Citations

2004 Background: With the approval of novel agents for glioblastoma (GBM) treatment, reliable historical outcome data for the common phase II endpoint of progression free survival (PFS) is not available. In particular, the association between progression and overall survival (OS) has not been evaluated after temozolomide (TMZ) became the standard therapy for newly diagnosed GBM. Methods: Datasets from 5 TMZ-including NCCTG clinical trials in newly diagnosed GBM (n=325, 2005-2011, 1 phase I only and 4 phase I and single arm phase II trials) were pooled and analyzed to evaluate the individual level correlation between PFS and OS using correlation coefficient, landmark analyses, and time-dependent variable analyses. A historical control group was constructed by pooling datasets from 12 pre-TMZ era NCCTG clinical trials in the same patient population (n=1359, 1980-2004). Each of the 5 newer trials was compared to the control group to estimate the treatment effect (hazard ratio) on PFS and OS, which were analyzed to evaluate the trial level correlation between PFS and OS using correlation coefficient and weighted linear regression. Results: The estimated correlation coefficient between PFS and OS at individual patient level is 0.75 (95%CI, 0.7 to 0.8). The estimated hazard ratios of death in the landmark analysis at 4 and 6 months are 2.15 (95%CI, 1.47 to 3.15) and 2.17 (95%CI, 1.57 to 3.12), respectively, and the estimated hazard ratio of death is 10.1 (95%CI, 6.6 to 15.4) when progression is treated as a time-dependent variable. For trial level correlation (against the historical control group), the estimated correlation coefficient between HRos and HRpfs is 0.51 (95%CI, -0.67 to 0.96), with moderate prediction: the predicted HRos is very close to the observed HRos in 4 of 5 cases, however the predicted HRos is significantly different from 1 in only 2 out of 5 cases due to small sample size in other 3 cases. Conclusions: PFS and OS are highly associated at the individual patient level but only moderately at the trial level, the latter possibly due to small sample size in some of the trials. Additional validation in other trials could support use of PFS as a primary endpoint for randomized phase II trials in GBM.

2046 Background: Vorinostat (VOR) is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single-agent activity in recurrent disease (Galanis,et al, 2009) and radiosensitizing properties, this phase I/II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts): the phase I portion of the trial is the focus of this report. Methods: A standard cohorts of three design was used to assess the safety of VOR in combination with RT and concomitant TMZ and establish the phase II dose of the combination. VOR was given orally days 1 - 5 every wk beginning with the first dose of RT (total dose 60 Gy) and (75mg/m²/day). Following a 4 - 6 week rest, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR on days 1-7 and 15 – 21 of each cycle; dose was based on NABTT trial 04-03 (Lee, et al, 2012). Results: The phase I component is complete with 15 pts, 12 pts at dose level 0 (VOR 300 mg/day days 1 - 5, weekly x 6 wks), and 3 pts at dose level 1 (VOR 400 mg/day, days 1 – 5 weekly x 6 wks) in combination with RT/TMZ. Dose limiting toxicity (DLT) in dose level 1 included grade 3 fatigue in 2 pts, grade 3 wound dehiscence in 1 pt, and grade 4 neutropenia and thrombocytopenia in 1 pt. In dose level 0, 1/6 pts had DLT (gr 3 dyspnea). An MTD expansion cohort of 6 additional patients was added to dose level 0; one patient experienced grade 4 thrombocytopenia and grade 3 fatigue, and 1 patient experienced grade 3 febrile neutropenia. In the 12 pts treated in the phase II dose, most common toxicities were hematologic, including lymphopenia (gr 3/4 in 66.7%), thrombocytopenia (gr 3 in 16.7%, gr 4 in 16.7%) and neutropenia (gr 3 in 16.7%, gr 4 in 8.3%). Grade 3 fatigue was observed in 8.3% of the pts. Conclusions: MTD for VOR in combination with TMZ/RT in newly diagnosed GBM patients is 300 mg/d, days 1 - 5 weekly during RT. Toxicity was primarily hematologic. This dose was used in the recently completed phase II trial of the combination (110 pts). RNA expression profiling in patient samples is in process to assess vorinostat responsive signatures observed in preclinical models. Clinical trial information: NCT00731731.

