ALBERT

Description: Introduction Achieving a PET-negative metabolic (m)CR with salvage chemotherapy prior to autologous stem cell transplantation (ASCT) in relapsed/refractory Hodgkin lymphoma (R/R HL) is a strong predictive factor for long-term progression-free survival (PFS). In a phase I dose-escalation trial we have shown a favorable toxicity profile of 3 cycles of DHAP in combination with brentuximab vedotin (BV) with a high mCR rate (12/12 patients). A subsequent phase II study in 55 patients has been performed; the 6 patients treated at full dose of BV-DHAP in the phase I part were added to the current analysis. Methods BV was given at a fixed dose of 1.8 mg/kg on day (d) 1 of 3 cycles of DHAP q 3 weeks (dexamethasone 40 mg iv d 1-4, cisplatin 100 mg/m² iv d1 and cytarabine 2x2 g/m² iv d2). Cycle 2 was used for stem cell mobilization; after the 1st and 3rd cycle patients received pegylated G-CSF to prevent prolonged neutropenia and dose delays. The primary endpoint of the study was the mCR rate after 3 cycles of BV-DHAP based on central PET-review. Patients with a partial or complete response proceeded to high dose chemotherapy (BEAM) and ASCT. Results Twenty-three of the 61 patients (29 males; median age 29 yrs, range 19-71) had not achieved a CR to 1st line treatment (37%), which consisted of ABVD (n=45), (escalated) BEACOPP (n=11) or other regimens (n=5). The median time from response to 1st line treatment to relapse was 6 months (range 0-160 months); 38 patients (62%) had either primary refractory disease or early relapse (

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

Description: Background: Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. 90Y-ibritumomab tiuxetan (Zevalin®, Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by 90Y-ibritumomab tiuxetan consolidation. Methods: Adult patients with refractory/relapsed DLBCL, more than one year after or not eligible for ASCT, were treated with R-PECC (Prednisone 40 mg/m2 po D1-5; Etoposide 100 mg/m2 po D1-5; Chlorambucil 8 mg/m2 po D1-5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1) q 28 days for 4 cycles. Complete (CR) or partial responders (PR) received consolidation with a single dose 90Y-ibritumomab tiuxetan (15 MBq/kg, 0.4 mCi/kg). Response was evaluated according to the revised Cheson criteria (2007). Results: Between November 2008 and February 2012 62 patients were enrolled. Median age was 70 years (range, 45-82). Secondary IPI score was high-intermediate or high in 42% patients. All patients had received CHOP at first-line, 12 without rituximab. Prior therapies consisted of (R)-CHOP (65%), R-CHOP and R-DHAP/VIM (24%) or R-CHOP and R-DHAP/VIM plus ASCT (11%). Fourteen patients (23%) were refractory to the last prior therapy. After 4 cycles of R-PECC the overall response rate (ORR) was 31/62 (50%), with 14 of 62 (23%) patients achieving a CR and 17 of 62 (27%) achieving a PR, 13 of 62 (21%) patients had progressive disease. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (63% vs 7%, p=0.0001). 29 of 31 responsive patients received consolidation with RIT. The remaining two patients with PR did not proceed to RIT because of one toxic death and one misinterpretation of the response. The ORR after the end of the entire treatment was 29% (23% CR, 6% PR), RIT consolidation improved the overall best response (from PR to CR) in 5 of the 17 PR pts after the R-PECC only regimen. The median follow-up time of patients still alive is 48 months (range, 0-67 months). The median response duration in the patients that received R-PECC only was 9 months (range 3-63 months). The median response duration in the patients that received RIT consolidation was 20 months (range 0-59 months). The failure free survival at 1 yr from start of RIT consolidation was 52% (95% CI=[33%,68%]) and the overall survival 62% (95% CI=[42%,77%]). There was one treatment related death, due to sepsis and pneumonia after the first R-PECC cycle. The R-PECC regimen was well tolerated by most patients. The most common grade 3 or 4 adverse events during R-PECC treatment were hematological toxicity (27%), infection (19%) and malaise (11%). Adverse events after RIT were primarily hematologic. Grade 3 to 4 trombocytopenia and neutropenia occurred in 8 patients (28%) and 5 patients (17%), respectively. Eight patients received platelet transfusions and 6 patients red blood cell transfusions. Conclusions: The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Consolidation with RIT was well tolerated and resulted in long response durations in half of the patients. Disclosures Lugtenburg: Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Roche: Consultancy; Celgene: Consultancy. Off Label Use: 90Ytrium-ibritumomab tiuxetan for diffuse large B-cell lymphoma. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Doorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Hoogendoorn:Gilead: Consultancy; Novartis: Consultancy.

