ALBERT

Description: Background: Prognosis of diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphoma entities has improved with the advent of Rituximab, and R-CHOP-21 and variants is SOC. Nevertheless, a substantial proportion of patients fail first line treatment. Salvage therapies are often effective. However, no more than 25-50% achieve a long term remission even when consolidative high dose chemotherapy (HDT) followed by hematopoietic stem cell transplantation (SCT) is applied. In case of failure or intolerance to HDT, regimen like Gemcitabine/Oxaliplatin are applied but show limited efficacy, indicating the need for new treatments. Obinutuzumab (GA101) is a type II anti-CD20 antibody. Superiority of Obinutuzumab could be demonstrated in xenograft models of mantle cell lymphoma and DLBCL. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclins from higher treatment lines. With Pixantrone, a drug structurally related to anthracyclines and especially anthracenediones, a re-exposition against this drug class has been shown to be feasible. In 70 heavily pre-treated patients, a best ORR of 40% (20% CR/CRu) was observed (Pettengell et al). Experiences from further antibody drug combinations lead to the assumption that the effects of Pixantrone will be augmented by a monoclonal antibody without increasing toxicity. We thus initiated a trial combining both agents for the first time. The trial has opened in Q4/2015 and recruitment is ongoing. Overall, a total of up 70 patients will be enrolled for a number of 64 evaluable patients. Primary endpoint will be the objective overall response rate, with secondary endpoints being safety, PFS and OS. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven DLBCL, FL grade IIIb or transformed indolent lymphoma, CD20 positive disease, no curative option available, relapsed disease, measurable disease, ECOG 〈 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. There was no upper limit or prior treatment lines. Treatment consisted of Pixantrone 50mg/m² day 1, 8 and 15 of each cycle, Obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. A total of 6 cycles was planned with interim staging after 3 cycles. Results: 24 patients (pts) have been included until now. Concerning clinical characteristics, all were caucasian, 12 were female and the other 12 male and median age was 75 years. Most of the patients suffered from DLBCL (18 pts, 82%). Median number of prior therapies was 2 (1 to 6). Until now 55 evaluable cycles of chemotherapy (median 2 cycles (0 to 6)) have been performed. At this time, the treatment seems to be well tolerated, with no unforeseen side effects. Observed toxicity was predominantly hematologic. The following hematologic adverse events of grade 3/4 were noted: leukopenia (4 pts, 17%), neutropenia (6 pts, 25%), granulocytopenia (1 pts, 4%), as well as thrombocytopenia (2 pts). Non-hematologic grade 3/4 adverse events were observed in at least two patients: hypertension (2 pts) and pelvic pain (2 pts). Response: currently, best responses were 4 PR, 1 SD, and 8 PD in 13 patients evaluable so far. Four patients died, all after progression of lymphoma. Summary: the combination of Obinutuzumab and Pixantrone seems to be feasible and safe with early signs of efficacy. Updated results of this trial in progress with a focus on safety will be presented. Disclosures Hess: Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Roche: Honoraria. Marks:Pfizer: Honoraria. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Viardot:Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Roche: Honoraria; Takeda: Other: travel support; Pfizer: Honoraria. Keller:Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Description: Abstract 2708 Background: The simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) has been shown to be a good predictor of patient survival (Blood 2008;111:558–65; Blood 2010;115:1530–1533). This post hoc study analyzed data from a randomized, phase III clinical trial investigating temsirolimus (TEM) in relapsed/refractory mantle cell lymphoma (MCL) in which TEM 175/75 (175 mg for first 3 weeks then 75 mg weekly) demonstrated significantly longer progression-free survival (PFS) vs investigator's choice of therapy (INV; 4.8 vs 1.9 months, respectively; hazard ratio [HR]=0.44; P=.0009; J Clin Oncol 2009;27:3822–9). Patients receiving TEM 175/25 (175 mg for first 3 weeks then 25 mg weekly) also had longer PFS vs INV, but this difference was not significant (3.4 vs 1.9 months; respectively; HR=0.65; P=.06). During the trial, baseline prognostic risk classification was not recorded; thus, patients were retrospectively assigned baseline prognostic scores, and outcomes were analyzed according to risk category. Methods: All patients (N=162) were classified as low, intermediate, or high risk using the simplified MIPI. The MIPI scores were based on 4 