ALBERT

Description: Although they produce high rate of molecular response second generation tyrosine kinase inhibitors or imatinib cannot eradicate CML primitive progenitors. Interferon has been shown to modulate gene expression, inhibits leukemic cell growth and induces an immunomodulatory response. In vitro studies support the use of combination of IM plus interferon. We designed a phase III randomised multicenter open-label prospective trial comparing IM 400 mg/d (n=223) with 3 experimental arms: IM 600 mg/d (n=171), IM 400 mg/d combined to s/c Peg-IFN2a (90 µg/wk) (n=221) and IM 400 mg/d combined to s/c Ara-C, (20 mg/m2/d, d15-28 of 28-day cycles)(n=172). Pts were allocated at a 1.1.1.1 ratio, stratified by Sokal risk groups. Molecular assessments were centralised, blinded and calculated according to the international standardised ratio (IS) As of December 31st 2010, date for closing accrual, 787 pts have been included. We first demonstrated that the addition of PegIFN increased the molecular responses. The planned molecular analysis after 1 year based on the outcome of 636 pts resulted in a highly significant superiority of MR4 (≤0.01 % Bcr-Abl/Abl on IS) of the combination IM 400mg-PegIFN (Preudhomme et al. N Engl J Med, 2010). The protocol was also amended after the demonstration that a lower dose of PegIFN (45 µg/week) resulted in less toxicity and similar molecular responses as compared with 90 µg/week. Of interest, a 3-months BCR-ABL transcript level of ≤10% IS was associated with PFS (Accelerated phase, blast crisis, deaths) and time to progression (TTP) improvement overall. However, results which were observed with the addition of PegIFN or an increased dose of IM frontline do not confirm the relevance of the 10% BCR-ABL cut-off level as a strong surrogate marker for progression. After a median observation time of 60 months, 5-year overall survival (OS) was 94%, and 5-year PFS was 93%. Overall 70 pts died because of blastic (n=24) or accelerated phases (n = 1). Out of the 35 pts who progressed to AP and BC, 11 are alive. A blastic phase was recorded in 27 pts (myeloid 20, lymphoid 6, biphenotypic 1), of these 4 are alive (2 myeloid, 2 lymphoid). Main causes of deaths in CP (n = 46) were infections (IM 400 n=4,IM 600 n=0, IM PegIFN n=4, IM Ara-c n=0 ), vascular events (IM 400 n=1,IM 600 n=2,IM PegIFN n=1, IM Ara-c n=1) malignancies (IM 400 n=3, IM 600 n=2 ,IM PegIFN n=4, IM Ara-c n=7 ). In addition, the following causes of death were recorded: suicide (n=2), GVHD (n=2), miscellaneous (n=13). Cumulative incidence of progression, PFS and OS by arms are shown in the table: Table 1 IM 400 (n = 223) IM 600 (n = 171) IM PegIFN (n = 221) IM Ara-c (n 172) Cumulative incidence of progression (p: 0.43)(a) N progressions 11 11 7 6 N competing events (deaths in CP) 9 7 15 15 At 60 months % (95%CI) 5% (3-8) 5% (3-9) 2% (1-4) 4% (2-8) PFS (p:0.92)(b) N (progressions and deaths) 20 18 22 21 At 60 months 93% 93% 94% 91% (95%CI) (89-96) (88-96) (90-97) (85-94) OS (p: 0.64)(b) N (deaths) 15 16 19 20 At 60 months 95% 94% 95% 91% (95%CI) (91-98) (89-97) (91-97) (86-95) Gray’s test Log-rank test Conclusions:The French SPIRIT trial demonstrated that the combination of imatinib with Peg-IFNα2a was associated with deeper molecular responses at 12 months and was able to counteract the risk of early progression in newly diagnosed CML-CP patients. The dose of 45µg/week is well tolerated and sufficient for achieving molecular responses and should be used in further trials. The risk of progression to blastic or accelerated phase, although currently non-significant, is lower with this combination. An update of outcomes will be presented. Disclosures Maloisel: Hospira: Consultancy; Sandoz: Research Funding; Pfizer: Research Funding. Gardembas:BMS: Honoraria. Legros:Novartis, BMS: Honoraria.

