Citations

PURPOSE Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma. METHODS We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma. Lenalidomide was administered orally at a dose of 25 mg on days 1 to 21 of a 28-day cycle. The primary end point was progression-free survival, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression. RESULTS One hundred eighty-two patients were randomly assigned—92 patients to the lenalidomide arm and 90 to the observation arm. Median follow-up is 35 months. Response to therapy was observed in 50% (95% CI, 39% to 61%) of patients in the lenalidomide arm, with no responses in the observation arm. Progression-free survival was significantly longer with lenalidomide compared with observation (hazard ratio, 0.28; 95% CI, 0.12 to 0.62; P = .002). One-, 2-, and 3-year progression-free survival was 98%, 93%, and 91% for the lenalidomide arm versus 89%, 76%, and 66% for the observation arm, respectively. Only six deaths have been reported, two in the lenalidomide arm versus four in the observation arm (hazard ratio for death, 0.46; 95% CI, 0.08 to 2.53). Grade 3 or 4 nonhematologic adverse events occurred in 25 patients (28%) on lenalidomide. CONCLUSION Early intervention with lenalidomide in smoldering multiple myeloma significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage.

Abstract Abstract 3165 Background: Accrual to large oncology group studies in the United States is often slower than planned, especially in less common malignancies such as Multiple Myeloma (MM). To improve the treatment of patients with MM, it is essential that we address the barriers to accrual (BtA) to national clinical trials. The NCI Myeloma Steering Committee (MYSC) formed the Accrual Working Group (AWG), charged to analyze this problem. Methods: The members of the MYSC have developed a list of 10 potential BtA to NCI MM-CT under the leadership of the AWG at meetings conducted in person and by monthly telephone conference. This list was distributed via Survey Monkey among investigators and research staff of the SWOG, ECOG/ACRIN and Alliance research bases for the purpose of ranking the perceived importance of the 10 selected BtA. Responses based on a 0–5 Likert Scale were analyzed as continuous and categorical. For the latter, responses were grouped: Impedes Accrual – No (0,1), Yes (2–5); Significantly Impedes Accrual – No (0–3), Yes (4,5). Results: 246 survey responses were received. 50 participants who indicated that they had never attempted to or actually never enrolled a patient into a MM-CT were excluded. Of 196 responders, 61% had enrolled at least 5 patients, 43% practiced in academic centers (A) and 57% in community centers (C). 26% identified themselves as research staff, 74% as primarily physician investigators including Principal Investigators (12%). 78% have current access to NCI MM-CT. 46% identified their research base affiliation with SWOG, 20% with ECOG/ACRIN, 17% with Alliance, 17% as CTSU, NRG and other. The majority of survey responders confirmed agreement in the perception that all 10 identified BtA impede accrual, ranging from 60–84% depending on the specific barrier identified, while significant impediment to accrual ascribed to these BtA ranged from 22–47%. The perceived barriers most often cited as impeding accrual were (1) spectrum of available treatment options, (2) level of reimbursement for clinical trial related expenses and (3) patient‘s need for prompt treatment intervention (84%, 80%, 76% respectively). The first two barriers along with the requirement that patients receive their treatment exclusively at the NCI designated treatment site were rated most often as significantly impeding accrual (37%, 47%, 34% respectively). The first two were also identified most often as perceived BtA independent of practice setting (A, C), type of research engagement (physician investigator, research staff) and level of experience with MM-CT. Interestingly, the perception that patients must receive their treatment at the NCI designated treatment site and competing industry sponsored clinical trials were substantially more often cited as impeding accrual in academic centers compared to community centers and by physician investigators compared to research staff. The complexity of required diagnostic work up and the complexity of the treatment protocol and follow up testing were substantially more often cited as BtA in the community setting and by research staff compared to their peers in the academic setting and by physician investigators. The NCI MYSC AWG has proposed specific solutions to potentially lower perceived BtA. These include guidelines to allow protocol specific administration of commercially available agents by the patient‘s local oncologist, a simplified diagnostic work up and treatment plan and eligibility inclusion of patients who have received up to one cycle of specified urgent therapy prior to enrollment in MM-CT. Conclusions: We have queried experienced clinical investigators and research staff on 10 potential MM-CT specific BtA and found substantial consensus among responding participants in this survey. There are apparent differences in perceived BtA between the respondents from academic and community centers as well as between research staff and physician investigators. These data suggest that a structured approach to identification of BtA to clinical trials is feasible and creates opportunities to overcome them. This may have application to clinical trials across other diseases and may also lead to improvements in accrual. Disclosures: Barlogie: Celgene, IMF, MMRF, Millennium, Genzyme: Consultancy; Celgene, IMF, Millennium: Honoraria; Celgene, Novartis, NCI, Millennium, Onyx, Icon: Research Funding; GEP: Patents & Royalties.