independent prognostic markers: age, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase level, and white blood cell count. Median PFS and overall survival (OS) were calculated using Kaplan-Meier estimates, and treatment effect was assessed using log-rank statistics. P values of ≤.05 indicated significance of the treatment effect between the 2 treatment groups. As the phase III study was not powered to analyze patients according to MIPI risk categorization, statistical analyses shown are for explanatory purposes. Results: Distribution was relatively even across MIPI risk categories (55 patients low, 59 patients intermediate, 48 patients high). MIPI distributions in the 2 TEM arms were: 175/75 (n=54: 28% low, 43% intermediate, 30% high); 175/25 (n=54: 28% low, 33% intermediate, 39% high). Relative to the TEM arms, the INV arm (n=54) had a higher proportion of low-risk patients (46% low; 33% intermediate; 20% high). TEM 175/75 resulted in significant improvement in median PFS (independent assessment) vs INV in high-risk patients (P=.003) (Table); trends toward improvement were observed for intermediate-risk and low-risk patients (P=.06 in each group). By investigator assessment, TEM 175/75 improved median PFS vs INV by 7.9 months in the low-risk category (P=.0007) and by 2.8 months (P=.06) and 1.1 month (P=.001) in the intermediate-risk and high-risk categories, respectively. A trend toward longer OS was observed in the low-risk patients treated with TEM 175/75 vs INV (P=.0502). In the low-risk category, maintenance of stable disease or better response was achieved in more patients receiving TEM 175/75 (9/15 [60%]) vs INV (5/25 [20%]); objective responses were observed in 5 patients with TEM 175/75 and in no patients with INV. Patients in the low-risk category treated with TEM 175/75 received a longer duration of therapy vs INV (30.7 vs 9.0 wk, respectively). Across the duration of treatment, the average frequency of delay was once per 5.6 wk with TEM 175/75 vs once per 6.4 wk with INV. TEM was generally well tolerated. Grade 3/4 anemia, thrombocytopenia, and infection also were analyzed by patient risk category. In both the TEM 175/75 and INV groups, the selected grade 3/4 events occurred more commonly in high-risk than low-risk patients. In the low-risk category, a higher incidence of grade 3/4 thrombocytopenia and anemia was observed with TEM 175/75 vs INV. Conclusions: Retrospective risk analysis of patients according to the simplified MIPI demonstrated that TEM 175/75 was effective across patient risk categories. The greatest benefit trend was observed in low-risk patients. In this study of relapsed/refractory MCL patients, MIPI was a good predictor of survival outcome. Disclosures: Hess: Pfizer: Consultancy, Honoraria, Research Funding. Off Label Use: Torisel is licensed for treatment of relapsed and/or refractory mantle cell lymphoma and renal cell carcinoma in Europe. Torisel is licensed in the US for renal cell carcinoma. Kang:Pfizer: Employment. Moran:Pfizer: Employment.

Description: Abstract 2697 Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. Based on a phase III trial in relapsed MCL which proved superiority of temsirolimus to standard options, the drug is approved for this indication in the EU. Additionally, promising response rates could be observed in patients with follicular and diffuse large B-cell lymphoma (Smith et al, JCO 2010). Whereas combination to single agent rituximab seems feasible and with improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information on the feasibility and efficacy in combination with chemotherapy. Bendamustine has been shown to be effective in indolent lymphoma and has a beneficial side effect profile (Rummel et al, JCO, 2005). To evaluate the potential of the combination of temsirolimus with bendamustine and rituximab an ongoing phase I/II trial was initiated. Methods: This is a multicenter, national, prospective trial, approved by the centralized EC. Patients were eligible if they had histologically proven follicular (FL) or mantle cell lymphoma (MCL), the latter with Cyclin D1 positivity or detectable t(11;14), 1–3 prior treatment lines, no curative option available, no refractoriness to bendamustine, measurable disease, ECOG 〈 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of bendamustine 90mg/m2 day 1–2, rituximab 375mg/m2 day 1 and temsirolimus day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. In the ongoing phase I part (3+3 design) the following dose cohorts for temsirolimus were planed: A 25mg, B 50mg, C 75mg. Currently cohort C is ongoing. Toxicity was evaluated throughout the treatment and analysis for DLT was performed after 2 cycles. An independent data safety monitoring board decided on the escalation to the next dose level. Results: Overall 9 patients have been included until now (6 pts cohort A, 3 patients cohort B) and 