Reeder, Craig B.

Abstract Abstract 863 Background: Patients with MM who have progressed after multiple novel agents have limited treatment options. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent. Pom/dex using a dose of 2 mg/day has demonstrated response rates (≥PR) of 63% in relapsed MM (Lacy, JCO 2009, 27:5008-5014) and 32% in a lenalidomide-refractory cohort (Lacy, Leukemia, in press). The maximum tolerated dose has been determined to be 4 mg/day for 21 of 28 days (Richardson, ASH, 2009), We opened two sequential phase II trials using the Pom/dex regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Methods: Patients refractory to both lenalidomide and bortezomib therapy; defined as relapsing on or within 60 days of stopping each regimen, were enrolled. Pomalidomide was given orally 2 mg daily (Cohort A) or 4mg daily (Cohort B) on days 1–28 of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis. Results: 35 patients with relapsed and resistant/refractory to both lenalidomide and bortezomib were enrolled in each cohort. The median age was 62 years (range, 39–77) in Cohort A and 61 (range, 45–77) years in Cohort B. The median time from diagnosis to enrollment was 57 months for Cohort A (range 12–249) and 72 months(range, 13–183) for Cohort B. 15 patients had high risk molecular markers in Cohort A and 16 in Cohort B. The median number of prior regimens was 6 in both groups. The median (range) duration on treatment was 5(1-13) and 2(0-6) cycles in cohorts A and B respectively. Toxicity at least possibly attributed to drug consisted primarily of myelosuppression: grade 3/4 neutropenia (37% Cohort A vs. 55% Cohort B); grade 3/4 thrombocytopenia (11% Cohort A vs. 13% Cohort B); and grade 3/4 anemia (9% Cohort A vs. 16% Cohort B). Grade 3/4 non-hematologic toxicities occurred in 23% Cohort A vs. 13% Cohort B. Grade 1 or 2 fatigue was the most common non-hematologic toxicity seen in 43% Cohort A vs. 52% Cohort B. Grade 1 or 2 neuropathy occurred in 17% Cohort A vs. 16% Cohort B. Other non-hematologic toxicities occurring in <5% included pneumonitis, hyperglycemia, renal failure, thrombosis. One patient in cohort B had grade 4 hepatitis. Confirmed responses in Cohort A consisted of VGPR 14%, PR 11%, and MR 24% (ORR 49%, 95% CI: 31–66), and responses in Cohort B consisted of VGPR 9%, PR 20%, and MR 12% (ORR 40%, 95% CI: 23–58). The median follow-up on alive patients was 7.5 months, and 3 months in Cohorts A and B, respectively. The median PFS in cohorts A and B are respectively 6.4 months (95% CI: 4.7-NR) and 3.3 months (95% CI: 2.3-NR). Conclusions: Pom/dex is remarkably active and well tolerated in this heavily pre-treated population of dual bortezomib/lenalidomide-refractory MM patients. The majority of patients have not progressed and objective responses (MR or better) are seen in 40–49%. This study confirms therapeutic benefit for Pom/dex in patients relapsing after other novel therapies. These studies do not show an advantage for the 4 mg/day on days 1–28 of each 28 day cycle did not show an advantage over the 2 mg/day on days 1–28 of each 28 day cycle. Disclosures: Lacy: Celgene: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Fonseca:Genzyme: Consultancy; Medtronic: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Otsuka: Consultancy; Celegene: Consultancy, Research Funding; Intellikine: Consultancy; Cylene: Research Funding; Onyx: Research Funding; FISH probes prognostication in myeloma: Patents & Royalties. Bergsagel:Celgene: Consultancy; Centocor: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Stewart:Celgene: Honoraria.