Abstract Myeloproliferative disorders (MPD) are a group of heterogeneous diseases that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). They are characterized by increased hematopoiesis leading to elevated numbers of non-lymphoid cells and/or platelets in the peripheral blood. Beside thrombotic and hemorrhagic complications, MPD may evolve into secondary acute myeloid leukemia (sAML). Recently characterized markers suggest an opportunity to diagnose and identify subpopulations of MPD patients. In particular, altered expression and point mutations of PRV-1, MPL and JAK2 were commonly found in MPD, as well as deletions on chromosome 20q (del20q). Acquired uniparental disomy (UPD) on chromosome 1p (1pUPD) and 9p (9pUPD) leading to copy-neutral loss of heterozygosity (LOH) is a further mechanism found in MPD which often leads to homozygous activated mutations of MPL and JAK2, respectively. However, the molecular mechanisms involved in the transformation process to sAML remains unclear. Using standard metaphase cytogenetics (MC), chromosomal abnormalities are found in only a proportion of patients with MPD. We hypothesized that with new precise methods more genomic lesions can be uncovered that may be associated with leukemic transformation. To address this issue, we used 250K single nucleotide polymorphisms (SNP) Chip arrays to study chromosomal lesions in 40 sAML samples from patients who evolved from MPD; 7 had preexisting PV, 25 PMF, and 8 ET. Moreover, 43 additional samples of MPD (10 PV, 17 ET, and 16 PMF) were included in this study. SNP-chip analysis showed major chromosomal changes in almost all the sAML samples including monosomy 16, deletions of 1q-, 3p-, 6p-, 5q-, 7q-, 9q-, 12p-, 6q-, 3q-, 17p-, 19q-, and 20q- as well as trisomy 2, 3, 8, 9, 12, 15, 19, 21, and 22. We validated these data by MC. However, numerous new genomic alterations which contained potentially interesting genes that might contribute to leukemic transformation were detected by SNP Chip Array in patient samples with normal karyotype. Moreover, UPD was very frequent: 44% (19/43) of MPD and 53 % (21/40) sAML samples. 1pUPD occurred in 5 patients with MPD (1PV, 4 PMF; 12 %) compared to 5 patients with sAML (1 PV, 4 PMF; 13 %). 9pUPD was found in 16 MPD patients (8 PV, 7 PMF, 1 ET; 37%) and 6 sAML patients (3 PV, 2 PMF, 1ET; 15 %). All patients with 9pUPD proved to be positive for the JAK2 V617F mutation seen by allele specific PCR. Interestingly, the MPD samples only had UPD on 1p, 9p, and 12q. In contrast, sAML samples showed additional UPD regions on 7q, 11q, 12q, 16p, 17p, 19q, and 21q. Beside the evaluation of the non-matching groups of patients with MPD and sAML, we also evaluated 4 patients during their PMF and sAML stages by SNP Chip. The sAML samples acquired additional genomic changes including trisomy 8, 10, 14, 19, duplication on 3q and 6p, and heterozygote deletion on 18q. In contrast, 1pUPD, 9pUPD, and 12qUPD were detected in both MPD and sAML matching samples, suggesting that these changes do not play an immediate role in causing transformation. In conclusion, we detected chromosomal regions possessing genes which may be involved in the leukemic transformation of MPD patients.

