ALBERT

Description: Key Points Frontline FCA increases progression-free survival in CLL and, in a post hoc analysis, also survival in younger patients. With the low-dose approach, no increase in treatment related mortality is seen.

Description: Abstract 3955 Background: Patients (pts) with relapsed diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) or relapsing after ASCT have a poor prognosis and limited therapeutic options. New treatment options are needed for these pts. Ofatumumab is a human monoclonal antibody that targets a membrane-proximal epitope comprising both the large loop and small loop of CD20, and has shown effective lysis of chemotherapy-refractory DLBCL cells in vitro (Teeling et al. Blood 2004; Cillessen et al. Blood 2007; abstract 2346). We report the first results from an open-label, single-arm, international Phase II trial that evaluated ofatumumab monotherapy in relapsed or progressive DLBCL. Methods: Pts (age ≥18 years) with relapsed or progressive CD20+ DLBCL ineligible for ASCT or with relapsed or progressive disease after ASCT were enrolled between December 2007 and August 2009 (N=81). Relapsed or progressive disease was defined as relapse after a complete remission (CR) or disease progression after partial remission (PR). Pts received 8 weekly infusions of ofatumumab (dose 1, 300 mg; doses 2–8, 1000 mg). The primary endpoint was overall response rate (ORR) evaluated during the 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee according to the revised response criteria (Cheson et al. J Clin Oncol 2007). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety. Results: Baseline characteristics are shown in the Table. Pts were heavily pretreated (median 3 prior systemic therapies), and 32% of pts did not respond to their last prior therapy. Nearly all pts (96%) had received prior rituximab-containing treatment; 54% had received 2 or more courses of prior rituximab therapy (Table). Overall, 58% of pts completed all 8 infusions of ofatumumab, 65% received at least 6 infusions, and 81% received at least 4 infusions. The primary reason for treatment discontinuation was disease progression. The ORR (95% CI) was 11% (4–18%), including 3 CRs (4%) and 6 PRs (7%). Of these 9 responding pts, 8 had responded to their last systemic therapy. The median duration of response (95% CI) was 6.9 months (5.3–6.9) and median PFS (95% CI) was 2.5 months (2.3–2.9). Infusion-related events occurred in 59% of pts, primarily occurred during infusion 1 (40% of pts) and infusion 2 (22%), and subsided during subsequent infusions; these events were predominantly grade 1–2 in severity (96% of pts). The most common (〉10% of pts) adverse events (AEs; any grade) were diarrhea (17%), fatigue (15%), peripheral edema (15%), neutropenia (14%), abdominal pain (12%), constipation (12%), nausea (12%), pyrexia (11%), anemia (11%) and leukopenia (11%). Of these, ≥ grade 3 events included neutropenia (10%), leukopenia (6%), anemia (5%) and fatigue (1%). Grade 3 or greater thrombocytopenia and febrile neutropenia were reported in 6% and 4% of pts, respectively. The most common infectious events were upper respiratory tract infections (7% of pts), all of which were grade 1–2 events. In total, 13 pts died during the study; 3 pts died during the treatment period and 10 pts died during post-treatment follow up (until 24 months from study start). Deaths were due to disease progression (n=10), sepsis (n=1), circulatory collapse (no further details; n=1) and multi-organ failure (n=1). Conclusions: Single-agent ofatumumab was well tolerated with an ORR of 11% in heavily pretreated pts with relapsed or progressive DLBCL, nearly all of whom had received prior rituximab therapy. Response to last systemic treatment appeared to influence response to ofatumumab in this pt population. Further studies of ofatumumab in combination with chemotherapy in relapsed DLBCL are currently underway. Disclosures: Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Davies:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Padmanabhan:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Consultancy, Employment. Davis:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Losic:Genmab A/S: Employment, Equity Ownership. Lisby:Genmab A/S: Employment. Radford:GlaxoSmithKline: Equity Ownership; Genmab: Consultancy, Honoraria.