7030 Background: JAK2V617F occurs in approximately 50% of patients with essential thrombocythemia. Qualitative studies of mutation analysis have previously reported an association between JAK2V617F and advanced age, higher hemoglobin level, higher leukocyte count, and lower platelet count. A possible association with thrombotic complication has also been considered. Methods: Allele-specific, quantitative PCR analysis for JAK2V617F was performed on 176 patients with ET, using genomic DNA from archived bone marrow, which was collected within one year (n=72), between 1 and 5 years (n=64), or after 5 years (n=40) of diagnosis. Results: JAK2V617F was detected in 96 patients (55%), in whom mutant allele burden ranged from 1% to 100% (median 6.3%). Neither mutational frequency (p=0.37) nor mutant allele burden (p=0.62) was affected by the timing of bone marrow sample collection. Presence of JAK2V617F was significantly associated with higher hemoglobin level (p<0.0001), lower platelet count (p=0.001), higher leukocyte count (p=0.008), increased incidence of venous thrombosis occurring after diagnosis (p=0.02), and older age at diagnosis (p=0.03). All but age retained significance in multivariable analysis. In mutation-positive patients (n=96), JAK2V617F allele burden clustered between 1% and 22% in 94 cases, in whom it correlated directly and significantly with platelet and leukocyte counts, palpable splenomegaly at diagnosis, and venous thrombosis occurring after diagnosis. Conclusions: JAK2V617F allele burden imparts additional phenotypic effects in ET. No significant financial relationships to disclose.

2075 Background: Multiple variables may impact endpoints used to assess therapeutic efficacy for patients with recurrent gliomas. To identify prognostic factors for each of 3 outcome variables, a master analysis file was constructed by pooling datasets summarizing key baseline factors and outcomes obtained in 15 North Central Cancer Treatment Group (NCCTG) trials (n=583, 1980–2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n=596, 1998–2002). Methods: In addition to traditional variables (gender, age, performance score (PS), race, extent of primary resection, year of study entry, last known histology, time since initial diagnosis, baseline steroid use, prior chemotherapy (Y/N), prior nitrosoureas, baseline anticonvulsant use), we investigated prior t (TMZ), number of relapses, academic vs. community site and low grade at initial diagnosis. Outcome variables were: (1) overall survival (OS), (2) progression free survival (PFS) and (3) PFS6 = proportion of patients alive and progression-free 6 months after start of treatment. For all 3 endpoints, Classification and Regression Tree (CART) models and bootstrap samples were used to identify prognostic variables and to look for evidence of interactions among the independent variables affecting outcome. Results: For all outcomes the initial CART analysis selected last known grade (4 vs. 3) as the most important variable. Additional factors selected as predicting poor prognosis differed with grade and outcome measure and included prior TMZ, longer time since primary diagnosis, older age and poor PS. Community vs. academic was not a strong predictor in any of the models nor was low grade at initial diagnosis. Additional analyses are planned to better describe the impact of all the variables on outcome, including use of Cox models and logistic models considering all baseline variables with backwards selection. Conclusions: The results from analyses to date are consistent with current thinking that last known histology (grade) is an important factor. Time since initial diagnosis is likely a surrogate for number of relapses. More definitive conclusions await the completion of ongoing analyses. No significant financial relationships to disclose.

AbstractIntroductionPractical algorithms predicting the probability of amyloid pathology among patients with subjective cognitive decline or mild cognitive impairment may help clinical decisions regarding confirmatory biomarker testing for Alzheimer's disease.MethodsAlgorithm feature selection was conducted with Alzheimer's Disease Neuroimaging Initiative and Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing data. Probability algorithms were developed in Alzheimer's Disease Neuroimaging Initiative using nested cross‐validation accompanied by stratified subsampling to obtain 1000 internally validated decision trees. Semi‐independent validation was conducted using Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Independent external validation was conducted in the population‐based Mayo Clinic Study of Aging.ResultsTwo algorithms were developed using age and normalized immediate recall z‐scores, with or without apolipoprotein E ε4 carrier status. Both algorithms had robust performance across data sets and when substituting different recall memory tests.DiscussionThe statistical framework resulted in robust probability estimation. Application of these algorithms may assist in clinical decision‐making for further testing to diagnose amyloid pathology.