Description: Abstract 2729 Background. Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. The optimum salvage therapy for these patients is not known. Treatment results with second-line chemotherapy have generally been disappointing. In some centers in the Netherlands PECC (Prednisone, Etoposide, Chlorambucil and Lomustine) combination chemotherapy is used as salvage treatment for such patients. PECC is a completely oral schedule. The efficacy and toxicity of PECC in this patient category has not been evaluated systematically before. 90Y-ibritumomab tiuxetan (Zevalin®) showed clinical activity as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating induction therapy with Rituximab (R)-PECC followed in responsive patients by 90Y-ibritumomab tiuxetan consolidation. Methods. Patients aged ≥ 18 years with refractory CD20 positive DLBCL or first or second relapse, more than one year after or not eligible for ASCT, were enrolled. Treatment consisted of R-PECC (Prednisone 40 mg/m2 po D1–5; Etoposide 100 mg/m2 po D1–5; Chlorambucil 8 mg/m2 po D1–5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1), every 28 days for 4 cycles. Patients with progressive disease after 2 cycles went off protocol. Patients in complete or partial remission after 4 cycles received consolidation treatment with 90Y-ibritumomab tiuxetan at the standard single dose of 15 MBq/kg (0.4 mCi/kg) 6 to 12 weeks after start of the last R-PECC cycle. Response to treatment was evaluated according to the revised 2007 Cheson criteria. Results. Between November 2008 and February 2012 64 patients were enrolled. We report preliminary data for the first 50 patients evaluable for response and toxicity after the induction treatment with R-PECC. The median age was 70 years (range, 45–82) and median time since first diagnosis was 17 months (range 3–172). All patients had been treated with CHOP as first-line treatment and 8 patients (16%) had not been exposed to rituximab at first-line. Prior therapies consisted of (R)-CHOP (72%), R-CHOP and R-DHAP/VIM (16%) or R-CHOP and R-DHAP/VIM plus ASCT (12%). Eleven patients (22%) were refractory to their last prior systemic therapy. According to the secondary IPI, 26%, 28%, 34% and 8% of the patients belonged to the low-, low-intermediate-, high-intermediate-, and high risk group, respectively. Median relative dose intensities for the myelosuppressive agents of the PECC regimen were 93.7% (90% CI = 62.8–106.9%), 94.3% (90% CI = 71.6–104.7%) and 97.4% (90% CI 76.0–104.7%) for Lomustin, Etoposide and Chlorambucil, respectively. Progressive disease occurred in 14 patients (28%). Overall response rate (ORR) after induction treatment was 52%, including 34% complete response and 18% partial response. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (64% vs. 9%, p=0.099). Patients more than one year from start of upfront treatment had a significant higher ORR than that of patients less than one year from start of upfront treatment (81% vs 21%, p=0.005). Median response duration was 13 months. One patient died because of treatment related toxicity due to sepsis and pneumonia after the first R-PECC cycle. The most common grade 3 or 4 adverse event was haematological toxicity (42%), followed by infection (14%), malaise (13%) and gastro-intestinal toxicity (6%). Eighteen serious adverse events (SAEs) occurred in 14 patients, 14 of the SAEs were possibly related to treatment (mainly hospitalisations because of infections). Approximately half of the patients (46%) have entered the 90Y-ibritumomab tiuxetan consolidation phase of the study. Conclusions. The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Disclosures: Off Label Use: 90Y-ibritumomab tiuxetan is not registered for DLBCL.