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: Abstract 2972 Introduction Siltuximab is a chimeric monoclonal antibody that binds human interleukin (IL)-6 with high affinity. Formal assessments of siltuximab's effects on cardiac repolarization using triplicate electrocardiograms (ECGs) have not yet been performed in clinical studies. A phase 1 study was conducted to evaluate the effect of siltuximab, administered at the highest dose level used in clinical studies, on the QT interval in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or indolent multiple myeloma (IMM, i.e., asymptomatic MM with ≤3 lytic bone lesions but no other end organ damage). Methods Thirty patients with MGUS, SMM, or IMM who met the following criteria on ECG at screening: pulse 45−90 bpm, QTcF and QTcB ≤500 ms, QRS

Description: Background The role of up-front consolidation for newly diagnosed, transplant eligible MM (NDMM) patients (pts) has not yet been prospectively addressed in the novel agents era. Methods The EMN02/HO95 trial was designed to randomly (R) compare (R1) 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), either single or double, as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (M Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation (R2) was performed after intensification, to be followed by lenalidomide maintenance (lenalidomide 10 mg continuously) until progression or toxicity in both arms. (VRD: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11; lenalidomide 25 mg orally days 1 - 21; dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 of a 28 days cycle). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. A first planned interim analysis for R2 was performed in July 2016 when at least 33% (= 172) of the required events for PFS had been observed. Results From February 2011 to April 2014, 1510 pts aged ≤ 65 years with symptomatic MM were enrolled, of whom 1499 were eligible. Of these, 1211 were randomized (stratification by ISS stage) to VMP (505 pts) or HDM (1 or 2 ASCT) (706 pts). For R2 903 eligible patients were randomized to consolidation (459 pts) or no consolidation (444 pts). Median follow up from R2 was 25 months (maximum 53). Response status at time of R2 was ≥ CR (23%), ≥ VGPR (67%), ≥ PR (93%), and will be updated for status at start of maintenance. At the time of analysis, 258 events for PFS after R2 had been reported. 3-year. PFS from R2 was 62% in all patients, i.e., 60% without consolidation and 65% in patients with consolidation, and median PFS had not yet been reached. PFS from R2 with adjustment for R1 was prolonged in pts randomized to VRD (HR=0.78; 95% CI=0.61-1.00; P=0.045), a benefit retained across predefined subgroups with revised ISS stage III (HR=0.67; P=0.26) and in patients randomized in R1 to VMP (HR=0.76; P=0.19) and to HDM (HR=0.79; P=0.13). The benefit of consolidation was observed in patients with low-risk cytogenetics (HR=0.68; P=0.03), but not in patients with high-risk cytogenetics (del(17p) and/or t(4;14) and/or t(14;16); HR=1.03; P=0.91). At 3 years OS from R2 was 86% and 87%, respectively. Toxicity from VRD was limited with 5% CTCAE grade 4, mainly hematological. Conclusions Consolidation treatment with VRD followed by Lenalidomide maintenance until progression or toxicity shows promising results as compared to maintenance alone for younger NDMM pts, but further study follow-up is needed. This trial was registered at www.trialregister.nl as NTR 2528, EudraCT 2009-017903-28 This trial was supported by unrestricted grants from Celgene and Janssen. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Driessen:janssen: Consultancy; celgene: Consultancy; Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Mundipharma: Other: Advisory Board; Amgen: Honoraria; BMS: Honoraria; Janssen-Cilag: Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. Cavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

Description: Background The role of upfront autologous stem cell transplantation (ASCT) for younger patients with newly diagnosed (ND) multiple myeloma (MM) has been questioned in the novel agent era. Methods A prospective, multicenter, phase III study was designed to compare (first randomization, R1) (1:1 ratio; stratification according to ISS stage) four 42-day cycles of bortezomib-melphalan-prednisone (VMP) given at the same dosing schedule reported in the VISTA study (NEJM 2008; 359:906-17) vs either a single course or two sequential courses of melphalan at 200 mg/m2 (HDM) followed by single or double ASCT, respectively, as intensification therapy after three to four 21-day cycles of induction therapy with bortezomib-cyclophosphamide-dexamethasone and subsequent collection of peripheral blood stem cells. A second