Abstract Abstract 3963 Background: Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with relapsed multiple myeloma (MM). Between November 2007 and November 2010, we opened 5 sequential phase 2 trials using the pomalidomide at differing doses with weekly dexamethasone (Pom/dex) regimen to study the efficacy of this regimen. Methods: The five cohorts consisted of: Cohort 1 (N=60): relapsed MM with 1–3 prior regimens, 2 mg dose; Cohort 2 (N=34): lenalidomide refractory, 2 mg dose; Cohort 3 (N=35): bortezomib/lenalidomide refractory, 2 mg dose; Cohort 4 (N=35): bortezomib/lenalidomide refractory, 4 mg dose; and Cohort 5 (N=60) lenalidomide refractory, 1–3 prior regimens, 4 mg dose. Pomalidomide was given orally 2 mg daily or 4mg daily on days 1–28 of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis or full dose anticoagulation. Results: A total of 225 patients were enrolled across all 5 cohorts. One patient was ineligible and excluded from analysis. The median age was 63 years (32.0–88.0). The median time since diagnosis was 53 months. Forty percent had high-risk molecular markers. Eighty-nine percent had received previous IMIDs including thalidomide (53%) and lenalidomide (81%). Sixty-two percent had previous bortezomib and 73% had prior transplant. The median follow-up is 12.6 months, but varies from 9.4 months for the most recent cohort to 30 months for the first cohort. Sixty-nine percent are alive and 30% remain progression free. Toxicities ≥ grade 3 are shown in table 1 and patient outcomes are shown in Table 2. Conclusions: Pom/dex is remarkably active and well tolerated even in heavily pretreated patients. Responses are durable. Response rates and toxicity are similar between the 2 mg and 4 mg doses. Disclosures: Lacy: Celgene: Research Funding. Fonseca:Consulting:Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Abstract Abstract 229 Introduction: Optimal rational combination targets with Cytarabine (AraC) have not been identified. After the development of a high-throughput, small-interfering RNA (siRNA) platform for suspension cells, we performed the first RNAi sensitizer screen of the human kinome with AraC in myeloid cell lines. Herein we present the final data of this first siRNA-sensitizer screen in leukemias in combination with AraC. Our results include full validation of the selected targets as well as ex vivo data assessing the first in class clinically tested WEE1 inhibitor MK1775 with AraC providing a pre-clinical rationale for using the combination of AraC with WEE1 inhibitors in leukemias. RNAi Screens and siRNA Validation: In siRNA sensitizer screens, we silenced 572 kinases of the human kinome in combination with AraC. Few kinases strongly sensitized to AraC and the targets CHEK1 and the WEE1 related kinase PKMYT1 emerged as the most potent genes whose silencing sensitized leukemia cells to AraC. In secondary siRNA validation experiments, silencing of WEE1 kinase was found to be more potent than silencing of CHEK1, PKMYT1 or other kinases (i.e. ATR, BRCA, AURKB) in combination with AraC treatment. Importantly, the sensitizing activity observed with WEE1 inhibition was universal across all AML cell lines examined, whereas it was not for CHEK1 inhibition. siRNA assays were robust, exhibiting little (<10%) non-specific toxicity and siRNA silencing was specific for individual genes (i.e. WEE1 or CHEK1) as demonstrated by selective reduction of mRNA and protein level for the respective genes; confirming the validity of the siRNA assay. Pharmacological WEE1 Inhibitor Experiments In vitro and Ex vivo: In vitro treatment of eight AML, ALL and CML cell lines with commercial and the first clinically developed WEE1 kinase inhibitor MK1775, demonstrated strong sensitization to AraC up to 97-fold in individual cell lines. Ex vivo, MK1775 substantially reduced viability in 13 of 14 AML, MDS and CML patient samples compared to AraC alone. The optimal dose to achieve maximum sensitization was observed for AraC between ∼10–120 nM and for MK1775 between 200–400 nM. Synergy at these optimal concentrations was confirmed in all ex vivo samples tested for which sufficient data for analysis with CalcuSyn