4 patients are in the prescreening period (cohort C). Median age 64; Histology: 8MCL/1FL; sex 2F/7M, median number of pretreatments 2 (1–3). Adverse events: overall the treatment was well tolerated. Toxicity was predominant hematologic with mostly leukopenia and thrombocytopenia. In 29 evaluable cycles of chemotherapy the following grade 3/4 toxicities were noted: Thrombocytopenia in 3 (all grade 3); leukopenia in 11 (9 grade 3; 2 grade 4), and increase in triglycerides, hyperglycemia and hypertension in one patient each (all grade 3). Importantly, one case of pneumonitis occurred, which resolved after steroid treatment and study treatment could be resumed w/o further problems. In addition, one reaction to contrast agent, an allergic reaction to berries and a transient parasthesia during the study phase were noted, leading to hospitalization. All of these events occurred several days after the last application of study drug and were considered not to be associated to the study treatment. As the episode of hypertension led to hospital admission, it was considered to be potentially a DLT, and cohort A was escalated to 6 patients w/o further DLT. In cohort B no DLT were observed in 3 patients and cohort C has been opened for inclusion. 5 patients have completed the entire treatment, in one patient treatment was stopped after cycle 3 due to delayed recovery of platelets, and treatment is ongoing in 3 patients. At interim staging all 9 patients evaluable achieved a partial remission (ORR 100%). After completion of the entire treatment ORR was 100% with 1 CR and 5 PR in 6 evaluable patients. Summary: In this ongoing phase I/II trial the combination of temsirolimus with bendamustine and Rituximab was feasible applying 3 weekly doses of up to 50mg temsirolimus in a 4 week cycle. Until now promising response rates have been noticed. Cohort C is currently recruiting patients (Temsirolimus 75mg), updated results of the phase I part of the trial will be presented at the meeting. If no dose limiting toxicities are observed, the extended phase II part of the trial will be initiated with patients stratified according to lymphoma subtype (30 patients each with FL and MCL). Disclosures: Hess: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Keller:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Dreyling:Pfizer: Research Funding, Speakers Bureau, scientific advisory.

Description: Peripheral (mature) T-cell lymphomas (PTCL) are represented by distinct lymphoma entities, many of which with a rather unfavourable clinical outcome as compared to B-cell lymphomas. Standard treatment regimens have not been established, except in primary cutaneous T-cell lymphomas (PCTCL). With regard to the unfavourable prognosis we designed a treatment protocol using chemoimmunotherapy in peripheral T-cell lymphomas except PCTCL and ALK-positive large cell anaplastic T-cell lymphomas, consisting of alemtuzumab 3, 10, 30, 30 mg, days 1–4, fludarabine (Flu) 25 mg/m2 days 2–4, cyclophosphamide (CP) 600 mg/m2 day 3, and doxorubicin (Dox) 50 mg/m2 day 4. Included were patients with primary diagnosis or with first or second relapse. Rationales for this regimen were proven efficacy of CP and Dox in T-cell lymphomas, high efficacy of Flu and CP (FC) in other lymphomas and the possible synergism of antibodies with cytotoxic drugs. So far, 23 patients have been included, 18 are evaluable for response and toxicity. Of the latter, 10 patients were diagnosed with PTCL-NOS, 5 with AILD, one with enteropathy-associated T-cell lymphoma, one with NK-cell lymphoma, and one with T-PLL. 9 patients were enrolled with primary diagnosis and 9 patients in relapse. The median age was 60 years (range 21–77); the median non-age adjusted IPI 2.5 (0–4), 2 in patients with primary diagnosis and 3 in patients with relapse. The overall response rate was 61% (11/18). In patients with primary diagnosis the CR rate was 78% (7/9), one patient achieved no change, and one patient died from treatment associated complications before response could be evaluated. All responding patients are in ongoing CR at 2+, 2+, 6+, 11+, 15+,16+, and 17+ months. In the group of relapsed patients one CR and 3 PR (44%) were observed. The main toxicity was leukocytopenia (81% grade III and IV of all evaluable treatment cycles), other grade III and IV toxicities included anemia (18%), thrombocytopenia (39%), infections (18%) nausea/emesis (9%), and allergic reactions (4%). Ten (56%) patients reactivated CMV without CMV-related disease and one patient with suspected CMV-peumonia. In conclusion, this is the first study demonstrating that alemtuzumab can be integrated into a triple-agent chemotherapy regimen. The combination is effective in the first-line treatment of peripheral T-cell lymphomas, however, regarding the general outcome a longer follow-up period of a larger patient population is required.

