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Abstract Abstract 1876 Poster Board I-901 Background: Multiple Myeloma (MM) remains incurable in spite of new effective agents and combination regimens. SRC family kinases (SFK) are potential targets for therapy in MM: Hck, Fyn and Lyn are implicated in IL6-induced proliferation. Dasatinib is a potent inhibitor of not only BCR-ABL, but also SFK, c-KIT, PDGFRb, and EPHA. In myeloma and endothelial cells (ECs) isolated from MM patients (pts), dasatinib blocked proliferation, survival, adhesion, migration, and angiogenic potential, through a combined targeting of PDGFRβ as well as VEGF-triggered phosphorylation of SRC. Lenalidomide has clinical efficacy in the treatment of multiple myeloma (MM) as a single agent and in combination with dexamethasone. The combination of dasatinib, lenalidomide and dexamethasone exhibits synergistic inhibition of MMIS cells. Methods: The primary objective of this Phase I, multicenter, open-label, non-randomized study was to determine the maximum tolerated dose (MTD) of the combination of dasatinib, with lenalidomide and dexamethasone in pts with relapsed or refractory (RR) MM. Secondary objectives were to assess the tolerability of the combination, to establish the dose for future clinical investigations, and to assess the efficacy by International Uniform Response and EBMT Criteria. Pts ≥18 years with confirmed RR MM, measurable disease (at least 1 g/dL for IgG or 0.5 g/dL for IgA in serum or urinary excretion of 200 mg monoclonal light chain/24 hours), and at least one prior treatment were enrolled sequentially into increasing dose cohorts (using a 3+3 design). Pts received oral dasatinib daily on a continuous schedule, oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22). Cycles were repeated every 28 days. Dose-limiting toxicities (DLTs) were assessed in the first cycle. If there was no DLT, dose escalation continued to MTD, followed by an expansion phase of the established dose. Results: Enrollment is ongoing. 16 pts (6 M, 10 F; median age 70.5 years, range 51–80) were treated in cohorts 1, 2, 3 and 4; MTD has not been established (as by July 2009). The median number of prior lines of therapy was 3 (range 1–6). Seven pts had prior autologous stem cell transplantation; 8 pts had prior thalidomide, 4 prior lenalidomide and 3 pts both. Baseline β2 microglobulin levels of >3.5mg/L were reported in 4 pts. The most common (310%) treatment related adverse events (AEs) diarrhea 6 (38%); nausea 4 (25%); constipation 2 (13%); stomatitis 2 (13%); asthenia 3 (19%); weight decrease 5 (31%); dyspnea 2 (13%); rash 2 (13%); vertigo 2 (13%); insomnia 2 (13%). The most common grade 3 / 4 hematologic AEs included neutropenia 6 (38%), anemia 4 (25%) and thrombocytopenia 3 (19%). Two DLTs were identified in cohorts 1 and 4: 1 pt had 2 point decline in ECOG Performance Status and other pt had a drug interruption > 15 days due to nausea and vomiting, respectively. Six out of 16 pts discontinued treatment: 1 due to death in first cycle (D19); 3 for AEs (2 study drug related and 1 unrelated), 1 withdrawal of consent, 1 following maximal clinical benefit (minor response) after 12+ cycles. As of July 2009, 10 pts remain on treatment, with a median duration of treatment of 4.2 months (range 0.6–12). Responses were observed in 13 pts: 8 partial responses (PR), and 5 minor responses (MR). 1 pt had stable disease (SD) and 2 pts were not evaluable (1 pts died before completion of cycle 1 and other pt was too early for assessment). Conclusion: Dasatinib in combination with lenalidomide and dexamethasone is well tolerated and preliminary activity has been observed. Disclosures: Facon: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Garzon:BMS: Employment. Bleickardt:BMS: Employment. Gialelis:BMS: Employment. Tuozzoli:BMS: Employment. Derreumaux:BMS: Employment. Sonneveld:Janssen-Cilag: Honoraria.