randomization (R2) to consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was performed after intensification, to be followed by lenalidomide maintenance until progression or toxicity in both arms. A primary study end point was progression-free survival (PFS) from R1. Results From February 2011 to April 2014, 1510 patients aged ≤65 years with symptomatic NDMM were registered. Of these, 1192 were eligible for R1 and were randomly assigned to receive either VMP (n=497 patients) or HDM (1±2 courses) (n=695 patients). Median age was 58 years in both groups, ISS stage III was 21% in VMP and 20% in HDM, while revised ISS stage III was 9% in both groups. Data on cytogenetic abnormalities, as detected by FISH analysis of CD138+ plasma cells, were available in 71% of patients (n=354) randomized to VMP and in 76% of those (n=529) assigned to HDM. The frequency of conventionally defined high-risk cytogenetic changes, including t(4;14) and/or del(17p) and/or t(14;16), was 25% in both arms. Median follow-up from R1 was 26 (IQR: 19-37) months. On an intention-to-treat basis, median PFS was 44 months in the VMP arm and was not yet reached in the HDM arm; 3-year estimates of PFS were 57.5% and 66%, respectively (HR=0.73; 95% CI=0.59-0.90; P=0.003). PFS benefit with HDM was retained across predefined subgroups, including patients with ISS stage I (HR=0.69; CI=0.48-0.98; P=0.037), revised ISS stage II (HR=0.70; CI=0.54-0.91; P=0.008), revised ISS stage III (HR=0.54; CI=0.30-0.97; P=0.040), standard-risk cytogenetics (HR=0.75, CI=0.56-1.01; P=0.055) and a high-risk cytogenetic profile (HR=0.54; CI=0.37-0.80; P=0.002). The probability of achieving a very good partial response or higher quality response was 85.5% in the HDM group vs 74% in the VMP group (odds ratio=1.90; CI=1.42-2.54; P

Description: Background: Patients with follicular lymphoma (FL) have a heterogenous prognosis. Recently a simple score, the PRIMA-PI, was developed based on the PRIMA clinical trial (Bachy et al Blood. 2018). With only two factors (beta-2-microglobulin level 〉 3 mg/L and bone marrow involvement), this index was at least as discriminatory as FLIPI on the training and validation cohorts. The validity of the PRIMA-PI was confirmed on Czech and German FL cohorts and a patient group from the Nordic Lymphoma Group. However, further validation is needed to confirm the use of PRIMA-PI in place of FLIPI for prognostic assessment. Indeed, in the era of new chemo-free treatments, it seems important to challenge the potency of traditional prognostic factors and scores. Recently, rituximab combined with lenalidomide (R2) was compared to conventional immunochemotherapy (R-chemo) in the phase III RELEVANCE trial. The aim of our study was to validate PRIMA-PI in the RELEVANCE trial cohort and compare its performance with FLIPI (Solal-Celigny et al. Blood. 2004) and FLIPI2 (Federico et al. JCO. 2009). A secondary objective was to evaluate potential differences in terms of prognostic bio-clinical parameters between the R2 and R-chemo arms. Methods: All patients with available data for FLIPI, FLIPI2, and PRIMA-PI from the intention to treat population of the RELEVANCE study were included in the analysis. PFS according to each prognostic score were assessed in the total population and by treatment arms. Data were not mature enough to compare OS distributions. Performance metrics (log-rank p value and Net Reclassification Improvement [NRI]) were calculated for each group to assess concordance and discriminating ability of each score. Results: Median follow-up time for the study was 38 months. Overall, 846 RELEVANCE patients were included in the analysis. Data were available for 845 patients for FLIPI score assessment, 832 for FLIPI2 and 807 for PRIMA-PI. Group repartition according to the FLIPI and the FLIPI2 were largely imbalanced compared with PRIMA-PI. FLIPI classified very few patients in the low risk group (15% LR) while 49% of the patients were at high risk (HR), and 36% were at intermediate risk (IR). Similarly, FLIPI2 risk categories were as follow: 8% LR, 50% IR, and 42% HR. On the contrary, PRIMA-PI divided the study population into three equal groups (33%, 33% and 34%). In the total population, FLIPI and PRIMA-PI were predictive of PFS (p=0.029 and p=0.004, respectively); FLIPI2 showed poor performance (p=0.094). PFS curves based on each score are shown in Figure 1. NRI index indicated that the PRIMA-PI yielded analogous segregation for PFS with FLIPI (NRI 0.16; 95% CI: -0.008, 0.318; Table 1). In the R-chemo arm, both FLIPI and PRIMA-PI could isolate different prognostic groups for PFS, whereas FLIPI2 could not. Conversely, none of the indices were able to significantly discriminate outcomes for patients treated with R2. Interestingly, analysis showed that some usual prognostic factors, especially those likely to reflect tumor burden such as beta-2 microglobulin and LDH, were not predictive for PFS in the R2 arm. In contrast, low albumin (