Description: Introduction Autologous stem cell transplantation (AuSCT) is widely used in patients with histologic transformation of indolent lymphoma. Although probably superior to standard chemotherapy, there is still room for improvement. We are currently studying the effect of the addition of 90Yttrium ibritumomab tiuxetan (Zevalin) to BEAM conditioning followed by an AuSCT on survival in a prospective phase 2 trial. It is known that, after rituximab-BEAM-AuSCT, recovery of T cells occurs after 4 months and of B cells after 9 months, with normal levels only being reached after 1 and 2 years, respectively. (1,2) It is however unclear if, in patients uniformly pre-treated with rituximab-chemotherapy, followed by BEAM and AuSCT, the addition of Zevalin further hampers immune reconstitution. Materials and methods Patients (n=14) with histologically proven transformed lymphoma were included in this prospective phase 2 trial when conditioning for AuSCT was started. AuSCT was planned when CR or PR was reached after (re)induction containing a minimum of 6 courses of rituximab (375 mg/m2) and chemotherapy. Patients subsequently received pre-doses of rituximab on day -15 and -8 (250 mg/m2), Zevalin on day -8 (0.4 mCi/kg) and BEAM conditioning on day -7 to -1, followed by AuSCT at day 0. Blood samples were taken before the first predose of rituximab (day -15,t=0) and 3-6, 12-18 and 24-30 months after AuSCT. Absolute neutrophils were counted and samples were analyzed for NK-, B- and T-cell subsets using multicolor flowcytometry. T cells were defined using CD3 combined with either CD4 or CD8. NK cells were defined as CD45+, CD3-, CD56+ and/or CD16+, B cells as CD45+, CD3-, CD19+, memory B cells CD19+,CD27+. Recovery was defined as: Neutrophils 〉 0.5 x 109/l, CD19+ B cells 〉0,07 x 109/l (CD27+ B cells 〉0,03 x 109/l) CD4〉0,4 x 109/l,CD8〉0,13 x 109/l, NK cell 〉 0,08 x 109/l. (1,2) All infections after neutrophil recovery following AuSCT were registered. IgG levels were measured at baseline and after 2 years. Results A median of 3 (range 1-4) measurements were obtained depending on length of follow up. The median follow up was 26 months (range 3-30 months). Median time to neutrophil recovery was 22 days after AuSCT (range 17-29 days). As expected, patients were already severely B-cell depleted at start of consolidation (t=0, figure 1).B cells started to appear after nine months and reached (low) normal values after 12-18 months. T cell and NK cell recovery started after 3 months and took one year to normalize. (figure 1) All patients had IgG levels 〉5 g/l after AuSCT, without support. Only three infectious episodes were reported in 14 patients. In one patient an episode of herpes simplex virus infection with diarrhea was reported two months after AuSCT. In another patient a pneumonia was diagnosed two months after recovery from AuSCT (cultures stayed negative). Both had enough neutrophils but B cells and CD4 cells were not yet recovered. Both patients recovered completely after antiviral and empirical antibiotic and antimycotic therapy, respectively. One patient developed a herpes zoster virus infection at 2 years after AuSCT, recovering completely after antiviral therapy. Conclusion Compared to figures reported in literature (1,2), the addition of Zevalin to consolidation with BEAM and AuSCT after (re)induction with R-chemotherapy does not seem to lead to an increase of infectious complications or delayed immune-reconstitution as analyzed by T cell, B cell and NK cell recovery. References Kasamon YL, Jones RJ, Brodsky RA, Fuchs EJ, Matsui W, Luznik L, Powell D, Blackford AL, Goodrich A, Gocke CD, Abrams RA, Amvinder RF, Flinn IW. Immunologic recovery following autologous stem-cell transplantation with pre-and posttransplantation rituximab for low-grade or mantle cell lymphoma. Ann Oncol 2009: 1-8 van der Velden AMT, Claessen AME, van Velzen-Blad H, de Groot MR, Kramer MHH, Biesma DH, Rijkers GT. Vaccination responses and lymphocyte subsets after autologous stem cell transplantation.Vaccine 2007:8512-8517 Figure 1 Figure 1. Disclosures Wondergem: spectrum pharmaceuticals: Research Funding. Visser:spectrum pharmaceuticals: Research Funding.