Abstract Abstract 2699 Poster Board II-675 Introduction: High-dose chemotherapy with autologous stem cell transplant (SCT) is a standard treatment option for younger patients with aggressive non-Hodgkin's lymphomas (a-NHL) who fail to respond, or relapse after initial therapy. For patients who relapse after SCT there are few effective treatment options and prognosis remains poor (Vose et al Blood. 80(8):2142–8, 1992). A second SCT was shown to achieve only marginal responses and at an increased risk of toxic death (Lenain et al Hematol J. 5(5):403–9, 2004). Therefore, new approaches are needed for treatment of patients in this poor prognostic group. Lenalidomide (Revlimid®) is an immunomodulatory agent that has shown clinical activity in treatment of several B-cell malignancies. Two phase 2 studies of lenalidomide monotherapy in patients with relapsed or refractory (R/R) a-NHL were conducted in the US (NHL-002; Wiernik et al JCO 26:4952–7, 2008) and internationally (CC-5013 NHL-003). In an extended follow-up of the NHL-002 study, the overall response rate (ORR) was 35%, which included 12% of patients with a complete response (CR), and a median duration of response (DR) lasting 10.4 months (Wiernik et al 2008 EHA. Abst: 764). Comparable efficacy was observed in the larger confirmatory, phase 2, NHL-003 study of lenalidomide in a similar patient population. The goal of this analysis was to learn the ORR and DR to lenalidomide in patients with a prior SCT. Methods: Patient data from both phase II studies were pooled for this report. Eligibility for both studies was similar – patients with R/R a-NHL, which included diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), and follicular lymphoma grade III (FL-III), with measurable disease (≥ 2 cm), and ≥ 1 prior treatment regimen. Patients received oral lenalidomide 25 mg once daily on days 1–21 of a 28-day cycle. Protocol defined treatment continued for up to 52 wks in NHL-002, or until disease progression in NHL-003. Primary endpoint was ORR; secondary endpoints included DR, progression-free survival (PFS), and safety. Results: 87 patients with a prior SCT (14 patients from NHL-002; 73 patients from NHL-003) were included in this analysis. Median age of patients was 61 yrs (range, 23–76), with a median of 4 prior therapies (range, 2–12). The ORR to lenalidomide was 39% (34/87), with 13% (11/87) CR/CRu and 26% (23/87) partial response (PR). Median PFS for all 87 patients was 3.8 months (95% CI, 2.6, 5.6) and the DR for 34 responders was 9.7 months (95% CI, 4.2, 16.3). Responses occurred in 15 of 52 patients (29% ORR; 10% CR/CRu) with DLBCL, 12 of 19 patients with MCL (63% ORR; 26% CR/CRu), and in 6 of 10 patients with TL (60% ORR; 10% CR/CRu). The table summarizes responses for patients who did not have a transplant, for those who had a SCT anytime prior to lenalidomide; as the last therapy prior to lenalidomide; and not as last therapy prior to lenalidomide. Most common grade 3 or 4 adverse events were neutropenia (44%), thrombocytopenia (33%), and anemia (9%). Eighteen (20.6%) patients discontinued treatment due to adverse events. Patients with a prior history of SCT appeared to have a significantly higher rate of thrombocytopenia, all grades (51% v 30%; P = 0.001), and grades 3 or 4 (33% v 16%; P = 0.002). Patients with a prior SCT were also more likely to experience a dose reduction/interruption due to thrombocytopenia compared with those without a prior SCT (25% v 14%; P = 0.027). Conclusions: Based on a pooled dataset from two phase II studies, oral lenalidomide monotherapy appears to be a well tolerated and active therapy resulting in durable responses in patients with R/R a-NHL who had a prior SCT. Furthermore, the potential of achieving a response to lenalidomide appears to be independent of prior history of SCT. Disclosures: Vose: Celgene: Research Funding. Off Label Use: Lenalidomide for the treatment of relapsed/refractory aggressive non-Hodgkin's lymphoma. . Czuczman:Celgene: Research Funding. Zinzani:Celgene: Research Funding. Tuscano:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pietronigro:Celgene: Employment, Equity Ownership. Ervin-Haynes:Celgene: Employment. Witzig:Celgene: Research Funding.