Abstract BACKGROUND: Information regarding risk factors for leukemic transformation (LT) in primary myelofibrosis (PMF) is limited, although both leukocytosis and abnormal cytogenetics have previously been implicated. The current retrospective study examines clinical variables at diagnosis as well as specific treatment modalities for their effect on LT in PMF. METHODS: Diagnoses of PMF and LT were based on World Health Organization criteria. In addition, study inclusion required availability, for review, of bone marrow histology and clinical data obtained at or within 6 months of diagnosis but prior to treatment intervention. Statistical methods used were standard and included Cox regression analysis of leukemia-free survival (LFS). RESULTS: A master database of PMF patients seen at the Mayo Clinic from 1976 through 2006 was queried to identify 311 patients who fulfilled the aforementioned stipulated criteria for study inclusion; median age was 57 years and 41% were females. At presentation, 30% of the patients displayed a hemoglobin level (Hgb) of < 100 g/L, 20% a leukocyte count of < 4 or > 30 x 109/L, 18% a platelet count of < 100 x 109/L, 12% an absolute monocyte count (AMC) of ≥ 1 x 109/L, 28% hypercatabolic symptoms and 35% a peripheral blood (PB) blast percentage of ≥ 1; 27 patients (9%) had a PB blast percentage of ≥ 3. Dupriez prognostic scoring system distribution for high, intermediate, and low risk disease was 30 (10%), 94 (30%), and 187 (60%) patients. Among 182 and 139 evaluable patients, 74 (41%) and 80 (58%) displayed cytogenetic abnormalities and JAK2V617F, respectively. At a median follow-up of 27 months (range 0–282), 27 cases (9%) of LT were documented at a median time from diagnosis to LT of 26 months (range 0.8–266). Effect of clinical and laboratory variables at diagnosis on leukemic transformation By univariate analysis, LFS was negatively affected by anemia (p=0.04), leukocytosis (p=0.04), PB monocyte count ≥ 1 x 109/L (p=0.02), platelet count of < 100 x 109/L (p=0.004), hypercatabolic symptoms (p=0.03) and PB blast percentage of ≥ 3 (p<0.0001); LFS was not affected by PB blast percentage of > 1 but < 3 (p=0.49). By multivariable analysis, significance was sustained only for PB blast percentage of ≥ 3 (p = 0.0002) and platelet count of < 100 x 109/L (p = 0.02) with hazard ratios (HR) of 5.8 and 2.8 and 95% confidence intervals (CI) of 2.3–14.6 and 1.2–6.6, respectively. The presence of JAK2V617F did not affect LFS (p=0.98). Effect of specific treatment on leukemic transformation By univariate analysis, LT was significantly associated with history of splenectomy (p=0.01) and treatment with erythropoiesis stimulating agents (ESA; p=0.004), danazol (p=0.007), and androgens (p=0.03) but not with hydroxyurea (p=0.17), interferon alpha (p=0.95), thalidomide (p=0.26) or other drugs. On multivariable analysis, significance was sustained for both ESA (p = 0.005; HR 3.1, CI 1.4–6.8) and danazol (p = 0.01; HR 3.4, CI 1.3–8.5), even when the aforementioned prognostic indicators at diagnosis were added as covariates to the multivariable model. CONCLUSIONS: The current study identifies PB blast percentage of ≥ 3% and platelet count of < 100 x 109/L, at presentation, as independent risk factors for LT in PMF. Unexpectedly, the study also revealed an association between LT and treatment history with ESA or danazol. These observations are intriguing, considering recent reports on the possible harmful effects of ESA in certain solid tumors.