Software was available (n=7): with Combination Indices (CI) ranging from 0.21–0.45. At higher AraC and MK1775 concentrations antagonism was observed both ex vivo and in vitro. Thus, we have also established optimal suggested concentration dose ranges for the currently ongoing design of a clinical trial. Clinically relevant, WEE1 is expressed in primary AML, ALL and advanced CML specimens with a trend towards higher expression in relapsed samples. However, there was no direct correlation with WEE1 mRNA expression or TP53 status. Our initial in vitro experiments further suggest that inhibition of WEE1 with MK1775 in combination with AraC at optimal concentrations was associated with higher degree of caspase 3 cleavage, DNA damage induction as measured by gamma-H2AX, and greatest inhibition of proliferation. Thereby establishing a context of optimal drug concentration ranges with molecular correlates and anti-leukemic activity directly informing design of the clinical trial and correlative biomarkers. In conclusion, data from this first siRNA sensitizer screen of the kinome in leukemias identifies inhibition of WEE1 kinase as the most potent sensitizing target to AraC. Inhibiting WEE1 with pharmacological inhibitors in combination with AraC is a rational treatment strategy for myeloid and lymphoid leukemias that warrants clinical investigation. Furthermore, our RNAi loss-of-function genomics approach has high potential to rapidly identify and validate crucial genes whose inhibition modulate the response to cytotoxic agents. Establishment of the siRNA sensitizer platform allows accelerating the development of new rational combinations for leukemia therapy. Disclosures: Off Label Use: AraC in combination with the experimental Wee1 inhibitor MK1775. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding. Demuth:Merck and CO: Employment.

Abstract Abstract 2477 Background: Aurora A kinase (AAK) is a key mitotic regulator, inhibition of which results in mitotic spindle defects, mitotic delay, and apoptosis. AAK is amplified or overexpressed in a number of heme-lymphatic malignancies. This phase 1, multicenter study (NCT00697346) is the first to assess safety, tolerability, and pharmacokinetics (PK) of the investigational AAK inhibitor alisertib (MLN8237) in patients with advanced hematologic malignancies. Methods: Patients aged ≥18 years with relapsed/refractory hematologic malignancy, confirmed radiographically or clinically evaluable disease, and ECOG performance status 0–2, were eligible for inclusion. Patients with prior allogeneic transplant were excluded; there was no restriction on the number of prior therapies. Patients received escalating doses (standard 3+3 design) of alisertib as either a powder-in-capsule (PIC) or enteric coated tablet (ECT) formulation. Alisertib PIC was administered as a twice-daily (BID) loading dose on Day 1, then once daily (QD) on Days 2–14 or 2–21, followed by 14 or 7 days' rest, respectively, in 28-day cycles. Alisertib ECT administration followed the same scheme in the first dose group, and subsequent groups received divided (BID) doses for 7 days plus 14 days' rest in 21-day cycles. Endpoints included maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, PK, and response. Results: 55 patients were included (PIC n=28, ECT n=27); median age was 61 years (range 27–82), 42% had prior ASCT, and 78% had received ≥3 prior therapies. 60% of patients had non-Hodgkin's lymphoma, 35% multiple myeloma, and 5% chronic lymphocytic leukemia/small lymphocytic lymphoma. Patients received a median of 2 cycles (range 1–14); 8 patients are ongoing. The MTD on the alisertib PIC 14-day + 14 days' rest schedule was 45 mg QD, established following occurrence of DLTs in four patients at higher dose levels: Gr 4 thrombocytopenia, Gr 4 neutropenia (65 mg QD); Gr 3 febrile neutropenia, Gr 4 thrombocytopenia (90 mg QD). In patients receiving alisertib ECT, the MTD was determined as 50 mg BID on a 7-day + 14 days' rest schedule; four DLTs were observed in three patients: at 40 mg QD for 14 days, one patient had Gr 4 febrile neutropenia, and one patient had Gr 4 bullous dermatitis and Gr 4 neutropenia; at 50 mg BID for 7 days, one of nine patients had Gr 4 neutropenia. The most common drug-related adverse events (AEs) were neutropenia (PIC 46%, ECT 63%), thrombocytopenia (39%, 41%), and diarrhea (29%, 41%); most common Gr ≥3 drug-related AEs were neutropenia (PIC 36%, ECT 52%), thrombocytopenia (29%, 26%), and anemia (14%, 26%). 