Abstract The treatment and natural history of smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated benefit, likely as a consequence of lack of attention to the vast heterogeneity contained within the diagnosis. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression in a short time, using different methodology. Recently the PETHEMA group published a randomized clinical trial testing lenalidomide/dexamethasone vs observation among high risk smoldering patients, and demonstrated a clear benefit in terms of progression free and overall survival favoring early intervention. However, the risk criteria utilized a highly sensitive method of flow cytometry, a test not routinely available in the US. It is not clear that the group of patients defined in the PETHEMA study share similar outcomes with those defined as high risk using the ECOG/Mayo criteria. A recent publication demonstrated only 25% overlap for the highest risk smoldering patients when using either the PETHEMA or the ECOG criteria. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II/III trial testing the safety and efficacy of single agent lenalidomide. We report here on the safety and efficacy of the phase II portion of the trial. The phase II group of patients received lenalidomide alone at a dose of 25 mg days 1-21 every 28 days. The primary endpoint for the safety study was the rate of any treatment-related grade 4-5 non-hematologic toxicity plus grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events) observed within 6 cycles of treatment. Patients were to be diagnosed with high-risk smoldering multiple myeloma (SMM) within the past 12 months, as confirmed by both of the following: bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells and an abnormal serum free light chain ratio (<0.125 or >8.0) by serum FLC assay. Patients must have had measurable levels of monoclonal protein. Patients must have had no lytic lesions on skeletal surveys and no hypercalcemia (i.e. >= 11 mg/dL). Among the final phase II cohort (n=44 patients), 55% were female, and 43% were 65 years and older. Enrollment began in January 2011 and lasted 2 years with the last patient completing 6 cycles of treatment in August 2013. The median treatment duration of the entire cohort is 13.5 cycles (range 1-30 cycles). Mean percentage lenalidomide dose over the first 6 cycles was 94, 89, 82, 79, 76, 72. With a median follow up of 17 months, 2 patients had progression on therapy. Fifteen patients are off treatment for the following reasons: disease progression (n=2), AE/complication (n=5), death (n=2), patient withdrawal/refusal (n=5), other (n=1); 6 of the 15 patients ended treatment before completing 6 cycles. Of 44 patients assessed for toxicity, 11 patients [25.0%, 95% CI: (13.2%-40.3%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher based on CTCAE v4, with neutropenia and fatigue being the most frequent. This includes 2 fatal deaths (MI and TE). Two patients [4.6%, 95% CI: (0.1%-15.5%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis that included treatment-related grade 4-5 non-hematologic toxicity or any grade 3 toxicity affecting vital organ function (such as cardiac, hepatic, or thromboembolic events) during the first 6 cycles of treatment. Twelve patients achieved partial response or better [33.3%, 95% CI: (15.0%-42.8%)] along with 25 patients reporting stable disease. Lenalidomide has shown promise in the treatment of high-risk smoldering myeloma and based on this analysis, accrual to the phase III portion is ongoing. In the context of the encouraging data from the PETHEMA group, completion of the phase III portion of this study is needed to validate their findings using a different criteria, and using a steroid sparing approach. This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650, CA32102 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Disclosures: Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Abstract Abstract 2864 Introduction: Clinical trials have illuminated a number of unique treatment strategies for patients with CLL. The impact of these strategies on routine practice remains unknown as trial participants may not reflect the same population encountered outside of a clinical trial setting. Many questions remain regarding the sequencing of therapies based on age and performance status. By characterizing current patterns of care; patients, treating physicians, and regulatory agencies will be able to understand the current landscape of CLL treatment. The Connect® CLL registry was designed to report the natural history and real world management of patients receiving therapy for CLL. In this first report, we characterize