Description: Introduction In MCL, progression-free survival (PFS) generally declines with each successive line of chemoimmunotherapy (CIT). We have previously published that with ibrutinib, a first-in-class oral inhibitor of Bruton's tyrosine kinase and a standard of care treatment (tx) for R/R MCL, median PFS exceeded 2 years (yrs) when used at first relapse (Rule S, et al. Haematologica. 2018;104:e211-e214). Here we present an updated pooled analysis with 15 months (mos) of additional follow-up, and for the first time, a comparison of outcomes with ibrutinib versus the prior regimen. Methods Patients (pts) enrolled in SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) received ibrutinib 560 mg orally once daily until progressive disease or unacceptable toxicity, and pts benefiting at end of study could enroll in the open-label long-term extension study CAN3001 (NCT01804686). Tumor response (by Cheson B, et al; 2007 criteria) and PFS were investigator assessed. Positron emission tomography scans were not routine but confirmatory for complete responses (CRs). Disease evaluations in CAN3001 were per routine clinical practice and pts could continue tx as long as clinically benefiting. For the regimen prior to ibrutinib, time to next tx (TTNT: date of first dose of prior regimen to date of first dose of ibrutinib) was used as a surrogate for PFS. Progression of disease (POD) on frontline tx was categorized as early (TTNT 〈 24 mos) or late (TTNT ≥ 24 mos). Medians are reported with 95% confidence intervals (CIs). Results As of April 2019, the median (range) follow-up and exposure for 370 ibrutinib-treated pts (median 2 [range 1-9] prior lines of therapy [LOT]) were 41 (0.2-92.4) mos and 11.1 (0.03-92.4) mos, respectively, and 32/87 (37%) pts in CAN3001 remain on ibrutinib. Tx duration was ≥ 3 yrs in 22.4% of pts. At 5 yrs, PFS and overall survival (OS) rates (95% CI) were 19% (15-24) and 41% (35-47), respectively. Pts with 1 prior LOT and pts achieving CR had the best outcomes (Table). Median PFS and OS in pts with 1 prior LOT were 25.4 (17.5-51.8) and 61.6 (36.0-not estimable [NE]) mos, respectively (Figure A). Median PFS and OS in pts with CR were 67.7 (51.7-NE) mos and NR (NE-NE) mos, respectively. Overall, median PFS on ibrutinib was 12.5 (9.8-16.6) mos, while median TTNT on the prior regimen was 10.9 (9.1-12.6) mos (Figure B). PFS with ibrutinib was longer than TTNT on the prior regimen for 50% of pts and was ≥ 12 mos longer than TTNT on the prior regimen for 27% of pts. Factors ≥ 10% more common in pts achieving ≥ 12-mo longer PFS versus those who did not included low-risk simplified MCL International Prognostic Index (sMIPI), no extranodal disease, no bulky disease (≥ 5 cm), nonblastoid histology, TP53 wild type, and best response of CR. Ninety-nine pts received ibrutinib in second line (44% ≥ 70 yrs old, 26% with high-risk sMIPI, 1% with Eastern Cooperative Oncology Group performance status ≥ 2, 6% with blastoid variant). Forty-three of 99 pts (43%) had early frontline POD and 56 (57%) had late frontline POD. In pts with early frontline POD, median PFS with ibrutinib (13.8 [4.3-24.2] mos) was similar to median frontline TTNT (14.0 [12.0-16.1] mos); median duration of response (DOR) and OS on ibrutinib were 22.1 (10.6-35.6) and 23.5 (10.3-61.6) mos, respectively. In pts with late frontline POD, median PFS with ibrutinib (57.5 [31.1-NE] mos) was longer than median frontline TTNT (42.2 [35.2-46.5] mos); median DOR and OS on ibrutinib were NE (33.1-NE) and NE (51.9-NE), respectively. There was no late unexpected toxicity. Conclusions This pooled analysis of ibrutinib in R/R MCL with extended follow-up up to 7.5 yrs indicates a late plateau in the PFS curve with a significant number of pts experiencing remission 〉 5 yrs. Tx with ibrutinib in second versus later lines extended median PFS and increased likelihood of a CR. Pts achieving CRs with ibrutinib had durable responses, with a median duration 〉 5.5 yrs. Contrary to historical outcomes with CIT, half of all pts treated with ibrutinib experienced a longer PFS than with the prior regimen, and one quarter had ≥ 1 additional yr of benefit. In pts with early frontline POD, ibrutinib delivered a similar magnitude of PFS benefit in second line. In chemosensitive pts with late frontline POD, second-line ibrutinib PFS was 36% longer