Abstract Abstract 4104 Background: The International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) uses five predictors of inferior survival: age > 65 years, hemoglobin < 10 g/dL, leukocytes > 25 × 109/L, circulating blasts ≥ 1% and constitutional symptoms (Cervantes F et al. Blood 2009; 113: 2895). The dynamic IPSS (DIPSS) utilizes the same prognostic variables but can be applied at any time during the disease course (Passamonti F et al. Blood 2010; 115: 1703). IPSS-independent risk factors for survival have since been described and include unfavorable karyotype, red cell transfusion need and platelets < 100 × 109/L. Objectives: i) To determine if the aforementioned IPSS-independent risk factors for survival in PMF (i.e. unfavorable karyotype, red cell transfusion need and platelets < 100 × 109/L) are also DIPSS-independent. ii) To develop and validate a refined DIPSS model that incorporates DIPSS-independent prognostic factors for survival. iii) To establish a prognostic model for leukemia-free survival in PMF. Methods: The Mayo Clinic database for PMF was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of their referral. WHO criteria were used for PMF diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937). None of the patients in the current study were included in the original group of patients used to describe DIPSS (Passamonti F et al. Blood 2010; 115: 1703). Results: A total of 793 patients met the above-stipulated criteria. The study population was divided into two groups based on whether or not patients were seen at the Mayo Clinic within (n=428; training set) or beyond (n=365; test set) their first year of diagnosis. i) Objective 1: Multivariable analysis that included DIPSS risk category (low, intermediate-1, intermediate-2 and high risk), karyotype (favorable or unfavorable), platelet count (≥ or <100 × 109/L) and transfusion status (independent or dependent) was performed using the training set and all four variables were found to be significant as independent predictors of survival (p<0.0001, <0.0001, 0.0008 and 0.01, respectively). ii) Objective 2: Using the respective hazard ratios (HR) obtained during the multivariable prognostic analysis in the training set, HR-weighted adverse points were assigned: 3 points for high-risk DIPSS, 2 points for intermediate-2 risk DIPSS, and 1 point each for intermediate-1 risk DIPSS, unfavorable karyotype, platelets < 100 × 109/L or transfusion need. Accordingly, a refined DIPSS model (i.e. DIPSS-plus) was devised using the training set (Figure 1) and subsequently validated in the test set (Figure 2): low-risk (0 adverse points), intermediate-1 risk (1 adverse point), intermediate-2 risk (2-3 adverse points) and high-risk (4-6 adverse points). Considering the entire group of 793 study patients, the respective median survivals were 185, 78, 35 and 16 months (p<0.0001). ii) Objective 3: Multivariable analysis identified platelet count (p=0.0007) and karyotype (p=0.04) but not DIPSS or transfusion status as independent predictors of leukemia-free survival. We used these two variables to classify patients into a low (favorable karyotype and platelets ≥ 100 × 109/L) or high (unfavorable karyotype or platelets < 100 × 109/L) risk category for leukemic transformation; the respective 5- and 10-year risk of leukemic transformation were 6% and 12% vs. 18% and 31%, respectively (p<0.0001; HR 3.3, 95% CI 1.9–5.6). Conclusions: DIPSS-plus effectively incorporates prognostic information from karyotype, platelet count and transfusion status into the DIPSS prognostic model for PMF. Unfavorable karyotype or platelets <100 × 109/L is associated with a significantly higher risk of leukemic transformation in PMF. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4094 Background: Our group has previously reported the benefits of thalidomide-prednisone based regimens for improvement of anemia, thrombocytopenia, and splenomegaly for patients with MF; both primary myelofibrosis (PMF), and arising from essential thrombocythemia and polycythemia (Post ET/PV MF). We sought to evaluate the overall efficacy of these commonly used regimens by evaluating long-term outcomes and applying the IWG-MRT response criteria (Tefferi et. al. Blood 2006) which arose after completion of these trials. Methods: We retrospectively analyzed the long-term outcomes, and assessed the initial therapeutic responses using IWG-MRT criteria from three parallel completed trials of MF using a thalidomide (THAL-50 mg/day) and prednisone (3 month taper beginning at 40mg, stopped at 3 months) backbone. The trials had identical eligibility criteria including adequate organ function and need for MF therapy (defined as symptomatic: anemia and/or splenomegaly). The trials were 1) THAL-PRED alone, THAL only after 3 months 2) THAL-PRED-etanercept (ETAN - TNF- alpha inhibitor at 25 micrograms subcutaneously twice a week), THAL and ETAN only after 3 months and 3) THAL-PRED – oral cyclophosphamide (CTX 25mg daily orally), THAL alone after 3 months. Results: Patients: A total of 50 pts were enrolled in these 3 trials (Males n=36, 72%) with median age of 68.5 years (Range 43–85), with 79% having PMF. Patients had advanced disease in general with 88% having intermediate 2 or high risk MF by IWG criteria (Cervantes et. al. Blood 2009), 62% patients with red cell transfusion dependence and 50% with an abnormal karyotype. Therapy initial results: 80 % of patients reached the three month juncture on the trials, with 40% reaching 6 months. Initial toxicity was myelosuppression with 3 cases of grade 3 anemia, 3 cases of grade 3 neutropenia and 4 cases of grade 3 thrombocytopenia. There were no grade 4 or higher hematological toxicities noted. Initial neuropathy was uncommon and seen in only 4% of patients. No complete responses were observed and only 1 patient had partial response (by IWG-MRT criteria). 14 patients (28% overall) met the new IWG-MRT criteria for clinical improvement; 11 for anemia (22%), 2 for thrombocytopenia (4%) and 3 for splenomegaly (6%). Responses occurred relatively quickly at an overall median of 8 weeks (range 4–12) after enrollment. Long Term Outcomes: After a median follow-up of 36 months across this cohort we observed an overall median duration of response of 8.5 months (range 3–42). Responses to THAL based regimens can lead to periods of prolonged stabilization after cessation of therapy. We observed an overall median time to institution of next therapy of 3 months (range 1–50). At the time of this analysis 14 patients (28%) have expired of their MF and median survival across the entire cohort was 36 months (3-106). Comparison of Regimens: Comparison of these three independent trials (Table 1) suggests greater toxicity and inferior response rate, duration of response, and time to next therapy with the cyclophosphamide containing regimen. Conclusion: THAL-PRED based regimens are active in a subset of MF patients for therapy primarily of anemia, and for some patients a response of good duration (even after cessation of therapy) may be obtained. IWG-MRT response assessment demonstrates utilizing additional agents to a THAL-PRED regimen do not appear to augment (and may detract from responses). Newer agents such as pomalidomide may have similar to greater efficacy without neuropathy and less myelosuppression. Disclosures: Off Label Use: There is no FDA approved agent in Myelofibrosis. All the drugs discussed; Thalidomide, Prednisone, Etanarcept and Cyclophosphamide are off-label. Mesa:SBio: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Roche: Research Funding; eisai: Research Funding; telik: Research Funding.