Description: Introduction Febrile neutropenia (FN) is a frequent and potentially serious complication of cytotoxic chemotherapy (CT). It is defined as an oral temperature 〉38.5°C, or two consecutive readings of 〉38.0°C for 2 h, with an absolute neutrophil count

Description: Introduction the purine analogs (PA) cladribine (CDA) and pentostatin have dramatically improved the prognosis of HCL and are considered the standard of care both in front-line therapy and at relapse. However, some patients still fail to respond or will eventually relapse after treatment with PA. Chimeric anti-CD20 monoclonal antibody rituximab has shown significant activity in HCL and is an option for relapsed/refractory patients either alone or in combination with PA. Methods we retrospectively reviewed 49 treatments with rituximab for classical HCL, undertaken in 41 patients (pts) from 10 centers in France and Belgium between july 2002 and september 2012. Patients were included if they had received at least 3 infusions of rituximab. Eight pts were treated twice with rituximab. Complete hematologic response (CHR) was defined as recovery of normal blood counts (without circulating HCL cells) and absence of HCL-related symptoms. CHR was further divided into 3 groups: (i) stringent complete response (sCR), if bone marrow evaluation was normal; (ii) unconfirmed complete response (uCR), if bone marrow evaluation was not done and (iii) CHR with persistent medullar infiltration (iCHR). Partial response (PR) corresponded to a ≥ 50% improvement for every CHR-defining criterion or normalization of at least one blood count, without circulating HCL cells. Results characteristics of pts before treatment are summarized in table 1. Rituximab was given as front-line therapy in 8 cases (16.3%). When used at relapse/progression, the median number of previous lines was 3 (range 1-8) and all pts had already received PA (both CDA and pentostatin in one third of them). Rituximab was given alone in 55% of cases, while it was combined with a PA in the 45% remaining cases, mostly CDA (18 of 22 cases). The median number of infusions was 4 (3-12). After treatment, median absolute neutrophil count (ANC), hemoglobin (Hb) level and platelet count were 2.75 x 109/L, 135 g/L and 180 x 109/L respectively. Persistent significant neutropenia (ANC 〈 1 x 109/L) and anemia (Hb 〈 100g/L) were each found in only 2 cases and 10.6% of patients had platelets 〈 100 x 109/L. Overall response rate (ORR) was 89.6% with 70.8% CHR including 6 sCR (12.5%), 26 uCR (54.2%) and 2 iCHR (4.2%). PR was achieved in 9 cases (18.8%) and 5 pts were non responders (10.4%). All the 8 pts who received rituximab as front-line therapy (along with CDA in 5 of them) achieved CHR. In the relapsed pts, ORR was 87.5% (including 65% CHR) with a better outcome for those having received both rituximab and PA (100% ORR including 85.7% CHR versus 79.2% ORR and 54.2% CHR after rituximab alone). The 5 pts who failed to respond were relapsed pts treated with rituximab alone. Interestingly, all the 8 pts who were re-challenged with rituximab responded again to treatment (6 uCR, 1 iCHR and 1 PR). Multivariate analysis identified 3 independent prognostic factors for response to rituximab: absence of previous therapy (OR=0.027 [0,001-0,555], p=0,0192), combination therapy (OR=10,120 [1,227-83,485], p=0,0316) and ANC before treatment (OR=1,002 [1,001-1,004], p=0,006). The median follow-up is 36 months (4-117). Relapse or progression was observed in 15 cases (34.1%), with a median time to relapse of 19 months (2-39). Relapse rate was higher (54.5%) and time to relapse shorter (17.5 months) when rituximab was administered alone, as compared to combination therapy with a PA (10% and 38.5 months respectively). Overall, 3-year relapse-free survival is 68.3%. Six pts have died and 3-year overall survival is 90.3%. Conclusion this study confirms the efficacy of rituximab in HCL patients, mostly when combined to PA. Nevertheless, the relapse rate is high and time to relapse short when rituximab is used as monotherapy beyond front-line treatment. Further prospective studies are warranted to confirm the superiority of the combination PA + rituximab over PA alone. Disclosures: Off Label Use: Rituximab for the treatment of hairy-cell leukemia.