than frontline outcome. There was no notable emerging toxicity with additional follow-up. Disclosures Rule: Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Novartis: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Acerta: Other: scientific advisory board; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board. Goy:Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; Genentech: Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hackensack University Medical Center, RCCA: Employment; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding. Hess:Celgene: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; Roche: Consultancy, Employment, Honoraria, Other: personal fees, Research Funding; CTI: Consultancy, Employment, Honoraria, Research Funding; Pfizer: Other: personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: personal fees; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Auer:Hartley Taylor: Honoraria; Celgene: Other: personal fees; Janssen: Honoraria, Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees. Kahl:Seattle Genetics: Consultancy; BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Qi:Janssen: Employment. Deshpande:Janssen: Employment. Parisi:Janssen: Employment. Wang:Juno Therapeutics: Research Funding; VelosBio: Research Funding; Celgene: Honoraria, Research Funding; Aviara: Research Funding; Loxo Oncology: Research Funding; Dava Oncology: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding.

Description: In myeloma therapy retreatment after successful therapy is frequently considered. Here we present pooled data from a German and Swiss multicenter, retrospective survey (26866138MMY4014). The survey started in Germany and was later extended to Switzerland. German data have already been published before. Here we report on the entire cohort of patients for the first time. For inclusion into this analysis, patients with MM had to have had preceding bortezomib treatment, resulting in at least partial remission and a second therapy with Bortezomib on relapse. The intention of this trial was to provide further evidence of the value of a retreatment with bortezomib, description of predisposing factors and comparison of response quality and remission duration in this predefined patient group of bortezomib responders. Data from 36 centers and 94 patients were available for safety analysis. 34 patients had to be excluded from the efficacy analysis due to major deviations from the inclusion criteria, i.e. concomitant antineoplastic treatment, retreatment with bortezomib not being completed, no response during initial bortezomib treatment or missing information about MM-specific interim therapy. Thus 60 patients were left for the per protocol population (PP). Patients had a mean age of 65.5 years (40–89), 56.4% being male. Patients had received a mean of 3.7 prior therapies for multiple myeloma before initial bortezomib therapy, most frequently melphalan-prednisone (44.7%), dexamethasone (38.3%) and/or vincristine-adriamycin-dexamethasone (31.9%). Stem cell transplantation was undertaken in 26.6% of the patients. Mean cycle numbers for initial bortezomib therapy and retreatment were 5.8 and 4.5, respectively. The majority of patients (85.1% and 78.7%, respectively) received a bortezomib dose of 1.3 mg/m2. Concomitant dexamethasone therapy was administered to 43.6% and 62.8% of the patients, respectively. Between the initial bortezomib therapy and bortezomib retreatment 13.8% of the patients received other MM-specific interim therapy. The efficacy analysis was based on the PP population and revealed very encouraging responses. Overall response (OR) was defined as complete response (CR), nearly complete response (nCR) and partial response (PR). With a pre-defined OR of 100% for the initial bortezomib therapy, 63% (49.9–75.4%) responded again to retreatment. Best response is summarized in the table below. Subgroup analyses of the rates of clinical benefit (CR, nCR, PR or SD) were performed by treatment free interval (TFI) after initial bortezomib therapy ( 6 months) and by concomitant dexamethasone treatment. In patients with TFI 〉 6 months a higher rate of clinical benefit (89.7%) could be achieved as compared to TFI 6 months could be a good clinical marker for a higher rate of clinical benefit. Results of an ongoing prospective trial on bortezomib retreatment are awaited to confirm these results. Initial bortezomib therapy (N=60) Bortezomib retreatment (N=60) * based on n=47 patients responding to bortezomib retreatment. Complete response (CR) 12 (20%) 8 (13.3%) Nearly complete response (nCR) 7 (11.7%) 3 (5%) Partial response (PR) 41 (68.3%) 27 (45%) Stable disease (SD) - (not allowed by selection criteria) 10 (16.7%) Progressive disease (PD) - (not allowed by selection criteria) 12 (20%) Median time to response 3.1 months 3.3 months* Median duration of response 6.9 months 6.1 months* Median treatment free interval 8.6 months 5.7 months