24 patients (PIC n=12, ECT n=12) had serious AEs; the most common was febrile neutropenia (PIC n=1, ECT n=4). Tolerability appeared generally similar between the PIC and ECT formulations. Six patients (PIC n=3, ECT n=3) died during the study (PIC: renal failure, airway obstruction, progressive large cell lymphoma; ECT: progressive myeloma [n=2], hypercalcemia); no deaths were considered to be related to alisertib. Alisertib absorption was rapid with an overall median Tmax of 2 hours. The overall mean terminal half-life following multiple dosing was 19 hours. The mean peak/trough (P/T) ratio was 5 following QD dosing as PIC. The mean accumulation ratio and P/T ratio were 2.5 and 2.1, respectively, following BID dosing as ECT. At data cut-off (29 March, 2011), 42 patients were evaluable for response. Antitumor activity was observed in five patients (PIC n=3, ECT n=2) who had partial responses; 11 patients had a best response of stable disease (PIC n=6, ECT n=5) and 26 had progressive disease (PIC n=14, ECT n=12). Seven patients received ≥5 cycles of therapy, including one patient (PIC group; post-transplant grade 3B follicular lymphoma) with resolution of B symptoms who received alisertib for >1 year. Conclusions: The MTDs of the PIC and ECT formulations of alisertib are 45 mg QD for 14 days (+14 days' rest) and 50 mg BID for 7 days (+ 14 days' rest), respectively, in patients with advanced, non-leukemic hematologic malignancies. AEs were generally manageable and were consistent with inhibition of AAK in highly proliferative tissues (gastrointestinal and hematologic AEs). Current data support further investigation and expansion at the MTDs is ongoing. Data from PK, safety, and tolerability collectively support the progression of ECT formulation at 50 mg BID for 7 days in a 21-day cycle into phase 2 development. Disclosures: Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies and solid tumors. Goy:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Reeder:Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding; Celgene: Institutional research funding. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Danaee:Millennium Pharmaceuticals, Inc.: Employment. Xiao:Millennium Pharmaceuticals, Inc.: Employment. Benaim:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Shea:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

Abstract Abstract 987 Background: IMiD® compounds are effective in immunoglobulin light-chain amyloidosis (AL), a systemic plasma cell disorder related to multiple myeloma (MM). Pomalidomide is a new IMiD® compound. Methods: Persons with symptomatic, biopsy-proved, previously-treated AL were eligible for treatment with pomalidomide if they had measurable hematologic disease, ECOG PS≥2, adequate hematologic reserve and creatinine ≤2.5 mg/dL. Pomalidomide, 2 mg/d, and dexamethasone, 40 mg/w, were given orally along with low-dose aspirin. Dose-escalation to 4 mg/d was allowed for non-responders. Exclusion-criteria were uncontrolled infection, cancer, NYHA classification >II, serum troponin-T >0.1 ng/mL, ≥grade-3 neuropathy, thrombosis or other AL therapy within 2 weeks of enrollment. 31 subjects enrolled, but only 29 are evaluble for toxicity and response due to recent enrollment. Results: Median age was 66 y (range, 52 82 y); 19 were male. Median time from diagnosis to study-entry was 36 mo (range, 0.9–104.1 mo). 24 had cardiac involvement, 10, renal involvement and 8, nerve involvement. Cardiac biomarker staging was: I, N=3, II, 21, and III, N=7. Subjects were extensively pretreated: 28 received an alkylator (including an autotransplant in 13), 15, prior lenalidomide or thalidomide and 12, prior bortezomib. 193 cycles of pomalidomide were given to 29 subjects. 11 subjects had protocol-specified dose-increases (no response) and 16, dose-reductions (AEs). 