the therapeutic approaches used for the treatment of patients with CLL of different age groups (i.e. < 65 years, 65–75 years, and ≥ 75 years) and with an ECOG PS status score of 0 compared to 1 or greater. Methods: Connect® CLL is a prospective, longitudinal, observational, multi-center registry conducted in community and academic research centers in the United States. At present, 237 sites are actively participating with a projected study enrollment of 1500 patients. Eligible patients are to be enrolled within 2 months of being initiated on any line of therapy; whether initial therapy or salvage therapy. Each patient will be followed for up to 60 months. Clinical data, physician choices, patient-reported health-related quality of life, response and survival are to be collected approximately every 3 months during participation. Results: A total of 607 patients have been enrolled (4% from academic sites) with a median age of 70 years. 198 were < 65 years old (age group 1), 187 were between 65–75 years old (age group 2), and 222 were ≥ 75 years old (age group 3). ECOG status varied across the three age groups, with an ECOG status score of ≥ 1 for 39%, 52%, and 70% of patients respectively. Treatment patterns varied across the age groups and by ECOG status in the 496 patients reporting therapies. The most commonly recorded first-line regimens independent of age included fludarabine (F) cyclophosphamide (C) and rituximab (R) (33%), bendamustine (B) +/− R (19%), F +/− R (15%), or investigational therapy (15%). For second-line regimens and beyond, the most frequently recorded regimen was B +/− R (30%), FCR (23%), other F-based regimens (13%), or investigational therapy (8%). The use of FCR for first-line treatment decreased significantly with increasing age group, (45%, 32%, 20%, for age group 1, 2, 3 respectively, p=0.04, spearman correlation) while use of F +/− R remained level across the age groups (14%, 15%, 15%, respectively). Compared to age group 1, first-line therapy with B +/− R in age groups 2 and 3 (15%, 22%, 21%, respectively) was higher but did not achieve statistical significance. B +/− R represented the most common treatment for all age groups (37%, 26%, 29%, respectively) as second line therapy but did not vary by age (P=0.35). The use of chlorambucil was infrequent in all age groups, but was more common in age group 3 patients compared to the others (P=0.01), in both first-line (2%, 4%, 12%, respectively) and subsequent lines of therapy (0%, 1%, 8%, respectively). Treatment assignments did not vary by ECOG PS score for patients in age group 1. First-line therapy for patients with an ECOG PS score of 0 in age groups 2 and 3 consisted of FCR (32% and 15%, respectively), F +/− R (19% and 15%, respectively), B +/− R (16% and 15%, respectively), and alkylating agents (3% and 23%, respectively). Patients in age groups 2 and 3 with ECOG PS score ≥ 1 received B +/− R regimen (33% and 22%, respectively), FCR (23% and 21%, respectively), F +/− R (14% and 10%, respectively) and alkylating agents (7% and 9%, respectively) as first-line therapy. Further description and clarification on the various treatment regimens based on the three age groups and by ECOG PS score will be presented at the meeting. Conclusion: The Connect® CLL Registry is the largest prospective, multicenter registry in the United States evaluating management for patients with CLL. With the currently available data, we characterize the extent to which age and performance status are associated with treatment selection in both first-line and subsequent lines of therapy in routine practice. As enrollment increases and additional follow-up is completed, the data will provide more extensive and real world overview of the current treatment strategies used in CLL patients. Disclosures: Sharman: Celgene - consulting: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. Flowers:Consultancy: Celgene, Prescription Solutions, Spectrum (future), Seattle Genetics, Millennium (future), Genentech (unpaid): Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kay:Genenetech, Celgene, Hospira,: Research Funding. 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: Research Funding; Amgen: Research Funding. Lamanna:Celgene Corporation: Advisory board. Pashos:United BioSource Corporation: Research Funding. Flinn:Celgene: Research Funding. Kozloff:Celgene: Consultancy. Lerner:Celgene Connect: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene: Employment. Sullivan:Celgene: Employment. Street:Celgene: Employment. Keating:Celgene Connect: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 4184 Introduction: FACT-MM was developed with the aim to create a disease-specific, patient-reported outcomes (PRO) measure as part of the FACT measurement system to assess multiple myeloma (MM)-related symptoms. Literature review identified 52 MM specific symptoms and concerns. 