Abstract Abstract 2911 Poster Board II-887 BACKGROUND: Pomalidomide (POM) is an immune modulatory drug (IMiD® Immunomodulatory compound) recently shown to improve anemia in subjects with myelofibrosis (MF) in an adaptive phase-2 trial (0.5 mg or 2.0 mg/d with or without prednisone; Tefferi et. al. JCO 2009)). There were no dose limiting toxicities (DLT) observed. No other MF-features (splenomegaly, fibrosis) were identified/improved even at the highest dose. We performed a subsequent dose-escalation trial to determine whether higher doses of POM are effective and well tolerated. METHODS: The trial was classic 3 × 3 design on pts with symptomatic MF (anemia and/or symptomatic splenomegaly). POM was started at dose of 2.5 mg/days (d) for 21 d every 28 d. Dose increased in cohorts by 0.5 mg/d were done if no subject had a DLT (≥grade-4 hematologic toxicity, ≥grade-3 febrile neutropenia or ≥grade-3 non-hematologic toxicity) in cycle-1. Subsequent cohorts were enrolled until the maximum tolerated dose (MTD) was reached (dose level before that resulting in DLT in >1 of 6 subjects). In the phase 2 portion, subjects were treated at the MTD, those without response at the MTD after 3 cycles were lowered to the minimal effective dose (MED) of 0.5mg/d. RESULTS: Subjects: 19 subjects with MF were enrolled 06/2008-03/2009. 14 had primary MF, 3 post-polycythemia vera MF, and 2 post-essential thrombocythemia MF. Median age was 67 y (range, 43-83 y), 11 were female (58%). 16 had a JAK2-V617F mutation. 11 were RBC-transfusion–dependent (58%). 16 subjects had palpable splenomegaly, median 12.5 cm below the LCM (range, 1-26 cm). Median time since diagnosis was 24 mo (range, 1-173 mo). 15 were considered intermediate-high risk by IWG-MRT IPSS (Cervantes et al, Blood, 2009). Phase-1: 3 subjects each were enrolled at the 2.5 mg/d, 3.0 g/d, and 3.5 g/d mg dose cohorts. A DLT (bone marrow suppression) was seen at the 3.5 mg/d level. 3 additional subjects received 3.0 mg/d level cohort confirming this dose as the MTD. Phase-2: 10 additional subjects were enrolled at the MTD of 3.0mg/d. No improvement in anemia was seen, possibly because of bone marrow suppression. Consequently, the dose was decreased to 0.5mg/d in 7 subjects (2 remain on 3.0mg). 9 subjects remain on POM (all but 2 at 0.5mg/d. 104 cycles have been given (median, 4/ subject; range, 2-11). 10 subjects, all at ≥2.5mg/d discontinued because of lack of response/ withdrawal of consent (N=5), progression (N=4) or unrelated worsening co-morbidities (N=1). Toxicity: Dose-related bone marrow suppression was the main toxicity. 10/19 subjects had grade-3/-4 neutropenia (N=8) and/or thrombocytopenia (=3) and was only observed at doses ≥2.5mg/d. No substantial bone marrow suppression at 0.5m/d. Non-hematologic toxicity was uncommon at any dose level with grade-3 fatigue at 3.0mg/d in 1 subject. Efficacy: There was clinical benefit in 9 subjects. 7 subjects achieved an IWG-MRT response (Tefferi et al, Blood, 2006) including clinical improvement (CI) in anemia (N=6; rbc-transfusion-independence or hemoglobin increase >2g/dL for ≥2 mo) and/or splenomegaly (N=2; ≥50% reduction of palpable component for ≥2 months). 2 subjects had improved anemia below the IWG-MRT CI-threshold. Clinical benefit occurred after a median of 3.8 mo (range, 2.1-9.2 mo), and only after reduction to 0.5mg/d in 7 responders including both with spleen responses. There were 2 responses amongst 11 subjects receiving ≥2.5 mg/d compared to 7 of 8 subjects receiving '1.0mg/d. These responses occurred a median of 1 cycle after dose reduction (1-3 months). Responses were durable: 8 of 9 responders continue on-study. CONCLUSIONS: In subjects with myelofibrosis, POM doses ≥2 mg/d are associated with moderate to severe bone marrow suppression. Response occurred at doses ≥2 mg/d primarily after dose reduction to 0.5 mg/d where bone marrow suppression was infrequent. The authors suggest 0.5 mg/d as the preferred doses for a phase-3 trial. Disclosures: Litzow: Enzon: Honoraria, Research Funding.