Description: Introduction Febrile neutropenia (FN), a major risk factor for morbidity/mortality, is associated with dose delays and/or reductions in potentially cytotoxic chemotherapy (CT) regimens. It is defined as an oral temperature 〉38.5°C, or two consecutive readings of 〉38.0°C for 2 h, with an absolute neutrophil count 20% risk of FN or in less intensive CT regimens if certain risk factors (eg 〉65 years, advanced disease, history of prior FN) are present. Biosimilar filgrastim (Nivestim™, Hospira Inc.) is a G-CSF licensed for the treatment of neutropenia and FN induced by myelosuppressive CT. As the NEXT (Nivestim™ safety profile in patiEnts treated with cytotoXic chemotherapy in real-life clinical pracTice) study was conducted in France, the real-life usage of biosimilar filgrastim is compared with that recommended by current EORTC guidelines. Methods The NEXT study was a prospective, non-interventional, longitudinal, multicentre, national study. The primary objective was to evaluate the safety of biosimilar filgrastim by gathering adverse event (AE) data. Secondary objectives included the description of patients (pts) treated with, and patterns of use of, biosimilar filgrastim. Adult pts undergoing cytotoxic CT for malignancies (excluding chronic myeloproliferative and myelodysplastic syndrome) and receiving biosimilar filgrastim as primary or secondary prophylaxis, or as curative treatment, were included. The subanalysis presented here included only pts receiving prophylactic biosimilar filgrastim. Data were recorded on case report forms and included pt characteristics (demographics, medical history, CT-related data), biosimilar filgrastim treatment-related data (indication, dose, route of administration, treatment initiation) and treatment-emergent AEs, including FN. Individual FN risk factors were analysed. Pts were monitored for 1–6 CT cycles at three visits: inclusion, a follow-up visit during treatment and the final visit following CT. Results Overall, 2102 pts were included in the study analysis and 2065 pts received prophylactic biosimilar filgrastim. At inclusion, 73.9% of pts had no prior FN. Of the pts included in this analysis, 19.4% received CT associated with a high risk of developing FN (intermediate risk: 55.6%; low risk: 25.0%). Of the pts receiving CT regimens associated with an intermediate risk of FN, 95.4% had ≥1 risk factor for FN and of those receiving a regimen associated with a low risk of FN, 96.5% had ≥1 FN risk factor (Table 1). Of all pts receiving prophylactic biosimilar filgrastim, 3.5% developed FN after the first CT cycle, 1.8% developed an infection and 2.4% were hospitalised for FN and/or infection after the first CT cycle. Median time to initiation of biosimilar filgrastim was 2 days after the last CT dose; mean treatment duration ± SD was 6.0±3.8 days. Anti-infective prophylaxis was reported in 14.5% of pts. Conclusion The majority of pts received prophylactic biosimilar filgrastim according to EORTC guidelines (ie either had 〉20% risk of FN or had ≥1 FN risk factor). Biosimilar filgrastim (Nivestim™) is an alternative therapeutic option for pts with prophylactic CT-induced neutropenia. Table 1. Proportion of patients with risk factors for FN Risk factor Patients (%) Chemotherapy regimen associated with a high risk (〉20%) of FN Chemotherapy regimen associated with an intermediate risk (10–20%) of FN Chemotherapy regimen associated with a low risk (65 years 35.9 40.2 55.9 Advanced disease 40.4 41.9 66.4 ≥1 severe comorbidity 25.6 27.5 35.2 Poor nutritional status* 3.8 3.1 7.0 WHO performance grade ≥3 0.0 0.1 0.3 Haemoglobin