13 MM expert clinicians rated these 52 items on relevance to health-related quality of life (HRQL) for MM patients and added 11 items for comprehensive PRO assessment in MM. These 63 candidate items were rated by 13 MM patients recruited through the International Myeloma Foundation website. Disease-related symptoms and concerns were described and provided by patients through free-text comments. Information from both the MM expert clinician and MM patient surveys including free-text items was analyzed and 14 highest ranked items were selected for the FACT-MM. The FACT-MM subscale (score 0–56), the FACT-G physical and functional well-being subscales (score 0–28), and the FACT-Neurotoxicity (FACT-Ntx) subscale (score 0–44) was administered to 48 E1A05 participants to assess disease and treatment-related symptoms of patients with newly diagnosed MM receiving 8 cycles of VRd versus Vd. Methods: In this study, the first three of seven sequential assessments were evaluated: baseline, cycle 5 and end of treatment (after cycle 8 or early diconstinuation). Instruments were scored as per the FACT scoring guidelines. Descriptive statistics were provided for each timepoint and changes in scores from baseline. The Wilcoxon rank sum test was used to assess differences in scores by ISS stage and ECOG PS. Pearson correlation coefficients were obtained between the scores. Cronbach's alpha was used to evaluate internal consistency of the FACT-MM. Results: At baseline and end of treatment, 46 and 41 patients, respectively, completed assessments. The FACT-MM demonstrated good to very good internal consistency (Cronbach alpha 0.79 – 0.89). The FACT-MM subscale was significantly correlated with the FACT physical and functional well-being subscales at baseline (r = 0.72), cycle 5 (r = 0.64; r = 0.49) and end of treatment (r = 0.72; r = 0.66). All scores declined modestly by cycle 5 and end of treatment from baseline. While sample size was limited, there appeared association with ECOG PS with higher scores for patients with PS 0 status. Conclusions: The 14-item FACT-MM scale is feasible for use to measure myeloma-related symptoms and has demonstrated acceptable psychometric properties based on findings from E1A05, an ECOG myeloma trial. Disclosures: Cella: Novartis: Research Funding. Fonseca:Consulting:Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Abstract Abstract 3895 Poster Board III-831 A genome-wide single nucleotide polymorphism (SNP) screen led to the identification of 11q aUPD in patients diagnosed with various subtypes of myeloproliferative neoplasms (MPN), e.g. chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and myelofibrosis (MF) (Grand et al., Blood 2009;113:6182). Further molecular analyses revealed acquired activating point and length mutations in CBL exons 8 and 9 in 10% of CMML, 8% of aCML and 6% of MF cases. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. In this study, 160 patients with BCR-ABL and JAK2 V617F negative MPNs were screened for CBL mutations by PCR and direct sequencing. Eighteen known (Y371H, L380P [2x], C381R, C381Y [2x], C384Y, C396Y, H398P, H398Q, W408C, P417H, F418L, R420Q [5x]) and four new (F378L, G397V, I423N, V430M) missense mutations affecting fourteen residues were identified in 20 patients. Two patients harbored two different mutations. The clinical phenotype could be characterized more precisely in 17 patients. Median age was 68 years (range 59–85) with a slight female predominance (f, n=10; m, n=7). Striking hematological features were leukocytosis (14/17; 82%; median 29,000/μl, range 4,500-141,000) with continuously left-shifted granulopoiesis (blasts, promyelocytes, myelocytes, metamyelocytes) in 85% and elevated monocytes (median 2,500/μl, range 630-10,656) >1,000/μL in 88% (15/17) of patients. Eosinophilia (>1,500/μL) was rare (3/17, 18%). Anemia (normal values: f, Hb <12g/dL; m, Hb <14g/dL) was present in all 17 patients (f, median 10g/dL, range 8.7-11.8; m, median 11.2g/dL, range 8.6-12.9). Platelets did not exceed 300,000/μL in any patient while 11/17 (65%) patients presented with thrombocytopenia (median 125,000/μL, range 18,000-271,000). Splenomegaly was present in 11/17 patients (65%) and LDH was elevated (median 304U/L, range 189-729) in 9/17 patients (52%). Bone marrow histology and immunohistochemistry were available from 12 patients. Relevant features were hypercellularity, marked granulopoiesis and microlobulated megakaryocytes without clusters in 