20 subjects had dexamethasone dose-reductions. ≥Grade-3 AE's ≥possibly attributed to therapy occurred in 21 subjects. 7 of these subjects had only hematologic AE's. Neutropenia was the most common severe AE (N=10); severe thrombocytopenia occurred in 2 subjects. Other grade-3/-4 AEs included infection/fever (N=3); fatigue (N=4), and pleural effusion, ascites/edema, and edema each in one patient. 1 subject each had dyspnea, increased creatinine, thrombosis, muscle weakness, atrial tachycardia, and diarrhea. There were 2 episodes of syncope attributed to AL rather than therapy. A subject died 5 d after beginning therapy presumably from cardiac AL. As of 7/27/010, median time on-study is 8.4 mo (range, 0.2–16.2 mo). 18 subjects discontinued therapy for: progression/death (N=9); consent withdrawal (N=4), AE (N=3) and physician choice (N=2). Overall hematologic response rate (N=29) is 38% (95% CI, 20–58%) There were 8 PRs and 3 VGPRs including 4 PRs and 2 VGPRs among 14 subjects failing prior lenalidomide and/or thalidomide. 3 subjects had confirmed organ responses (2 heart and 1 kidney) and 4 unconfirmed organ responses. 1 y survival and PFS are 77% (95% CI, 60–98) and 56% (95% CI, 36–85). Conclusion: These data suggest that pomalidomide could provide a safe and effective therapy in previously-treated persons with AL including those failing lenalidomide and/or thalidomide. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Off Label Use: Non-FDA approved indication. Gertz:Celgene: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy. Bergsagel:Celgene: Consultancy; Centocor: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Stewart:Millennium: Consultancy; Celgene: Honoraria. Lacy:Celgene: Research Funding.

Abstract Abstract 1749 BACKGROUND: We have previously reported that transformation of a myeloproliferative neoplasm (MPN) to acute leukemia or blast phase (MPN-BP) is accompanied by a median survival of 2.6 months (range 0–24.2 months) (Mesa et. al. Blood 2005) despite treatment. Allogeneic stem cell transplantation (ASCT) offers a potential for cure. We reviewed 13 patients with MPN – BP who were candidates for ASCT, and 8 of those patients received ASCT after induction chemotherapy. METHODS: Retrospective analysis of individuals who had a clear antecedent myeloproliferative neoplasm (essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) (either primary (PMF) or post ET/PV)), transformed to MPN-BP, and were candidates for ASCT. Clinical characteristics at each phase of illness, therapy at each phase of illness, and outcome of ASCT were assessed. RESULTS: Patients (MPN details): Thirteen patients (8 male, 5 female, median age at diagnosis of MPN 42 years in those who underwent ASCT and 64 years in those who did not receive ASCT (combined median 53 years, range 26–70)) were identified who met the inclusion criteria, of whom 2 had ET, 4 PV, 2 Post-ET MF, 1 Post-PV MF and 4 PMF. Jak2-V617F mutation was present in 7 of 8 patients tested. Treatments used during the MPN phase included hydroxyurea in 9 (+ busulfan in 1 and + anagrelide in 1), and thalidomide/prednisone in 2 (two patients received no treatment prior to MPN-BP). Patients (MPN-BP details): Transformation of an MPN to blast phase (from diagnosis of MPN) occurred after a median of 11 years in those who underwent ASCT and 8 years in non-ASCT (range 3 months to 30 years). At the time of MPN-BP diagnosis, 9 patients had an abnormal karyotype, 3 with complex karyotypes, 3 with trisomy 8 (sole abnormality), 1 with del(7q), 1 with del(13q). Leukemic induction consisted of standard anthracycline/cytarabine combination therapy (+/− etoposide), except for one patient received a study medication voreloxin. One patient who did not receive ASCT had remission after induction, but later expired from relapse, two expired soon after leukemic transformation, and two were too ill to receive induction. In the ASCT group (N=8), 5 patients achieved complete remission (CR) of their leukemia/return to MPN chronic phase (one of the five patients required a second induction to achieve CR), while 3 patients were considered primary induction failures due to persistence of > 5% blasts in the blood (2) or