Description: Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients. Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp). Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years. 3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months. After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p

Description: Background. Combined modality treatment (CMT) consisting of two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and 20 Gy of involved-field radiotherapy (IFRT) is widely accepted standard of care for early-stage favorable Hodgkin lymphoma (HL). Recent clinical research suggests that metabolic response assessment after two cycles of chemotherapy using FDG-PET (PET-2) can predict the individual outcome and PET-2 negativity might allow reducing the overall treatment intensity. Aims. We assessed whether omitting consolidating radiotherapy in patients with negative PET-2 is feasible without loss of efficacy as determined by progression-free survival (PFS). Furthermore, we analyzed the prognostic impact of PET-2 among patients receiving CMT. Methods. Between November 2009 and December 2015, we recruited patients with newly diagnosed, early-stage favorable HL aged 18-75 years from Germany, Switzerland, Austria, and the Netherlands for this double-blind, randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard CMT with 2x ABVD and 20 Gy IFRT or PET-guided treatment, whereby IFRT was restricted to those patients with a positive PET after 2xABVD. PET-2 was centrally assessed by a panel blinded towards the randomization result, with FDG uptake not higher than the mediastinal blood pool (i.e., Deauville score 1-2) defined as negative. The trial was designed to exclude inferiority of 10% or more in 5-year PFS of ABVD only compared with CMT in a per-protocol analysis among PET-negative patients, corresponding to a non-inferiority margin of 3.01 for the hazard ratio, and to detect a 5-year PFS difference of 5% or more between PET-2-positive and -negative patients receiving CMT, each with 80% power. Results. A total of 1150 patients were enrolled; 628 patients with negative PET-2 were eligible for the per-protocol non-inferiority analysis and were treated with CMT (n=328) or ABVD alone (n=300). With a median follow-up of 47 months, the estimated 5-year PFS was 93.4% (90.4-96.5) with CMT and 86.1% (81.4-90.9) with chemotherapy only (difference 7.3%, 95% CI 1.6%-13.0%). The hazard ratio was 1.78 with a 95% CI ranging from 1.02 to 3.12, including the non-inferiority margin of 3.01. The PFS difference primarily resulted from a significant increase in disease recurrences with in-field recurrence rates of 2.1% vs. 8.7% (p=0.0003); there was no relevant difference regarding out-field recurrences (3.7% vs. 4.7%, p=0.55). Estimated 5-year overall survival in the per-protocol population was 98.1% (96.5-99.8) with CMT and 98.4% (96.5-100.0) with ABVD. 693 patients assigned to receive CMT were eligible for the analysis of the PET objective and had a negative (n=353) or positive (n=340) PET-2. With a median follow-up of 46 months, estimated 5-year PFS was 93.2% (90.2-96.2) among PET-2-negative and 88.1% (83.8-92.3) among PET-2-positive patients (p=0.035). When using the more common liver cutoff (Deauville score 4) for the definition of PET-2 positivity, the difference was more pronounced (5-year PFS 93.1% [90.7%-95.5%] vs. 80.1% [71.2%-88.9%], p=0.0004). Conclusion. In early-stage favorable HL, radiotherapy cannot be safely omitted from standard CMT without a clinically relevant loss of tumor control in patients with negative PET-2. PET positivity after 2xABVD represents a risk factor for PFS in HL patients treated with standard CMT, particularly when a Deauville score of 4 is considered as cutoff for positivity. Disclosures Greil: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Sandoz: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Tresckow:MSD: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Borchmann:Novartis: Consultancy, Honoraria.