Abstract Patients with very-high risk (purine analogue refractory and TP53 defective) CLL have limited treatment options. In these patients alemtuzumab can be effective against CLL cells in the circulation and bone marrow, and in combination therapy with fludarabine can be active in patients with bulky disease, but these regimens have a high risk of serious infections. Addition of rituximab to alemtuzumab can also improve efficacy but has limited activity against bulky disease. We conducted a phase II clinical trial to determine the efficacy and toxicity of therapy with pentostatin, alemtuzumab, and low dose higher frequency rituximab (PAR) in patients with relapsed/refractory or progressive CLL with 17p13 deletion. The rituximab schedule was designed to decrease the loss of CD20 expression by circulating CLL cells. Methods This two-stage phase II trial study (NCT00669318) conducted at the Mayo Clinic Rochester and University of Iowa with IRB approval had an accrual goal of 38 evaluable patients. Eligibility required a diagnosis of progressive CLL by standard criteria and either previous treatment for CLL (<4 purine analogue regimens) or 17p13 deletion (17p13-). Exclusion criteria were organ failure, poor performance status (ECOG >3), infection with HIV, hepatitis B, hepatitis C, active autoimmune cytopenia, or alemtuzumab therapy within the past 2 months. Rituximab 20 mg/m2 IV M-W-F started on day 1, alemtuzumab started on day 3 with an escalation of 3-10-30 mg/d SQ and then 30 mg M-W-F from day 8, and pentostatin 2 mg/m2 IV every 2 weeks started on day 8. Peg-G-CSF or GM-CSF was used after each dose of pentostatin and patients received Pneumocystis and Varicella prophylaxis. CMV PCR assays were done weekly during treatment and viremia was treated with either valganciclovir or ganciclovir. Cycle 1 was 5 weeks and subsequent cycles were 4 weeks. At the end of cycle 2 patients with a clinical CR had a CT scan and a bone marrow study with immunohistochemical (IHC) staining for residual CLL cells, and therapy was stopped if there was no radiological or IHC evidence of residual CLL (stringent CR). Patients with residual disease received a 3rd cycle of therapy. Results Forty-one patients were enrolled (July 2008 - February 2013) and all 39 who started therapy were evaluable for response: Median age 61 years (range 47-78), 30 (77%) males, 36 (92%) relapsed/refractory CLL (median prior regimens = 2, range 1-10), 3 (8%) previously untreated, 23 (59%) advanced stage (Rai III-IV), 16 (41%) intermediate stage (Rai I-II). Prognostic factors: FISH (hierarchical classification) 15 (38%) 17p13-, 6 (15%) 11q22-, 5 (13%) 12+, 3 (8%) no defects, 8 (21%) 13q14-, and 2 (5%) other abnormalities, IGHV analysis (n=38) 27 (71%) unmutated (<2%), ZAP-70 (n=37) 28 (76%) positive (>20%). Thirty (77%) patients completed planned therapy (28 had 3 cycles, 2 had 2 cycles with stringent CR). Nine patients received one (n=4) or two (n=5) cycles of therapy because of disease progression or complications. Grade 3-4 hematological adverse events (n=37) at least possibly related to treatment included neutropenia (n=22), thrombocytopenia (n=11), anemia (n=2) and hemolysis (n=2). Non-hematological adverse events (n=17) included infections/neutropenic fever (n=8), fatigue (n=3), and hemorrhage (n=2). CMV reactivation was detected and treated in 14 patients (grade 1-2). No patients died during treatment or from treatment related complications. The overall response rate was 56% (95% CI 40-72) with 4 (10%) CR, 7 (18%) CRi, 11 (28%) PR, 7 (18%) SD, and 10 (26%) PD. Four patients (3 CR and 1 CRi) had IHC negative bone marrow studies. Thirteen (33%) patients have died due to progressive CLL (n = 11), sepsis (n=1), and pneumonia (n=1). Median follow up for surviving patients is 23 months (range 3-55). Seven (18%) patients proceeding to RIC allogeneic transplant were censored for time to next treatment. Twenty-one (54%) patients required therapy for progressive CLL and 7 (18%) have required no further therapy. Median progression free survival was 7 months (95% CI: 5-16), time to next treatment 9 months (95% CI: 6-27) and median overall survival has not been reached. Discussion PAR was effective and tolerable therapy for high-risk CLL. This study suggests that alemtuzumab can be used safely in combination with a purine analogue in a short-duration regimen. Disclosures: Zent: Genentech : Research Funding; Genzyme: Research Funding; Biothera: Research Funding; GlaxSmithKline: Research Funding; Novartis: Research Funding. Off Label Use: Pentostatin therapy for CLL, use of lower doses of rituximab.