marrow (1) at the time of pre-transplant response assessment. The median time from diagnosis of MPN-BP to ASCT was 128 days. ASCT Details and Outcomes: Patients (median age of 55 years at time of ASCT; range 44–73) underwent ASCT (all HLA identical, 3 matched unrelated donors, 5 matched sibling donors) with either reduced intensity conditioning (n=6) or fully myeloablative conditioning (n=2). After a median follow-up of 488 days (range 127 – 1206), 6 of 8 patients are alive and free of disease. MPN-BP recurred in two patients at day 69 and 77 post-transplant; both patients eventually died of progressive leukemia, one after a second transplant. Acute GVHD occurred in 3 patients (1 grade III, 2 grade II), and chronic GVHD in 4 (2 mild, 2 moderate). All five patients who achieved CR (marrow and PB blasts < 5%) after induction therapy remain in continuous CR, while 2 of the 3 patients with evidence of persistent leukemia relapsed and died of MPN-BP. No patient died of transplant-related causes and all patients engrafted promptly. CONCLUSION: Rapid induction followed by ASCT can offer a curative path for individuals with MPN-BP. Although limited by small numbers, our data suggest that leukemic clearance (marrow blast percentage < 5%) prior to ASCT is associated with improved outcome. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Abstract Abstract 1977 Introduction: Transplant options are limited for adult patients (pts) who lack a fully matched related or unrelated donor. We hypothesized that in-vivo T-cell depletion with r-ATG would allow safe allo-SCT from mismatched, unrelated donors, thus expanding the potential donor pool for pts with hematologic malignancies who require allo-SCT. Patients and Methods: Thirty seven adult pts (age 20 – 70, median 45) underwent a first unrelated, mismatched, allo-SCT between 1/1/2006 and 6/30/2011 at Mayo Clinic Arizona for hematologic malignancy (35 PBSC, 2 marrow). All pts had at least a one allele or one antigen mismatch (MM) at HLA-A, -B, -C, or -DRB1, and all except one pt received r-ATG as part of the GVHD prophylaxis strategy (dose range 2.5 – 10 mg/kg in daily dose of 2.5 mg/kg depending on degree of mismatch, with the last dose generally given on day −1). One pt received Campath after experiencing anaphylaxis to r-ATG. Pts were transplanted for acute myeloid leukemia (n = 19; 10 CR1, 6 CR2, 3 other), acute lymphoblastic leukemia (n = 8; 4 CR1, 4 CR>/= 2), chronic myeloid leukemia (n = 1), myelodysplastic syndrome (n = 5), or non-Hodgkin lymphoma (n = 4). Conditioning was myeloablative in 20, reduced intensity in 16, and non-myeloablative in 1. Mismatches were as follows: 1-allele MM (n = 7); 1 antigen MM (n = 15); 2 allele MM (n = 4); 1 antigen, 1 allele MM (n = 7); and 2 antigen MM (n = 4). Additional GVHD prophylaxis included tacrolimus plus either methotrexate (n =21), mycophenolate mofetil (n = 14), or other (n = 2). Results: The median follow-up for surviving pts is 12 months. As of 6/30/11, 31 pts were alive, and 6 had died of the following causes: multiorgan failure (n = 1), relapse (n = 3), and veno-occlusive disease (n = 2). To date, there have been no deaths related to acute or chronic GVHD. The 1- and 2-year estimated rates of overall survival are 84.5%/78.8% (Fig. 1); of progression-free survival 79.7%/72.0%. The estimated rate of relapse at 1 and 2 years is 11.8%/18.7%, and of non-relapse mortality 8.1%/10.5%. Four pts (10.8%) have developed severe (grades III-IV) acute GVHD by day 100 (days 19, 27, 30, 43; one pt after withdrawal of prograf due to transplant-associated microangiopathy). No late onset severe acute GVHD has been seen. Moderate to severe NIH-defined chronic GVHD occurred in a single pt at risk (cumulative incidence estimate 2.4% at 1 year, 4.7% at 2 years; Fig. 2). Four pts have reactivated EBV, with one developing PTLD (all have been treated with Rituximab). CMV reactivation was seen in 24 pts (65%), CMV disease in 4, with no deaths directly related to CMV. Conclusions: In vivo T-cell depletion with r-ATG abrogates severe acute and chronic GVHD, and allows use of mismatched unrelated donors for allo-SCT in adult pts with otherwise incurable hematologic malignancies. Long-term survivors are generally free of severe chronic GVHD, with good quality of life. There does not appear to be an increased incidence of disease relapse, and non-relapse mortality is low. This approach is safe, effective, and considerably expands the donor pool for adult pts who require allo-SCT. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Abstract Background WM remains an incurable cancer despite recent advances. While a phase II trial has demonstrated efficacy of dexamethasone, rituximab and cyclophosphamide (DRC) in the treatment-naïve (TN) patients, this regimen has not been studied systematically in the relapsed/refractory (R/R) setting. Recent data has suggested the MYD88mutation status in WM patients can serve as a predictive marker with therapies such as ibrutinib. We examined the efficacy and tolerability of up to 6 cycles of DRC, with focus on R/R population and activity of this regimen with respect to the patients' MYD88L265Pstatus. Methods Records of WM patients seen consecutively at Mayo Clinic campuses in Rochester, Arizona and Florida from 01/2007 to 12/2014 were reviewed. MYD88L265P status, as assessed by AS-PCR, was recorded when available. Data obtained from symptomatic patients treated with DRC (dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5) were analyzed. Time-to-event analyses were performed from DRC therapy using the Kaplan-Meier method. We used the Consensus response criteria (6th International Workshop). Results Of 100 symptomatic patients who received DRC, 50 had R/R WM (40% refractory) and 50 were TN. Table 1 shows the patients' baseline characteristics. In the R/R population, DRC was 2nd line (range 2-8) therapy in 58% of patients. The median IgM levels declined from 3,870 mg/dL to 1,846 mg/dL (p=0.0001) at best response. Median follow-up from DRC was 51 months (95% CI: 38-55). The median time-to-best response was 6.8 (0.5-28) months. Overall response rate (ORR) was 87% [VGPR 4%, PR 64%, MR 19%]. Four patients (9%) achieved SD and 2 patients (4%) had PD. Of the sixteen deaths (32%) noted at time of analysis, 11 were related to progressive disease. The median disease-specific survival (DSS) from DRC was not reached (NR) (95% CI: NR-NR). The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 months (95% CI: 15-51) and 50 months (95% CI: 35-60), respectively. In contrast, in the TN patients the median IgM levels declined from 4,130 mg/dL to 1,250 mg/dL (p=0.0001) at best response; median time to best response was 11 (0.6-47) months; median follow-up from DRC was 30 months (95% CI: 21-36). ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. Of the 7 deaths (14%) at time of analysis, 4 were related to WM progression. Median DSS from DRC was NR (95% CI: NR-NR); median PFS and TTNT were 34 months (95% CI: 23-NR) and NR (95% CI: 37-NR), respectively. Among 29 genotyped patients in whom MYD88 mutation status was available, MYD88L265P was present in 25 patients (8 of 10 TN and 17 of 19 R/R patients). The response rates and the time-to-event outcomes were similar in the MYD88L265P and wild-type patients. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Conclusions Similar to the frontline setting, DRC is an active and well-tolerated salvage regimen. In contrast to ibrutinib, DRC offers a less expensive, limited-duration treatment option, with preliminary data suggesting activity independent of patients' MYD88 mutation status. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kumar:Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