Description: Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS). Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count 〉 0.5 x 109/l and platelets 〉 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation. Results . Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%). Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2). The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group. With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively. Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

Description: Background: Patients with MYC rearrangement positive large B cell lymphoma other than Burkitt lymphoma (MYC+ LBCL), have a dismal prognosis following standard first line therapy with R-CHOP. Retrospective studies report complete remission rates 〈 50% and 2-year overall survival (OS) of approximately 35%. Lenalidomide is an immunomodulatory drug and is able to down-regulate MYC and its target genes and proteins in B cells that harbor a MYC rearrangement. We report data of a prospective phase II study evaluating the efficacy of lenalidomide in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients. Methods: A national screening program for MYC rearrangement by fluorescence in situ hybridization (FISH) was performed in newly diagnosed LBCL patients. Patients with a proven MYC rearrangement, ≥ 18 year, Ann Arbor stage II-IV, were offered participation in a single arm phase II study. Treatment consisted of 6 cycles R-CHOP21 plus lenalidomide 15 mg on day 1-14, followed by two additional rituximab administrations. Use of G-CSF was mandatory. All patients received intrathecal methotrexate prophylaxis. 18F-FDG PET-CT (PET-CT) scans were performed at baseline, midterm (after 3 cycles) and end-of-treatment (EOT). Diagnostic lymphoma samples were centrally reviewed including immunohistochemical (IHC) work-up and complementary BCL2 and BCL6 FISH analysis. Cell of origin classification was determined by IHC (Hans) and by gene expression profiling (Lymph2Cx). The primary endpoint was complete metabolic response rate (CMR) on EOT PET-CT scan, according to the Deauville criteria and assessed by 2 independent nuclear medicine physicians performing central review. In case of discordance, a third adjudicator reviewed. Confirmation of bone marrow (BM) negativity at EOT for patients with positive BM at diagnosis was not required for CMR. Secondary endpoints included disease free survival (DFS), progression free survival (PFS), OS and predictive value of midterm PET-CT for EOT PET-CT scan. Data cut-off was July 4th 2018. Results: From April 2015 to February 2018, 85 patients were included at 20 hospitals. Planned interim analysis (after 26 consecutive patients completed treatment) revealed no safety concerns. At data cut-off, central data management, pathology and imaging review processes were completed for the first 60 patients. The remaining patients (60 to 85) are still on treatment or have recently finished treatment. Among the first 60 patients, 2 were declared ineligible, leaving 58 patients for this analysis (demographics and disease characteristics in table 1). Central pathology review confirmed diagnosis of MYC+ LBCL in all patients. Additional FISH analysis revealed that 41/58 patients (71%) had MYC and BCL2 and/or BCL6 rearrangements (double hit or triple hit), 11/58 (19%) had a single MYC rearrangement, 6/58 (10%) had a MYC rearrangement but no information on BCL2 and BCL6. At EOT PET-CT scan (primary endpoint), 36/58 patients (62%) were in CMR (95% confidence interval (CI) 50%-71%). 2/58 patients (3%) reached a partial metabolic response (PMR), and 20/58 patients (34%) had progressive disease (PD). At midterm PET-CT, 39/58 patients (67%) were in CMR; of these 29 were still in CMR and 10 showed PD at EOT PET-CT. 18/58 patients (31%) were in PMR at midterm; 7 of them converted to CMR, 2 remained in PMR, 9 showed PD at EOT. One patient went off protocol after two cycles due to progression. With a median follow-up of 17.2 months, 1-year estimates for OS were 79% (CI 66%-88%), for DFS 74% (CI 59%-85%), and for PFS 60% (CI 47%-72%). Grade 3 and 4 adverse events (AE) were seen in 26 (43%) respectively 9 patients (15%). Most common grade 3-4 AEs were gastrointestinal disorders, infections, and neutropenia. 