Abstract Abstract 2742 Poster Board II-718 Background: The BCR-ABL inhibitor imatinib has revolutionized the treatment of CML, and improves the efficacy of chemotherapy in Ph+ ALL. Acquired imatinib resistance (IR) is an emerging problem. Patients who develop IR have a dismal prognosis and novel therapeutic strategies are needed. Mechanisms of resistance include mutations and overexpression of BCR/ABL. In addition, BCR/ABL-independent pathways may contribute to resistance. Mounting evidence suggests that aberrant histone deacetylase (HDAC) expression plays a key role in acquired IR. HDAC inhibition has been shown to downregulate BCR/ABL expression via multiple mechanisms. The functional effects of HDAC inhibition include cell cycle arrest and induction of mitochondrial damage and caspase-dependent apoptosis, both in cells that are imatinib sensitive (IS) and IR. We hypothesized that HDAC inhibition will demonstrate synergistic activity in combination with imatinib in IR cells. To test this hypothesis, we employed entinostat (SNDX-275), a novel, class I HDAC isoform selective inhibitor currently being tested in multiple phase 2 clinical trials. We explored the use of SNDX-275 alone and in combination with imatinib and dasatinib in IR and IS p210BCR/ABL expressing cell lines. Methods: K562 (p210BCR/ABL expressing CML cell line), IR K562 cells (Weisberg E, et al. Blood. 2000;95:3498), Ba/F3 cells, Ba/F3 cells transfected with p210BCR/ABL and Ba/F3 cells transfected with the T315I mutant form of BCR/ABL were treated with increasing concentrations of SNDX-275 (0.2 to 1.6μM), imatinib (0.1 to 1.6 μM), and dasatinib (0.3 to 250 nM) for 72 hours. The cells were also treated with combinations of SNDX-275 plus imatinib and SNDX-275 plus dasatinib at the same range of concentrations for 72 hours. All experiments were done in triplicate. Drug-related effects on cell viability were determined by MTT cytotoxicity assays. CalcuSyn software was used to calculate the IC50 for each drug in each cell line and to calculate the combination index (CI) for cell lines treated with combinations of imatinib or dasatinib plus SNDX-275. A CI from 0.9 to 1.1 indicates that the two drugs have an additive effect, below 0.9 indicates synergy between the two drugs and above 1.1 indicates antagonism. Results: In the Ba/F3 p210BCR/ABL and Ba/F3 T315I cells, SNDX-275 alone had minimal activity up to 1 μM. In K562 and IR K562 cells SNDX-275 alone led to significant cytotoxicity with an IC50 of 0.662 μM and 0.495 μM respectively. In the IR cell lines, cotreatment with SNDX-275 enhanced the activity of both imatinib and dasatinib. For the IR K562 cells, imatinib plus SNDX275 was potently synergistic with a CI of 0.6234. Dasatinib plus SNDX275 treatment of IR K562 cells was additive with a CI of 1.1015 (figure 1). Similarly, in the Ba/F3 T315I cells imatinib plus SNDX275 resulted in synergistic activity (CI = 0.87) and additive activity when treated with dasatinib plus SNDX275 (CI = 0.97). On the contrary, cotreatment of non-IR cell lines with dasatinib or imatinib plus SNDX-275 did not result in synergistic activity and revealed evidence of antagonism. In the K562 cells, the combination of imatinib plus SNDX-275 was antagonistic with a CI of 1.308 (figure 1A). In the Ba/F3 p210BCR/ABL cells, the combination of dasatinib plus SNDX-275 was strikingly antagonistic with a CI of 2.9. Conclusions: BCR/ABL-independent mechanisms of resistance, including aberrant acetylation of histone and non-histone proteins secondary to the deregulation of HDACs, contribute to IR in patients with CML and Ph+ ALL. Our data support this hypothesis, as the HDAC inhibitor SNDX-275 enhances the activity of imatinib and, to a lesser extent, dasatinib in IR p210BCR/ABL expressing cell lines. Therefore, SNDX-275 may represent a novel therapeutic approach to patients with IR CML and Ph+ ALL, and a phase I clinical study is planned. In contrast, SNDX-275 may antagonize the activity of the tyrosine kinase inhibitors in nonresistant CML and Ph+ ALL. To our knowledge, this is the first report of antagonism between a HDAC inhibitor and tyrosine kinase inhibitors in CML. Further investigation is necessary to define the mechanism and clinical significance of this antagonism. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Atacicept (TACI-Ig) is a recombinant fusion protein that inhibits BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand), cytokines that are involved in B-cell homeostasis and immunoglobulin (Ig) expression and are overexpressed in B-cell malignancies. In vitro, atacicept decreases the survival of lymphoma cells and in vivo, atacicept decreases serum immunoglobulin levels. Based on its effects on B cells, atacicept may offer a novel treatment for B-cell malignancies. Methods: A Phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was performed. Atacicept was administered subcutaneously for 5 weeks in single weekly doses of 2, 4, 7, or 10 mg/kg to sequential patient cohorts. After 8 weeks, patients with responding or stable disease were eligible for treatment on an extension study at the dose previously received for up to 24 weeks or until disease progression. The primary study objective was evaluation of overall safety and the maximum tolerated dose. Pharmacokinetics and biomarkers were also investigated. Results: As of July 2006, 15 patients with relapsed and refractory diffuse large B-cell lymphoma (7), follicular lymphoma (4), small lymphocytic lymphoma/chronic lymphocytic leukemia (2), and mantle-cell lymphoma (2) received 2, 4, or 7 mg/kg atacicept (4 patients per dose cohort) or 10 mg/kg atacicept (3 patients). All patients were heavily pretreated (median number of previous treatments was 5, range 1–10) and 4 patients had previously received a stem cell transplant. All patients completed study treatment (5 doses), except 2 who withdrew due to disease progression after receiving 2 and 4 doses. Atacicept was well tolerated at all doses. The most common adverse events (AEs) that occurred in ≥20% of patients were fatigue (47%) and injection site bruising (20%). Three AEs with ≥ grade 3 severity were reported for 1 patient including pain in jaw, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Four SAEs considered unrelated to atacicept were reported for 2 patients who withdrew due to disease progression. Pharmacokinetic results were nonlinear and consistent with observations in other indications. Five weekly doses produced low to moderate accumulation of free total atacicept and atacicept/BLyS complex in serum. IgA, IgG, and IgM concentrations decreased in a dose-related pattern with a mean decrease of 15–40% from baseline after 4 weeks of atacicept. Peripheral B-cell numbers were variable and were difficult to evaluate due to low B-cell values at baseline in the majority of patients. At the 8-week evaluation, no objective responses were observed. Two patients had stable disease (1 with mantle cell lymphoma and 1 with follicular lymphoma) at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns. Both patients however later discontinued treatment due to disease progression. Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and demonstrated biological activity by decreasing Ig concentrations in this heavily pretreated cohort of patients with refractory B-cell lymphoma, although tumor responses were not observed.

Abstract Background. Transfusion of blood products is an integral component of the management of patients with acute leukemias. However, high-quality evidence and clinical trial data to support specific practices of blood product transfusion in this population are limited. We hypothesized that there is wide variation in blood product transfusion practices among providers in North America who manage patients with acute leukemia. Methods. A 30-question web-based survey about transfusion practices was emailed to members of the Eastern Cooperative Oncology Group (ECOG)-ACRIN Cancer Research Group, Alliance for Clinical Trials in Oncology (Alliance), and the Southwest Oncology Group (SWOG), and the Cancer Trials Support Unit (CTSU) on 7/6/2015 with 4 subsequent weekly reminders. The distribution list included 9,859 recipients, of whom at least 741 were providers who treated patients with acute leukemia. Responses were anonymous, and the survey distribution was approved by the respective cooperative group chairs. Descriptive statistics were used to analyze the data. Results. Of 254 responses received, 113 were excluded as they were returned by recipients not directly treating patients with acute leukemia. Another 30 responses were excluded due to incomplete data, leaving 111 responses (43.7%) eligible for the primary analysis. Of those, 109 responders were from North America representing 83 institutions in 33 states and the province of Ontario. Eighty-four of the included responders (75.7%) were physicians, and 44 (39.6%) were females. Median age of responders was 44 years (range, 26-76). A hemoglobin (Hb) level of ≤7 g/dL was the most commonly used threshold (44%) for red blood cell (RBCs) transfusions to asymptomatic stable hospitalized patients, followed closely by 8 g/dL (38%) (Figure 1). In the outpatient setting, the most commonly reported threshold was 8 gm/dL (49%) (Figure 1). Most providers reported that they "always" use leukocyte-reduced (93%) and irradiated (79%) RBCs. A platelet level of 10,000/µL was the threshold for platelet transfusions in the stable non-bleeding hospitalized patients cited by the majority of responders (76%) (Figure 2). This platelet level remained the most common threshold for platelet transfusions for non-bleeding patients in the outpatient setting (49%), although 31% of responders reported a higher threshold of 20,000/µL. A preference for single-donor apheresis platelets was reported by 81% respondents, and 57% use these products exclusively. Most providers (70%) reported always using irradiated platelets. With respect to cryoprecipitate and plasma infusions, nearly half of the respondents reported a threshold fibrinogen level of 100 mg/dL as a trigger for administering a product to a stable non-bleeding patient (Figure 3). The most commonly reported platelet threshold for performing a bone marrow biopsy (BMB) was 10,000/μL (69% of responders), followed by 20,000 (21%), 50,000 (6%), and 30,000 (4%). Therapeutic anticoagulation was held by most responders (80%) before performing a BMB. Most responders (73%) reported a platelet level of 50,000/µL as the lowest level for performing a lumbar puncture (LP) without prophylactic platelet transfusion. Conclusions. This survey demonstrates wide variability in blood product transfusion patterns among providers who treat patients with acute leukemias. A platelet level of 10,000/µL is the most common trigger for platelet transfusions for stable non-bleeding patients in both inpatient and outpatient settings. This, along with a platelet threshold of 50,000/µL for performing an LP, appear to be most widely accepted practices. Our findings emphasize the need to obtain high-quality data to develop consensus evidence-based guidelines for transfusion practices in acute leukemia with the goal of limiting unnecessary transfusions without compromising patient outcomes. Figure 1. The most common reported hemoglobin level thresholds for red blood cell transfusions in the inpatient and outpatient settings. Figure 1. The most common reported hemoglobin level thresholds for red blood cell transfusions in the inpatient and outpatient settings. Figure 2. The most common reported platelet level thresholds for platelet transfusions in the inpatient and outpatient settings. Figure 2. The most common reported platelet level thresholds for platelet transfusions in the inpatient and outpatient settings. Figure 3. The most common reported fibrinogen level thresholds for cryoprecipitate or plasma transfusions in the inpatient and outpatient settings. Figure 3. The most common reported fibrinogen level thresholds for cryoprecipitate or plasma transfusions in the inpatient and outpatient settings. Disclosures Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Onconova: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Prebet:CELGENE: Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding. Stone:Merck: Consultancy; AROG: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Novartis: Research Funding; Juno: Consultancy; Amgen: Consultancy; Roche/Genetech: Consultancy; Celator: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy. Erba:GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; Millennium/Takeda; Celator; Astellas: Research Funding; Seattle Genetics; Amgen: Consultancy, Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Barbarotta:Celgene, BMS, Novartis: Speakers Bureau. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract Background Denintuzumab mafodotin (SGN-CD19A) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. CD19 is a B cell-specific marker that is expressed in nearly all patients (pts) with B-lineage acute leukemia or lymphoma. Methods A phase 1 dose-escalation study is ongoing to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of denintuzumab mafodotin in pts with relapsed or refractory (R/R) B-ALL, B-cell lymphoma (B-LBL), or Burkitt leukemia/lymphoma (NCT 01786096). Eligible pts are ≥1 year of age and are R/R to ≥1 prior systemic regimen; patients with Philadelphia chromosome-positive (Ph+) disease must have failed a 2nd-generation TKI. A modified continual reassessment method was used for dose allocation and maximum tolerated dose (MTD) estimation. The study evaluated 2 dosing schedules: first weekly (Days 1 and 8 of 21-day cycles) and then once every 3 weeks (q3wk). This report presents data from the adult subset of pts in the study (≥18 years). Results To date, 71 adult pts with R/R B-ALL (n=59), B-LBL (n=6) or Burkitt leukemia/lymphoma (n=6) have been treated; median age is 45 years (range 18−77). Pts received a median