Description: Introduction Febrile neutropenia (FN) is a major risk factor for infection-related morbidity/mortality as well as a dose-limiting toxicity in patients (pts) undergoing chemotherapy (CT). Biosimilar filgrastim (Nivestim™, Hospira Inc.) is a granulocyte-colony stimulating factor (G-CSF) licensed for the treatment of neutropenia and FN induced by myelosuppressive CT. The NEXT (Nivestim™ safety profile in patiEnts treated with cytotoXic CT in real-life clinical pracTice) study aimed to assess the safety of biosimilar filgrastim in pts undergoing CT for malignancies. Methods The NEXT study was a prospective, observational, non-interventional, longitudinal, national, multicentre study conducted in France. The primary objective was to evaluate the safety of biosimilar filgrastim by gathering adverse event (AE) data. Adult pts (n=2114) undergoing cytotoxic CT for malignancies (excluding chronic myeloproliferative and myelodysplastic syndrome) and receiving biosimilar filgrastim as prophylaxis, or as curative treatment, were included. Data collected included pt characteristics, biosimilar filgrastim treatment-related data and treatment emergent AEs, including FN. Pts were monitored for 1–6 CT cycles at three visits: inclusion, a follow-up visit during treatment and the final visit following CT. Here we present data for pts with haematological malignancies. Results Of the pts analysed, 525 had haematological malignancies (chronic lymphoid leukaemia [CLL]/acute lymphoid leukaemia [ALL]: 70; lymphoma: 408; myeloma: 47). Overall, the mean age ± standard deviation (SD) of pts with haematological malignancies was 64.8 ± 15.4 years (64.4% male). At inclusion, 88.0% of pts had no prior FN (CLL/ALL: 88.6%; lymphoma: 89.2%; myeloma: 76.6%); 31.1% had prior CT (CLL/ALL: 32.9%; lymphoma: 27.5%; myeloma: 59.6%) and 27.1% had prior G-CSF therapy (CLL/ALL: 21.4%; lymphoma: 26.7%; myeloma: 38.3%). Of the pts prescribed a prior G-CSF therapy, 39.2% received biosimilar filgrastim. The majority of pts (98.9%) received biosimilar filgrastim prophylactically (CLL/ALL: 100.0%; lymphoma: 98.8%; myeloma: 97.9%). Of the group receiving biosimilar filgrastim with curative intent, the median time to initiation of biosimilar filgrastim therapy was 14.0 days after the start of the last CT cycle (lymphoma: 14.0 days; myeloma: 14.0 days); mean treatment duration ± SD was 4.8 ± 1.6 days (lymphoma: 5.2 ± 1.5 days; myeloma: 3.0 ± 0.0 days). In this group, 50.0% of pts received a dose of 30 MIU (lymphoma: 40.0%; myeloma: 100.0%) and biosimilar filgrastim was administered subcutaneously in all pts. In the prophylactic biosimilar filgrastim group, the median time to initiation of biosimilar filgrastim was 6 days after start of the last CT cycle (CLL/ALL: 6.0 days; lymphoma: 6.0 days; myeloma: 6.5 days); mean treatment duration ± SD was 6.7 ± 4.6 days (CLL/ALL: 7.5 ± 7.0 days; lymphoma: 6.6 ± 4.0 days; myeloma: 5.9 ± 4.5 days). In this group, 70.9% of pts received a dose of 30 MIU (CLL/ALL: 57.1%; lymphoma: 72.5%; myeloma: 78.3%) and biosimilar filgrastim was administered subcutaneously in all pts. Anti-infective prophylaxis was reported in 51.2% of pts (CLL/ALL: 88.6%; lymphoma: 42.9%; myeloma: 67.4%). In the prophylactic group, 7.5% (95% confidence interval [CI] 5.5, 10.1) experienced FN (CLL/ALL: 7.1% [2.7, 16.0]; lymphoma: 7.1% [4.9, 10.1]; myeloma: 10.9% [4.3, 23.5]). Of the pts with haematological malignancies, 18.6% experienced ≥1 AE (CLL/ALL: 8.6%; lymphoma: 21.5%; myeloma: 8.5%). The most common AEs (〉5.0% of pts) were bone/muscular disorders (total: 13.7% [CLL/ALL: 7.1%, lymphoma: 16.0% myeloma: 4.3%]) and muscle pain (total: 13.4% [CLL/ALL: 7.1%, lymphoma: 15.5% myeloma: 4.3%]). In this analysis, 7.5% of pts were hospitalised for FN and/or infection (CLL/ALL: 7.1%; lymphoma: 7.1%; myeloma: 10.9%). The mean duration of hospitalisation ± SD for FN and/or infection after the first CT cycle was 11.3 ± 16.2 days (CLL/ALL: 10.5 ± 6.4 days; lymphoma: 11.4 ± 17.4 days; myeloma: 0.0 ± 0.0 days), 3.4% of pts had a CT dose reduction (CLL/ALL: 2.1%; lymphoma: 2.8%; myeloma: 2.3%) and 7.7% of pts (CLL/ALL: 15.7%; lymphoma: 5.9%; myeloma: 11.4%) had a delay in administration of CT due to FN and/or infection. Conclusion Biosimilar filgrastim was effective and well-tolerated in pts undergoing CT for haematological malignancies and is an alternative therapeutic option for pts with CT-induced neutropenia. Disclosures Maloisel: Pfizer: Research Funding; Novartis: Research Funding; Hospira: Research Funding; Amgen: Research Funding. Albrand:Hospira: Employment.

Description: Key Points Adding siltuximab to VMP did not improve CR, progression-free survival, or overall survival but improved very good partial response in MM. This suggests that the association of less than CR with long-term outcomes and the role of IL-6 in MM should be reassessed.