11/12 patients (92%), respectively. Increased fibres were seen in 8/12 (67%) patients of whom one showed severe fibrosis. Clinical follow-up was available from 17 patients. Thirteen patients (76%) have died because of progression to secondary acute myeloid leukemia/blast phase (n=7), cytopenia-related complications (n=2) or for unknown reasons (n=4) after a median of 23 months (range 3-60) following diagnosis. In conclusion, point mutations of CBL exons 8 and 9 are present in approximately 6-12% of BCR-ABL and JAK2 V617F negative MPNs. They are associated with a distinct clinical and hematological phenotype presenting with myeloproliferative features allowing diagnosis of a proliferative subtype of CMML rather than aCML or MF in the majority of cases. Patients with left-shifted leukocytosis, monocytosis, anemia and lack of thrombocytosis who are negative for BCR-ABL and point or length mutations of JAK2 should be routinely screened for CBL mutations. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: The Surveillance, Epidemiology & Risk Factors for TTP (SERF-TTP) study is the largest prospective cohort of idiopathic TTP cases to date. Methods: Patients with first episode of idiopathic TTP were enrolled at 11 sites in the US. Exclusion criteria include solid organ or allogeneic stem cell transplant, anti-neoplastic therapy or malignancy. All patients underwent therapeutic plasma exchange (TPE). Remission is defined as platelet count >150,000/mm3. ADAMTS13 activity was measured by fluorescence resonance energy transfer assay (FRETS-vWF73, Peptides Int.). ADAMTS13 inhibitor was assessed by ELISA (Technozym ADAMTS13 INH ELISA, Technoclone) and functional inhibition of normal ADAMTS13 activity (modified FRETS). Differences between the groups was evaluated by Chi-square test, t-test or Fisher’s exact test. Results: Complete data is available for 57 cases. 84% were female & median age was 42. ADAMTS13 was severely deficient (<10%) in 53%, moderate (10–50%) in 8%, & normal (>50%) in 39%. Adverse events were frequent & most commonly include citrate toxicity and allergic reactions. Long-term followup was available for 56 patients, and overall relapse rate was 25% with median time to relapse of 11 months. The relapse rate was 41% in patients with severe ADAMST13 deficiency & 0% in patients with normal ADAMTS13 activity (p=0.0077). Conclusions: Severe ADAMTS13 deficiency does not define all cases of idiopathic TTP, yet is associated with a unique syndrome characterized by severe thrombocytopenia, normal renal function, presence of ADAMTS13 neutralizing autoantibodies & high risk of relapse. Non-ADAMTS13 deficient idiopathic TTP has clinical features similar to thrombotic microangiopathies associated with stem cell transplant or drugs such as quinine, yet has a better than expected overall survival after TPE. There is likely an alternate disease mechanism for this cohort, possibly immunologic, which may be responsive to TPE and warrants further study. ADAMTS13 < 10% n=30 ADAMTS13 > 50% n=22 p-value * t-test, ** Fisher’s Exact Test, # Chi-Square Test Presenting Labs Hemoglobin (mean) 8.5 9.2 0.22* Platelet count (mean x10^9/L) 19 57 <0.0005* Serum creatinine (mean) 1.33 3.9 0.0012* ADAMTS13 antibody (neutralizing & non-neutralizing) % 100 63.6 0.0004** ADAMTS13 neutralizing antibody % 83 35 .0003# Presenting Symptoms Neurologic symptoms present 45 52.4 0.23# Diarrhea 23 30.4 0.79# Infection 40 43.5 0.79# Past Medical History Connective Tissue Disease % 10 8.5 0.28# Family history of TTP % 0 4.6 0.11# Remission Labs Hemoglobin (mean) 12.2 8.5 0.16* Platelet count (mean x10^9/L)) 169 152 0.15* Serum creatinine (mean) 1.02 3.7 0.0009* Outcomes Therapy-related Adverse events % 71 55 0.24# Time (days) to remission (plt > 150,000) 9.7 9.2 0.89* Early remission (< 8 days) % 73 57 0.20# 30 day Exacerbation rate % 35 28 0.63# 30 day Survival % 96.6 90.0 0.56** Long-term Relapse % 41 0 0.0077**

Abstract Abstract 2085 Introduction. Although advanced patient age is commonly used as a factor in selecting therapy for patients with chronic lymphocytic leukemia (CLL), based on presumed associations with functional status, limited data exist regarding the relationships between age and physical, emotional, social, and functional well being. We examined the relationships between age and these domains of health-related quality of life (HRQOL) for CLL patients treated in US community practices. Methods. Baseline data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by patients in the clinic at enrollment. Patients completed 3 psychometrically validated instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Standard analyses were conducted of each instrument given clinical characteristics at that time. Reported mean BFI, EQ-5D and FACT-Leu scores were analyzed by age group (<65, 65–74, >74). Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. Baseline HRQOL data were reported by 604 patients, enrolled from 161 centers. Patients were predominantly male (62%) and white (90%) with mean age at 69.9 (standard deviation [SD] 11.2) yrs. HRQOL scores by age group are presented: There were no significant differences between the age groups in fatigue as measured by the BFI, or differences in overall HRQOL as measured by the EQ-5D Visual Analogue Scale (VAS) or the FACT-G. Anxiety/depression and self care are EQ-5D domains that also did not vary by age. Although mobility was most impaired in the oldest age group compared to the two younger groups, usual activities and pain/discomfort were worse in both the younger and older cohorts compared to those 65–74 years of age. FACT-Leu results indicated that the social/family domain scores did not vary by age, but that physical, emotional, and functional domains did vary statistically with the oldest typically doing better than the 65–74 year olds, but not necessarily better than those <65. Conclusions. Initial results from the Connect CLL® Registry indicate that HRQOL does not worsen monotonically with older age. In this cohort, both the youngest and oldest age groups had worse HRQOL in certain domains, presenting an inverted v-shaped relationship. Future analyses should be conducted on: (1) how HRQOL may be affected over time with changes in disease; and, (2) how HRQOL may be influenced by alternative therapies. Results reported here should serve as a useful 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 Abstract 1280 Poster Board I-302 Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) are defined as clonal hematopoietic stem cell disorders. These disorders show an inherent tendency for transformation into leukemia (MPN-blast phase) which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, obtained a comprehensive profile of genomic alterations associated with leukemic transformation by using single-nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. A relatively high number of genomic alterations was found in MPN after leukemic transformation with 4.6 ± 0.6 abnormalities per sample compared to only 1.4 ± 0.2 changes per patient in chronic phase (p<0.001). Compared to the cytogenetic data, SNP-chip analysis detected about 47% additional chromosomal changes in the MPN samples, and 31% more in the MPN-blast phase cases, whereas SNP-array allelokaryotyping practically captured all cytogenetic abnormalities in our study population. Several additionally altered regions were detected in patients with MPN-blast phase compared to chronic phase, including both deletion and copy-number neutral-loss of heterozygosity (CNN-LOH) on chromosome 12p (9%) and 21q (9%), involving ETV6 and RUNX1. Notably, deletion and CNN-LOH on 17p involving TP53 were diagnosed in 18% of MPN-blast phase samples, which was highly associated with preceding treatment with alkylating agents (p=0.016). Moreover, trisomy 8, as well as amplification of 8q24.21 involving the MYC gene, were detected in 13% of patients with MPN-blast phase who were almost exclusively negative for the JAK2V617F mutation. Genome-wide inspection of further critical regions with promising new candidate genes involved in the evolution to the MPN-leukemic phase included deletion and CNN-LOH on 7q22.1 (SH2B2) in 18%, duplication/amplification on 19p13.2 (PIN1, ICAM1, CDC37) in 13% and 21q22.2 (ERG) in 9% of MPN patients with blast crisis. In contrast, we detected a decreased frequency of JAK2V617F in MPN-blast phase samples (52%) compared to chronic phase (71%). Also, the percentage of patients with homozygous mutant JAK2 as a result of CNN-LOH was lower in the MPN-blast phase (43%) compared to the chronic phase (53%). Taken together, the data suggest that gain-of-function mutation of JAK2 is not a perquisite for leukemic transformation. Remarkably, CNN-LOH on either 7q or 9p was related to decreased survival after leukemic transformation (p=0.02 and p=0.012, respectively). Given the variety of allelic imbalances, our data suggest that MPN-blast phase appears to be a heterogeneous disease prone to have evolved multiple mechanisms to provide a proliferative advantage to the abnormal leukemic clone. Our analysis of MPN genomes in the chronic compared to the leukemic stage provided new prognostic insights, as well as novel causative genes which might be involved in the transformation to MPN-blast phase. Disclosures No relevant conflicts of interest to declare.