our data suggest that this approach could allow characterizing profiles of responder versus non responder pts. Our study must be extended to a larger cohort and relevant anomalies must be confirmed by more sensitive techniques such as high-scale sequencing. Disclosures: Cluzeau: Celgene: Consultancy. Raynaud:Celgene: Consultancy.