Description: Abstract 3782 Background: Nilotinib, a second generation tyrosine kinase inhibitor, is indicated in Ph+ chronic or accelerated phase-CML patients with imatinib-resistance or -intolerance. A 400mg BID schedule is recommended for this indication, with doses taken approximately 12 hours apart, outside meal times. No food should be consumed for 2 hours before and at least 1 hour after dose intake. Such recommendations may affect the compliance to nilotinib treatment, a critical factor for therapeutic success. Aims: The primary objective of EOSTA was to evaluate the compliance rate to nilotinib using the Morisky score, after 12 months of follow-up (FU). The other objectives were to describe the changes in compliance over a 12 months period, factors associated with non-compliance, and changes in QoL of patients treated with nilotinib. Data recorded by physicians and patients are summarized in Table 1. Results: Here are presented the results based on the interim analysis of the whole population at 6 months of FU. From November 2008 to September 2010, 145 patients were included in 30 sites in France. At the last time of analysis, 87 patients (60%) had a Morisky score documented at 6 months and could be analyzed for compliance. Forty four out of 87 (50,6%) patients were males, the median age was 57.5 years (24 to 83), 42% had a professional activity and 45% were retired. At inclusion, 77 patients were already treated with nilotinib (47 for less than 1 year, 30 for more than 1 year) and 67% of the patients received nilotinib 800 mg daily (mean 671 mg). The mean daily dose of nilotinib at 6 months was 680 mg, comparable to that at inclusion. Previous therapies included imatinib in all cases (57.5% resistant), 22% have been previously treated with dasatinib and 24 % of patients were taking more than 3 concomitant long-term medications in addition to TKI. According to Morisky score rated at 6 months, compliance was high (Morisky score ≥3) in 87% of the patients and was stable over 6 months. Occasional missing dose was declared by 28% of patients. Compliance was high in all patients ≥ 60 years old, retired and receiving more than 3 long term concomitant treatments, in 64% of patients less than 40 years, 83% of active patients, and 82% of patients receiving up to 3 concomitant treatments. In a separate questionnaire, occasional missed dose were reported in 45% of patients, one day a week maximum in 81% of them, mainly because of forgetting (40%) and inadequate timing (26%). Interestingly 80% of patients declared not to be disturbed by nilotinib modalities of administration. According to the QoL questionnaire EQ-5D, EVA (self-rated health index) was stable over the first 6 months of FU (mean 70.6 to 70.3). Autonomy was not impacted, few issues (roughly 25% of patients) were notified in terms of mobility, usual activities, and some problems of pain/discomfort and anxiety/depression were notified in respectively 62% and 43% of patients. QLQ-C30 scores were analyzed, showing good global health status (mean 69, 33 to 100), good functional score (mean 80, 37 to 100), and poor symptom score (mean 20, 0 to 85). These results were stable over time since inclusion regardless of duration of previous nilotinib treatment. At least one adverse event (AE) was reported in 29% of patients and a serious AE in 5%. They were mainly grade I/II. No grade IV was reported. The most frequent AEs were cutaneous (8.3%), gastrointestinal (6.9%) and musculoskeletal (6.2%) disorders. Conclusion: Based on preliminary results at 6 months, reflecting nilotinib use in the real life in CML patients with resistance or intolerance to imatinib, compliance to treatment was favourable especially in patients treated for less than one year and elderly patients. Overall, QoL was not impaired despite some issues on mobility, usual activities, pain/discomfort and anxiety/depression. The safety profile was favourable. These results need to be confirmed on the final analysis planned at 12 months of FU. Updated results will be presented. Disclosures: Rea: Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Maloisel:BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Okada:Novartis: Employment. Bourdeix:Novartis: Employment. Nicolini:Bristol Myers Squibb France: Consultancy, Speakers Bureau; Norvartis Pharma France: Consultancy, Research Funding, Speakers Bureau. Tulliez:Novartis: Honoraria; BMS: Honoraria. Etienne:consultant for Novartis Pharma France and Bristol Myers Squibb: Consultancy.

Description: Long-term responses have been reported after autologous stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL). We conducted a prospective, randomized trial of ASCT in previously untreated CLL patients. We enrolled 241 patients 〈 66 years of age with Binet stage B or C CLL. They received 3 courses of mini-CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone/prednisolone) and then 3 courses of fludarabine. Patients in complete response (CR) were then randomized to ASCT or observation, whereas the other patients were randomized to dexamethasone, high-dose aracytin, cisplatin (DHAP) salvage followed by either ASCT or 3 courses of fludarabine plus cyclophosphamide (FC). The primary end point was event-free survival (EFS). After up-front treatment, 105 patients entered CR and were randomized between ASCT (n = 52) and observation (n = 53); their respective 3-year EFS rates were 79.8% and 35.5%; the adjusted hazard ratio was 0.3 (95% CI: 0.1-0.7; P = .003). Ninety-four patients who did not enter CR were randomized between ASCT (n = 46) and FC (n = 48); their respective 3-year EFS rates were 48.9% and 44.4%, respectively; the adjusted hazard ratio was 1.7 (95% CI: 0.9-3.2; P = .13). No difference in overall survival was found between the 2 response subgroups. In young CLL patients in CR, ASCT consolidation markedly delayed disease progression. No difference was observed between ASCT and FC in patients requiring DHAP salvage.