55 serious AEs were reported in 27 patients (all hospitalization). 1 patient went off protocol due to grade 3 diarrhea. Univariate regression analyses revealed no significant prognostic factors for achieving CMR or prolonged survival yet. Conclusion: These data represent the first prospective trial worldwide for newly diagnosed MYC rearrangement positive LBCL patients. Treatment with R2CHOP demonstrates acceptable toxicity and promising efficacy with 62% CMR on centrally reviewed PET-CT scan and a 1-year OS rate of 79%. In December 2018, all 85 registered patients will have finished treatment and complete analysis of the primary endpoint and additional biological studies will be available. Disclosures Chamuleau: Gilead: Research Funding; celgene: Research Funding; Genmab: Research Funding; BMS: Research Funding. Mous:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; sandoz: Membership on an entity's Board of Directors or advisory committees. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Kersten:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 765 Purpose: Combined modality treatment consisting of 4 cycles of chemotherapy and IF-RT is the standard treatment for early unfavorable HL. Overall survival (OS) and freedom from treatment failure (FFTF) at 5 years in this group of patients was 91% and 83%, respectively, in our prior HD8 study. Thus, the rationale for HD14 was to improve on these results by increasing dose intensity using BEACOPP escalated. Methods: Between January 2003 and July 2008, 1655 patients with histologically confirmed diagnosis of Hodgkin lymphoma in early unfavorable stages were randomized. Patients had to be 16–60 years old and have CS I, IIA with one of the following risk factors: large mediastinal mass (a), extranodal disease (b), elevated ESR (c), or ≥ 3 nodal areas (d), IIB with risk factors c or d). Patients were randomized to either 4 cycles of ABVD (arm A) or 2 cycles BEACOPP escalated followed by 2 cycles ABVD (arm B). All patients received 30Gy IF-RT after chemotherapy. Primary objective was the improvement of FFTF. Results: The full analysis set comprised 1623 patients (98.1%) who were documented and followed for treatment effects; 818 were in arm A and 805 in arm B. Patient characteristics were well balanced between the two arms with a median age of 33.6 years and most patients in stage IIA (67%). The overall response rate to treatment was 95% in each arm. With a median follow-up of 42.4 months, 20 patients had died in each arm; 19 patients in arm A had secondary neoplasia compared to 16 patients in arm B. Progressive disease was observed in 2.9% versus 0.9% of patients in arms A and B, respectively; early relapse rates were 2.8% versus 0.9%, and late relapse rates were 2.3% versus 0.9%. The estimated 4-year FFTF rate was 89.3% in arm A and 94.7% in arm B (p=0,0001, hazard ratio HR=2.04, 95%-CI: 1.39–2.94). There was no significant difference in overall survival yet (p=0.95). Acute grade III-IV toxicity rates of chemotherapy were higher in arm B (87.1%) than in arm A (50.7%) with leucopenia rates of 79% versus 24%, hair loss 48% versus 24%, thrombocytopenia 22% versus 0.1% and anemia 9% versus 1% in arms B and A respectively. 7.3% of patients had grade III/IV infections in arm B as compared to 3.4% in arm A. However, we observed no differences in treatment-related death or secondary neoplasia rates between treatment arms. Conclusion: Intensifying treatment for patients with early unfavorable HL using 2 cycles of BEACOPP escalated followed by 2 × ABVD and IFRT results in a significant improvement in tumor control as compared to our prior standard of 4 × ABVD plus IFRT. As defined in the study protocol, this more aggressive treatment was implemented as new standard of care for early unfavorable HL in our follow-up study (GHSG HD17). Disclosures: Greil: Cephalon: Research Funding.