of 2 prior therapies (range 1−8); 20 pts (28%) had prior allogeneic stem cell transplant. On the weekly schedule (0.3−3 mg/kg), 40 pts received a median of 2 cycles (range 1−27); 2 pts remain on treatment. On the q3wk schedule (4−6 mg/kg), 31 pts received a median of 3 cycles (range 1−6); 4 pts remain on treatment. An MTD was identified at 5 mg/kg q3wk and was not reached with weekly dosing. Best clinical responses to date for pts with B-ALL are summarized below: Table 1.Response category per Cheson 2003Efficacy-evaluable adult pts with B-ALLweekly dosing, N=32 n (%)q3wk dosing, N=23 n (%)Complete remission (CR)6 (19)3 (13)CR with incomplete platelet recovery (CRp)−3 (13)CR with incomplete blood recovery (CRi)−2 (9)Partial remission (PR)1 (3)−Resistant disease with clinical benefit15 (47)12 (52)Resistant disease without clinical benefit2 (6)-Progression8 (25)3 (13)CRc (CR+CRi+CRp), % (95% CI)19% (95% CI 7, 36)35% (95% CI 16, 57) In the q3wk schedule, the CRc rate was similar at 4, 5, and 6 mg/kg. The median duration of response across schedules is currently 27 weeks (95% CI 7, −). Of 12 pts with CRc and available minimal residual disease (MRD) assessment, 7 were MRD negative. 3 patients with MRD-negative CRs have been in remission for >1 year, 2 of whom have been on continuous treatment for 19 and 22 months. In the subset of pts with Ph+ B-ALL, 4 of 8 pts achieved CR and 1 pt a PR. In 6 pts with Burkitt leukemia/lymphoma, 1 achieved a CR. In 6 pts with B-LBL, objective responses were 1 CR and 2 PR. The adverse event (AE) profiles were similar across both dosing schedules; the most frequently reported AEs were pyrexia (54%), nausea (52%), fatigue (51%), headache (44%), chills (38%), vomiting (37%), blurred vision (35%), and anemia (34%). Ocular symptoms and corneal exam findings consistent with superficial microcystic keratopathy were observed in 40 pts (56%); symptoms were less severe than the associated corneal exam findings. Keratopathy was managed with topical steroids and dose modifications, and improved/resolved within a median of ~3 wks (range 1-17) in pts with sufficient follow-up. ADC exposures increased with dose, and in leukemia patients, target-mediated disposition was observed that diminished with higher doses in the q3wk schedule. Post treatment, flow cytometry data demonstrate that unbound CD19 on peripheral blasts inversely correlates with ADC concentration in circulation, and is present in the majority of evaluable patients at the end of the q3wk cycle. Conclusions Denintuzumab mafodotin is generally well tolerated and demonstrates activity in heavily pretreated adult pts with B-ALL and B-lineage highly aggressive lymphomas, including durable MRD-negative responses. The results of this trial indicate that the q3wk schedule, with a CRc rate of 35% in B-ALL, warrants further clinical investigation. Based on the encouraging responses observed to date in Ph+ B-ALL (CRs in 4 of 8 pts), an expansion cohort of these pts is currently enrolling on the q3wk schedule. Disclosures Fathi: Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use.. Borate:Seattle Genetics: Research Funding; Genoptix: Consultancy; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. DeAngelo:Agios: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. O'Brien:Seattle Genetics, Inc.: Research Funding. Trippett:OSI Pharmaceuticals: Research Funding; Seattle Genetics, Inc.: Research Funding. Shah:NCCN: Consultancy; SWOG: Consultancy; Seattle Genetics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Plexus Communications: Honoraria; Spectrum: Speakers Bureau. Hale:Seattle Genetics, Inc.: Research Funding; Hyundai: Research Funding; V Foundation: Research Funding. Silverman:Seattle Genetics, Inc.: Research Funding. Pauly:Seattle Genetics, Inc.: Research Funding. Kim:Bayer: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Eli Lilly: Consultancy. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Huang:Seattle Genetics, Inc.: Employment, Equity Ownership. Pan:Seattle Genetics, Inc.: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau.