Abstract Background: Mantle cell lymphoma (MCL) remains challenging particularly in the relapsed/refractory setting, where patients often show chemoresistance. Novel molecular-based therapies have shown impressive and durable activity in that setting, although primary and acquired resistance remains problematic. A recent retrospective series of 114 patients who had failed ibrutinib (median of 4.7 month exposure) showed very short median overall survival of 2.9 months after ibrutinib cessation (Martin et al. Blood 2015). Here we report the results from the observationalMCL-004 study investigating outcomes of patients treated with lenalidomide (an IMiD® immunomodulatory agent) after failing ibrutinib; patients were either relapsed, progressed, refractory, or intolerant to ibrutinib. The objective here is to evaluate the clinical effectiveness of lenalidomide monotherapy or a lenalidomide-containing regimen in relapsed/refractory MCL after ibrutinib failure or intolerance. Methods: MCL-004 is a multicenter study in patients with MCL who relapsed/progressed after or were refractory/intolerant to ibrutinib, and were subsequently treated with lenalidomide. With patient informed consent, data were collected retrospectively from patients who, after their disease failed to respond to ibrutinib, received lenalidomide-based therapy from March 1, 2009 to June 9, 2015. The primary endpoint was investigator-assessed overall response rate (ORR) based on 2007 International Working Group criteria, with required patient monitoring and routine imaging. Results: Thirty patients were enrolled at 7 US sites and 1 EU site, including patients receiving lenalidomide monotherapy (n=8), lenalidomide + rituximab (n=8), and lenalidomide + other treatment (n=14). Lenalidomide + other treatment included combination with rituximab, carfilzomib, and dexamethasone (n=3); other combinations were given in ≤2 patients. Patients had a median age of 69 years (range, 50-84), and median time from last dose of ibrutinib to first dose of lenalidomide was 1.3 weeks (range, 0.1-21.7). All patients received ≥2 prior lines of therapy, and 83% received ≥3 prior therapies (median prior therapies, 3.5; range, 2-8). With prior ibrutinib, the best responses achieved were 10% complete response (CR), 43% partial response (PR), 3% stable disease, 40% relapse/progressive disease (PD), and 3% unknown. Primary reasons for ibrutinib discontinuation were 50% relapse/PD, 40% refractory, and 10% intolerance. Patients received a median of 2 cycles (range, 1-11) of lenalidomide-based treatment. Eight patients' disease responded (4 CR, 4 PR), resulting in an ORR of 27% (95% CI, 12%-46%). Five of 8 maintained their response at data cut-off (3 CR, 2 PR). ORR was similar for patients with relapse/PD vs. those refractory to ibrutinib (29% vs. 33%, respectively). Median duration of response (DOR) was 18 weeks (95% CI, 2.9-25+) for all patients. Median DOR was not reached in patients who previously relapsed/progressed with ibrutinib compared with a median of 11 weeks for those whose disease was refractory to ibrutinib. Most common treatment-emergent adverse events (TEAEs) were 33% fatigue; 27% nausea; and 23% each dyspnea, neutropenia, dizziness, or rash. In general, TEAEs were less common with lenalidomide monotherapy. The most frequently reported serious AEs were pneumonia, dyspnea, deep vein thrombosis, hypotension, and acute kidney injury (7% each). At data cutoff, 15 patients (50%) had died, mostly due to MCL and none due to second primary malignancy. Conclusions: Most patients received ≥3 prior lines of treatment, and median time from last dose of ibrutinib to first dose of lenalidomide was short. Lenalidomide-based treatment showed clinical activity in this difficult-to-treat patient population, including 27% ORR and 13% CR. No new safety signals for lenalidomide were identified. Overall, our results show that lenalidomide is active in a selected group of patients with relapsed/refractory MCL that previously failed ibrutinib. Disclosures Wang: BeiGene: Research Funding; Asana BioSciences: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Onyx: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin:Acerta: Consultancy; Teva: Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda: Research Funding. Ghosh:Gilead: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding.

Abstract Background Waldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades. Methods The medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method. Results Younger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003). Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1). In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001]. Conclusion Striking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.