Description: Introduction Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell proliferation with a very poor prognosis. The prevalence of poor-risk genetic lesions is higher compared with newly diagnosed multiple myeloma. pPCL requires urgent control of clinical manifestations to prevent early death because of irreversible disease complications. The aim of the EMN12/ HOVON129 study is to improve the outcome of younger and elderly patients with pPCL by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance. This trial was registered at www.trialregister.nl as NTR5350. Methods In this ongoing non-randomized, phase 2, multicenter study, patients with previously untreated pPCL receive induction therapy with carfilzomib-lenalidomide-dexamethasone (KRd; 28-day cycles with carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23). In patients ≤65 years, 4 cycles of KRd induction is followed by tandem autologous stem cell transplantation (SCT), KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16) and lenalidomide (10 mg on days 1-21/28 days) until progression. Patients who are eligible for allogeneic SCT, may also receive autologous-allogeneic tandem transplantation. Patients ≥66 years receive 8 cycles of KRd followed by carfilzomib+lenalidomide maintenance. Supportive care consists of antibacterial-, herpes zoster-, and thrombosis-prophylaxis. Inclusion criteria are newly diagnosed pPCL (〉2x109/L circulating monoclonal plasma cells or plasmacytosis 〉20% of the differential white cell count) and WHO-performance status 0-3. Main exclusion criteria are severe cardiac or pulmonary dysfunction; and creatinine clearance of

Description: Abstract 3911 Introduction Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for relapsed CLL patients with fludarabine refractory disease or a deletion 17p (del 17p). Retrospective analyses identified bulky disease and lack of response to last treatment as predictors for poor survival. The optimal salvage regimen for these patients is not clear, nor is it known what percentage of these patients does respond to salvage therapy before the transplantation. Here we report our results with R-DHAP studied in an international multicenter phase 2 study. The rationale for choosing R-DHAP is that in vitro treatment with platinum and a nucleoside analogue of fludarabine refractory CLL cells with or without dysfunctional p53 in vitro induces cell death independent of p53.1 Patients up to the age op 70 years with fludarabine refractory CLL (defined, according to the EBMT consensus, as relapse within 1 year after fludarabine monotherapy or within 2 years after fludarabine plus a monoclonal antibody) or with relapsed CLL with a del 17p (assessed by FISH), and in need of treatment were eligible for inclusion. Patients were treated with at least 3 cycles of R-DHAP salvage therapy (rituximab 375mg/m2 1st cycle, 500 mg/m2 later cycles, cisplatinum 100mg/m2, cytarabine 2×2000mg/m2 and dexamethasone 4×40mg) once per 4 weeks. A planned interim analysis as to toxicity and efficacy was performed following remisison-induction completion by the 20th patient. According to protocol, the study had to be reconsidered if less than eight out of the first 20 patients actually had received alloSCT, or in case of excessive toxicity. Results Twenty patients were included from Feb 16, 2009 till Jan 19, 2011. The median age was 59 years (range 43–68) and the median number of prior therapies was 3 (range 1–5). Fourteen were refractory to fludarabine monotherapy and 16 refractory to fludarabine containing immuno-chemotherapy. Ten of these 20 patients also had del 17p. Six had bulky lymph-adenopathy (〉5 cm). Eleven patients completed all 3 R-DHAP cycles on protocol. Responses in these 11 patients were 1xCR, 6xPR and 4x stable disease (SD). Six of these 11 patients also had del 17p and their responses were 1xCR, 3xPR and 2x SD. All 11 patients subsequently proceeded to alloSCT. Three patients received only one or two cycles of R-DHAP as the treatment was considered to toxic and went off-protocol. All three had responsive disease. One patient responded to 1 cycle of R-DHAP but went of protocol due to infectious toxicity and did not proceed to alloSCT. Another patient had disease progression after the 1stR-DHAP and died. All eleven patients treated with 3-R-DHAP cycles and all three responding off-protocol patients received alloSCT immediately following R-DHAP. CTC grade 5 infectious toxicity was noted in 4 patients, including three with fatal septic shock and one with fatal