Description: Temsirolimus (Torisel®) is a specific inhibitor of the mTOR kinase with antitumor activity in patients with relapsed or refractory mantle cell lymphoma. In a phase 3, randomized, open-label study, patients treated with temsirolimus 175 mg weekly 3 times followed by 75 mg weekly (175/75-mg) had significantly longer progression-free survival (PFS) than those treated with investigator’s choice therapy (p-value temsirolimus: investigator’s choice = 0.0009; hazard ratio = 0.44; 97.5% CI = 0.25, 0.78; Hess et al. J Clin Oncol.2008, 28:abs 8513). Patients treated with temsirolimus 175 mg weekly 3 times followed by 25 mg weekly (175/25-mg) showed a trend towards longer PFS than those treated with investigator’s choice therapy (p-value = 0.0618; hazard ratio = 0.65; 97.5% CI = 0.39, 1.10). Patients treated with temsirolimus 175/75-mg and 175/25-mg had 22% and 6% objective response rates, respectively, compared with a 2% rate for patients treated with investigator’s choice therapy (p=0.0019 and 0.6179). These results were obtained for the intent-to-treat population, which included all randomized patients (n=54 for both temsirolimus groups and the investigator’s choice group). We now report the results of sensitivity and subgroup analyses for the recommended temsirolimus dose, 175/75-mg, compared with those for investigator’s choice therapy. The primary endpoint of the study was PFS, the time from the date of randomization to the earlier date of either progressive disease (PD) or death from any cause, if within 4 months of the last valid tumor assessment (per FDA guidance), censored at that assessment. Progression was assessed by independent review of radiographic and clinical data. Progression-free survival was analyzed by Kaplan-Meier estimates and an unstratified Cox proportional hazards model. Sensitivity analyses for PFS included: evaluable population: those who remained on treatment for at least 8 weeks and did not discontinue early for PD or death, had no major protocol violations, and had at least 1 screening tumor assessment and at least 1 postbaseline independent tumor assessment to which an overall response was assigned all deaths: those patients who had PD or died at any time during the study all deaths + withdrawal from therapy + initiation of anticancer therapy: those patients who had PD, died, or stopped treatment because of withdrawal from therapy or initiation of other anticancer therapy; and all deaths, excluding patients with blastoid histology. The latter analysis was performed because 0 patients in the 175/75-mg group and 4 patients in the investigator’s choice group had blastoid histology. The characteristics of PFS for the 4 sensitivity analyses are shown (Table). In each analysis, PFS was significantly longer for the patients treated with temsirolimus 175/75-mg than for those treated with investigator’s choice therapy, consistent with the PFS results for the intent-to-treat population. Thus, based on several analyses, temsirolimus 175/75-mg benefits patients with relapsed or refractory mantle cell lymphoma. Additional exploratory analyses will be presented. PFS Analysis Temsirolimus 175/75-mg Investigator’s Choice p-Value Hazard Ratio (95% CI) n Median PFS, Mo n Median PFS, Mo Evaluable population 29 5.2 26 1.9 0.0002 0.29 (0.15, 0.57) All deaths 54 5.2 54 2.0 0.0007 0.46 (0.29, 0.72) All deaths + withdrawal from therapy + initiation of anticancer therapy 54 2.6 54 0.8

Description: We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin 〉 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, β2-microglobulin and the number of O-FC courses were significantly correlated (P 〈 .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at www.clinicaltrials.gov as NCT00410163.