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin’s lymphoma (NHL) comprising 3 molecular subtypes: germinal center B-cell (GCB), activated B-cell (ABC) and class III. ABC patients (pts) have a poor prognosis. The immunomodulatory drug lenalidomide (Len) produces durable responses in pts with aggressive NHL (Witzig 2011), with preferential activity reported in non-GCB DLBCL (Hernandez-Ilizaliturri 2011). Methods: This randomized, multicenter, open-label, phase 2/3 study was conducted to determine the efficacy and safety of single-agent Len vs single-agent investigator’s choice (IC) in relapsed/refractory DLBCL pts who received ≥2 prior therapies, or were ineligible for stem cell transplantation or further combination chemotherapy. DLBCL subtype (GCB vs non-GCB) was determined by a central pathology lab using immunohistochemistry (IHC) per the Hans method (Hans 2004). Pts were stratified by subtype, then randomized 1:1 to receive Len (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin) until progressive disease (PD), unacceptable toxicity, or voluntary withdrawal. In the event of radiologically confirmed PD, pts in the IC arm were allowed to cross over to Len. The primary endpoint for Stage 1 was overall response rate (ORR), as determined by an Independent Response Assessment Committee. Progression-free survival (PFS), overall survival (OS) and subtype analysis using gene expression profiling (GEP) were exploratory endpoints. Concordance of GEP and IHC was evaluated from 3 separate laboratories. Results: IHC subtyping agreement rate among the 3 laboratories ranged from 87.5%-97.9%, and sensitivity of IHC to detect ABC or GCB subtypes vs GEP ranged from 92.3%-100.0%. By IHC, 102 DLBCL pts (GCB, n=48; non-GCB, n=54) were treated with ≥1 dose of Len or IC (modified intent-to-treat population) in Stage 1. In this heavily pretreated population, >90.0% of pts received ≥2 prior systemic chemotherapies; 25 pts in Len and 32 pts in IC received ≥3 prior systemic chemotherapy regimens. Median age was 65 y in the IC arm vs 69 y in the Len arm. Twenty-nine pts crossed over from IC to Len after confirmed PD. All pts, regardless of subtype or therapy group, experienced ≥1 treatment-emergent adverse event, with neutropenia, anemia, and thrombocytopenia being the most common. Efficacy data are presented in the Table. Pts with GCB or non-GCB DLBCL (per IHC) treated with Len had similar ORR, but the data suggested greater improvements in PFS and OS with Len vs IC in the non-GCB pts. In an exploratory analysis of pts subtyped by GEP, ABC pts treated with Len vs IC-treated showed greater improvements in ORR, PFS, and OS compared with GCB pts. Prespecified criterion to advance to Stage 2 was a 2-sided 15% significance level in ORR in favor of Len based on IHC-defined subtype. The data did not fulfill this requirement, and Stage 2 was not opened. Conclusion: Len monotherapy showed clinical activity in heavily pretreated pts with DLBCL. The data suggest improved ORR, PFS, and OS with Len vs IC in the non-GCB population as defined by IHC, and the difference appears to be more pronounced in the ABC population as defined by GEP. Subtyping by GEP is warranted in further studies of Len in DLBCL. Abstract 628. Table 1.Table. Efficacy DataBy IHCBy GEPOverallGCBNon-GCBGCBABCLen(n=51)IC(n=51)Len(n=23)IC(n=25)Len(n=28)IC(n=26)Len(n=14)IC(n=16)Len(n=11)IC(n=16)ORR, % (95% CI)27.5 (15.9-41.7)11.8 (4.4-23.9) 26.1 (10.2-48.4)12.0 (2.5-31.2)28.6 (13.2-48.7)11.5 (2.4-30.2)21.4 (4.7-50.8)12.5 (1.6-38.3)45.5 (16.7-76.6)18.8 (4.0-45.6)P Value .079 .279 .179 .642 .206PFS, med wk (95% CI)13.6 (8.6-17.7)7.9 (6.3-9.0) 10.1 (8.3-22.3)29.0 (6.3-20.6)15.1 (8.3-24.1)7.1 (5.3-8.4)13.2 (8.3-24.9)7.1 (6.0-20.6)82.0 (7.3-NA)6.2 (4.3-10.1)P Value .041 .550 .021 .506 .105HR (95% CI) 0.64 (0.41-0.99) 0.82 (0.43-1.57) 0.50 (0.27-0.92) 0.77 (0.35-1.68) 0.44 (0.15-1.23)OS, med wk (95% CI)31.0 (16.6-41.3)24.6 (12.7-33.9) 30.0 (14.9-44.4)24.9 (13.7-58.3)32.3 (15.9-48.1)20.4 (10.3-33.9)30.0 (18.0-34.6)20.1 (13.7-36.9)108.4 (9.6-108.4)18.6 (6.6-48.0)P Value .673 .526 .253 .767 .144HR (95% CI) 0.91 (0.59-1.41) 1.23 (0.65-2.34) 0.70 (0.38-1.30) 1.12 (0.52-2.42) 0.47 (0.17-1.33) Abbreviations: CI, confidence interval; HR, hazard ratio; med, median; NA, not applicable/not available. Disclosures Czuczman: Celgene: Consultancy. Off Label Use: This abstract describes a clinical trial of lenalidomide, which is an orally-available immunomodulatory agent under investigation for treating patients with diffuse large B-cell lymphoma.. Davies:GlaxoSmithKlein: Research Funding; Hoffman La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Gascoyne:Celgene: Consultancy, Research Funding. Salles:Pfizer: Honoraria; Gilead: Honoraria; Jansen: Honoraria; Hoffman La Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Witzig:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Mundipharma: Honoraria; Pfizer: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Millennium Takeda: Honoraria; Celgene: Honoraria; Teva: Membership on an entity's Board of Directors or advisory committees. Wright:Celgene: Research Funding. Staudt:Celgene Corporation: Research Funding. Repici:Celgene: Employment. Song:Celgene: Employment. Manzke:Celgene: Employment.

Abstract Background Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells. Patients (pts) with SM are treated with recombinant interferon-alpha or cladribine. Responses to these agents are poor. Malignant mast cells in SM carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V) resulting in constitutively activated c-kit receptor tyrosine kinase believed to be important for disease progression. Agents that antagonize this mutated form of c-kit may have clinical benefit in SM. Dasatinib is one such agent, proven effective in pre-clinical in vitro and in vivo models of SM. Study Design In pilot Phase II trial for SM, Dasatinib was administered at 70mg PO BID. Response was assessed after minimum of 3 months (3 cycles) of therapy. Therapy was discontinued in pts who showed no response after 6 cycles of therapy. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). In addition, all symptoms related to SM were recorded and monitored. Results Thus far, a total of 30 pts have been treated; 24 are evaluable for response and toxicity, including 6 with aggressive SM (ASM), 4 with SM and associated hematologic non-mast cell disease (SM-AHNMD; 2 with chronic myelomonocytic leukemia and one each with myelofibrosis [SM-MF; JAK2 mutation positive and abnormal cytogenetics] and hypereosinophilic syndrome [SM-HES; FIP1L1-PDGFRa negative]) and 14 with indolent SM (ISM) with uncontrolled symptoms despite optimal supportive care measures. Median age is 57 years (range, 35–73); these were 10 males and 14 females; time from diagnosis to dasatinib therapy 49 months (range, 0–233), performance status 1 in 23 and 2 in 1 pt. Eleven patients were previously treated: imatinib mesylate in 6; denileukin diftitox in 4; and erythropoietin, interferon-alpha, or cladribine in 2 each. One pt, who had undergone splenectomy, had hepatomegaly prior to start of therapy. Median Hb 12.4g/dL (range, 8.5–15.4), WBC 6.7×109/L, (range, 3.5–53.3), and platelets 263×109/L (range, 60–377); no patient was transfusion dependent. Percent bone marrow mast cell varied from <10% in 9 pts, to 60% in 4 pts; blood tryptase level was ≤20ng/mL (not significant) in 7 pts and >200ng/mL (upper limit of the test) in 7 pts. A total of 94 cycles of therapy were administered. The median number of cycles was 4 (range, 1–8). Ten patients stopped therapy: 1 due to progression of AHNMD to acute leukemia, 1 lost a response (symptomatic improvement), 2 had no response after 3 months of therapy, and 6 due to toxicity. No grade 4 toxicity was observed. Twelve patients decreased the dose of dasatinib to 50mg PO BID, of which four to 40mg PO BID. Two patients (8%) achieved complete remission, one with SM-MF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). No significant response in % bone marrow mast cells (4 pts are too early in therapy) or blood tryptase levels have been observed in other patients so far. Symptoms related to SM improved significantly in 7 patients (29%). Conclusion Dasatinib is active in SM (overall response rate 37%). Updated clinical and molecular results will be presented.

Abstract Abstract 2738 Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin's lymphoma (NHL) with poor prognosis that necessitates the development of new treatments. Lenalidomide is a unique immunomodulatory agent with antiproliferative and tumoricidal effects on MCL cells. NHL-003 was a phase II, open-label, multicenter trial for subjects with relapsed aggressive NHL that tested single-agent lenalidomide 25 mg PO days 1–21 every 28 days. The primary endpoint was overall response rate (ORR); secondary endpoints included complete response (CR) rate, duration of response (DOR), survival, and safety. At the time of the initial publication (Witzig et al. Ann Oncol.2011;22:1622–1627), MCL subgroup analysis showed an ORR of 42%; the median DOR had not been reached. The purpose of this report is to provide long-term efficacy and safety results for the MCL subgroup from NHL-003. Results: Subjects with MCL (N=57) had a median age of 68 y (range, 33–82), were predominantly male (77%) with good ECOG performance status (89% PS 0–1) and advanced-stage disease (88% stage III/IV). Subjects had received a median of 3 (range, 1–13) prior systemic therapies. According to the current central review at a median follow-up of 12.4 mo, subjects achieved an ORR of 35% (CR/CRu 12%) following lenalidomide, including a median DOR of 16.3 mo (Table 1). The ORR to single-agent lenalidomide was 44% (CR/CRu 21%) by independent assessment, with a median DOR not yet reached. Median PFS was 8.8 mo by central review and 5.7 mo according to investigators. Subjects responded quickly, with a median time to first response of 1.9 mo (central and investigator). Median DOR for subjects in CR and overall survival for all subjects have not yet been reached. The most common grade 3/4 adverse events (AEs) were neutropenia (46%), thrombocytopenia (30%), fatigue (9%), and diarrhea (5%). Other AEs included one subject with grade 1 to 2 tumor flare reaction, one subject with grade 3 deep vein thrombosis, and two subjects with second primary malignancies suspected of being related to treatment (one grade 3 squamous cell carcinoma of the skin that resolved and one grade 4 AML in a heavily pretreated individual with 5 prior cancer therapies). Conclusions: This subset analysis from a phase II study further confirms the efficacy of lenalidomide in subjects with relapsed MCL. Responders have a long DOR with manageable side effects. These results support continued investigation of lenalidomide alone or in combination for the treatment of MCL. Disclosures: Zinzani: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Czuczman:Celgene: Consultancy, Consultant Celgene Advisory Board Other. Reeder:Celgene: Mayo Clinic receives funding from Celgene to support clinical trials Other, Research Funding. Haioun:Celgene: Celgene Advisory Board Consultant Other, Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pietronigro:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Li:Celgene: Employment. Witzig:Celgene: Research Funding.