encephalitis in 1. Nine other patients suffered from grade 4 infectious toxicity: febrile neutropenia (n=7), septic shock (n=1), pneumonia (n=3), urinary tract infection (n=1), or catheter-related infection. Despite infections, eight of these 13 patients could proceed to alloSCT. Optimized antibacterial and antifungal prophylaxis was amended to the protocol as from the 16th patient onwards. Since then 13 additional patients were entered in the study and until now none developed severe bacterial or fungal infection or died. Conclusions R-DHAP is an effective remission-induction regimen for fludarabine-refractory or early relapsed patients with or without del 17p, allowing a relatively high percentage of patients to proceed to alloSCT (14/20) Despite efficacious, significant infectious toxicity accompanied R-DHAP, necessitating strict adherence to antimicrobial prophylaxis. 1. Tonino SH, van Laar J, van Oers MH, Wang JY, Eldering E, Kater AP. ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia. Oncogene. 2011;30:701–713. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 57 Background The ACT trial (ACT-1, younger patients aged 18–60 yrs and ACT-2, elderly patients aged 〉60 yrs) is the first international randomized phase III trial in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). It tests, in both younger and elderly patients, the efficacy of the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP followed, only in younger patients (ACT-1), by high-dose therapy with autologous stem cell rescue. A dose reduction amendment tapering the cumulative ALZ dose from 360 mg (30 mg on days 1 and 2 of CHOP courses 1–6) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively, was introduced early on due to two cases of systemic fungal infection (Blood 2011,118;4110). To date, the trial has accrued a total of 186 patients (ACT-1 n=98; ACT-2 n=88). Aim Here, we present the results from the first interim efficacy and safety analysis of the ACT-1 trial based on the first 68 randomized patients. Results Of the 68 patients, 63 had a complete set of treatment data. The median follow-up was 15 months (range 0.5–42 months). Thirty-two patients belonged to the experimental arm (exp) and 31 to the standard arm (std). Of the 32 patients treated according to exp, 4 received the higher dose of ALZ and 28 the lower. Treatment arms were well balanced with regard to main prognostic features such as age (std: median 53 yrs, range 21–60 yrs; exp: median 50 yrs, range 22–64 yrs; p=0.705), IPI subgroups (std: low 10%, low-intermediate 51%, intermediate-high 29%, high 10%; exp: low 12%, low-intermediate 44%, intermediate-high 19%, high 25%; p=0.392), advanced clinical stage (std: stage III-IV 94%; exp: 97%; p=0.613), performance status ECOG〉1 (std: 23%; exp: 28%; p=0.613), elevated LDH (std: 68%; exp: 69%; p=0.932), presence of B-symptoms (std: 68%; exp: 75%; p=0.524), bulky disease (std: 13%; exp: 13%; p=1.0) and bone marrow involvement (std: 39%; exp: 31%; p=0.535). Histological subtypes were also similarly distributed among both treatment arms (std: PTCL-NOS 55%, AILT 23%, other 22%; exp: PTCL-NOS 56%, AILT 28%, other 16%). No cases of anaplastic large cell PTCL (regardless of ALK-protein status) were included. Neither of the treatment cohorts showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 4 leucopenia was more frequent in ALZ-treated patients (std: 24%, exp: 69%; p=0,001), whereas grade 3–4 anemia and grade 3–4 thrombocytopenia were not significantly different between treatment arms (anemia, std: 19%, exp: 31%; p=0,278; thrombocytopenia, std: 20%, exp: 12%, p=0,682). Non-hematological toxicity unrelated to infectious complications was mild and had a similar frequency in both arms. The number of serious adverse events (SAEs) per patient was 0.86 for patients treated at post-amendment ALZ dose levels, representing a significant reduction compared to the pre-amendment value (3.25), and 0.46 for patients treated in the control arm (p=0.002). The frequency of bacterial and fungal infections (grade ≥3) was similar in both treatment arms. ALZ treated patients had more viral events (9/32; 28% vs. 3/31; 10%), mainly (6 out of 9) consisting of asymptomatic cytomegalovirus reactivations. The overall (non-arm specific) 1-year event-free survival (primary end-point), progression-free survival and overall survival were 55% (95% CI: 42%-67%), 54% (95% CI: 42%-67%) and 78% (95% CI: 67%-88%), respectively. Conclusion The safety profile of the current standard and experimental treatment schedules, as well as the interim outcome results, support a continuation of the trial. A final analysis will be performed in Q2 2015. Disclosures: Jantunen: Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria.