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We studied the incidences, associations, and prognostic roles of NOTCH1 and SF3B1 mutations (NOTCH1(mut), SF3B1(mut)) as compared with TP53(mut) in fludarabine-refractory chronic lymphocytic leukemia (CLL) patients treated with alemtuzumab in the CLL2H trial. We found NOTCH1(mut), SF3B1(mut), and TP53(mut) in 13.4%, 17.5%, and 37.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) were mutually exclusive, whereas TP53(mut) were evenly distributed within both subgroups. Apart from correlation of SF3B1(mut) with 11q deletion (P = .029), there were no other significant associations of the mutations with any baseline characteristics or response rates. However, NOTCH1(mut) cases had a significantly longer progression-free survival (PFS) compared with wild-type cases (15.47 vs 6.74 months; P = .025), although there was no significant difference with overall survival (OS). SF3B1(mut) had no significant impact on PFS and OS. In multivariable analyses, NOTCH1(mut) was identified as an independent favorable marker for PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00274976.

Background Chemotherapy-induced polyneuropathy (CIPN) is a common toxicity after chemotherapy, immunomodulatory drugs or proteasome inhibitors, which is difficult to treat and may also have impact on quality of life. The objective of the study was to evaluate whole-body vibration (WBV) on the background of an integrated program (IP) including massage, passive mobilization and physical exercises on CIPN. Patients and methods In an exploratory phase-2 study patients with CIPN (NCI CTC grade 2/3) were randomized for WBV plus IP (experimental) to IP alone (standard). 15 training sessions within 15 weeks were intended. As primary endpoint we used chair-rising test (CRT) to assess physical fitness and coordination. In addition, locomotor and neurological tests and self-assessment tools were performed. Results A total 131 patients with CIPN were randomized (standard, n = 65; experimental, n = 66). The median age was 60 (range 24–71) years; 44 patients had haematological neoplasms and 87 solid tumors. At baseline, all patients presented with an abnormal CRT. Fifteen (standard) and 22 (experimental) patients left the program due to progression/relapse or concomitant disease. There was no significant difference in the proportion of patients with normal CRT (

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

Purpose To assess the impact of allogeneic hematopoietic stem-cell transplantation (HSCT) from matched related donors (MRDs) and matched unrelated donors (MUDs) on outcome in high-risk patients with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. Patients and Methods Between 1998 and 2004, 844 patients (median age, 48 years; range, 16 to 62 years) with AML were enrolled onto protocol AMLHD98A that included a risk-adapted treatment strategy. High risk was defined by the presence of unfavorable cytogenetics and/or by no response to induction therapy. Results Two hundred sixty-seven (32%) of 844 patients were assigned to the high-risk group. Of these 267 patients, 51 patients (19%) achieved complete remission but had adverse cytogenetics, and 216 patients (81%) had no response to induction therapy. Allogeneic HSCT was actually performed in 162 (61%) of 267 high-risk patients, after a median time of 147 days after diagnosis. Graft sources were as follows: MRD (n = 62), MUD (n = 89), haploidentical donor (n = 10), and cord blood (n = 1). The 5-year overall survival rates were 6.5% (95% CI, 3.1% to 13.6%) for patients (n = 105) not proceeding to HSCT and 25.1% (95% CI, 19.1% to 33.0%; from date of transplantation) for patients (n = 162) receiving HSCT. Multivariable analysis including allogeneic HSCT as a time-dependent covariable revealed that allogeneic HSCT significantly improved outcome; there was no difference in outcome between allogeneic HSCT from MRD and MUD. Conclusion Allogeneic HSCT in younger adults with high-risk AML has a significant beneficial impact on outcome, and allogeneic HSCT from MRD and MUD yields similar results.

Background Pomalidomide (POM) in a 1-arm phase-1/-2 study and a randomized 4-arm phase-2 study in MPN-associated myelofibrosis improved anemia. Pomalidomide was evaluated at doses of 0.5 and 2.0 mg/d. Aims To evaluate efficacy of POM alone at two different doses and combined with prednisolone (PRED) in patients with MPN-associated myelofibrosis and cytopenia (ClinicalTrials.gov No. NCT00949364). Methods Main inclusion criteria were RBC-transfusion-dependence or hemoglobin Results 38 patients were treated in cohort-1 and 58 in cohort-2 (N=27, PRED-mo-4; N=31; PRED-mo-7). Median follow-up was 30 mo in cohort-1 and 10 mo in cohort-2. Median age was 72 y (range, 49-85 y). 34% were female, 72% had primary MF. Disease-stage at study-entry (DIPSS) was high-risk, 24%, intermediate-2 risk, 65% and intermediate-1 risk 12%; JAK2V617Fand MPLW515L were detected in 58% and 6% of patients; 76% of patients were RBC- and 17% platelet-transfusion-dependent. There were no significant differences in pretreatment characteristics between cohort-1 and cohort-2 or between the 2 arms of cohort-2. Median durations of POM treatment were 12, 8, and 4 mo, respectively. PRED was added in cohort-1 and in the PRED-month-4 as well as PRED-month-7 arms of cohort-2 in 50%, 59% and 26% of patients. Response-rates were: 34% (95%-CI, 21-50%), 19% (95%-CI, 8-37%) and 16% (95%-CI, 7-33%), respectively; p=0.086. Responses occurred after 6 mo (range, 1-15 mo), 7 mo (range, 1-12 mo) and 4 mo (range, 3-7 mo). Anemia responses were observed more frequently in cohort-1 (29% [95%-CI, 17-45%]) compared to cohort-2 (14% [95%-CI, 7-25%]; p=0.059). Platelet response in patients with platelets100/nL were achieved in 56% (95%-CI, 27-81%) and 25% (95%-CI, 9-53%; p=0.20). 13 patients (12 high risk) experienced blastic transformation; 4 patients developed solid neoplasms. Conclusions Response rate to POM at a dose of 2mg/d was higher compared to 0.5 mg/d. Early addition of PRED at 4 mo compared to 7 mo was associated with longer treatment duration. Disclosures: Schlenk: Novartis: Research Funding; Amgen: Research Funding; Chugai: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Reiter:Sanofi: Honoraria. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy. Platzbecker:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Heidel:Novartis Inc.: Research Funding; Novartis Inc.: Honoraria.

Abstract 716 CLL patients characterized by 17p-, TP53 mutation or refractoriness to fludarabine (F)-based therapy show a very poor prognosis (“ultra high-risk CLL”). Although alemtuzumab (A) showed efficacy in these cohorts, the rate and duration of remissions remain unsatisfactory. Aim of the CLL2O study was to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A during induction and investigating the consolidation effect of prolonged A or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A, 30 mg weekly × 3 for 28 days, combined with oral D, 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Treatment duration was up to max. 12 weeks. Consolidation was at discretion of pt and physician with either allo-SCT or maintenance A with 30 mg every 14 days for up to 2 years (y). Between Jan. 2008 and Dec. 2011, 131 eligible pts were recruited at 26 centers. Pts were generally subdivided into three cohorts: 61 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or similar (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=42) or relapsed CLL (n=28). The median age was 66.5/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 45/57/77% Binet C, 40/32/31% B symptoms, 38/40/56% ECOG 1 or 2, median TK levels of 36/49/26 U/L, median β2MG levels of 3.8/5.3/4.7 mg/L, and unmutated IGHV in 90/93/87%. In the F-refractory group, 49% exhibited 17p- and 20% had 11q-. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse) and 93/72% had received rituximab. 5 pts had previously undergone autologous and 1 pt allo-SCT. This analysis includes data for induction therapy of all eligible pts (n=42/28/61). Of these 74/57/54% received the full induction of 36 A applications, with a median duration of 11.6 weeks (range 0.6 – 33.4). ORR was generally high with 98/79/70%. Current CR rates are 19/4/3%, in part due to missing bone marrow examination (5/0/1 pts). After a median follow-up of 21 months (mo), median progression-free survival (PFS) was 38/10.3/11.6 mo. Median overall survival (OS) was not reached (>36 mo) in the 1st line group, and 21.3/17.3 mo in 17p- relapse/F-refractory pts. Consolidation treatment was maintenance A (median duration 34 weeks, range 2 – 112) in 37%, and allo-SCT in 27%, with a median age of 69 and 57.5 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (12%, n=16, of these 13 in the F-refractory cohort and 10 without response), PD (10%), and toxicity (10%). Among the 47 pts not receiving consolidation, there were 32 (68%) deaths, 23 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 23 (49%) and 12 (35%) PD events, respectively, with a trend favoring SCT (median 24.7 vs. 17 mo, p = 0.13). During induction, grade 3/4 consisted of anemia 30%, neutropenia 46%, thrombopenia 42%, and non-CMV infection 24% of 17p- 1st-line, 29% of 17p- relapsed, and 38% of F-refractory pts. CMV reactivation was observed in 55/33/43%, without severe sequelae. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 43% pts and thrombopenia in 6% pts with 10 SAEs (ITP, diarrhea, infection (2), septic shock, erythema, tachycardia and cardiac decompensation, syncope, pulmonary embolism and thrombosis), reported for 7 pts (4/1/2 pts). So far, 7 pts with consolidation by allo-SCT have died, of these 5 due to infection, 1 due to PD (Richter transformation), and 1 due to complications of acute GVHD. Conclusions: The combination of A and D shows relatively high CR and ORR, with promising preliminary findings for PFS and OS, as compared to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the FCR arm of the CLL8 study. On the other hand, in F-refractory CLL, the higher ORR does not seem to translate into a major improvement of long-term results, when compared to single-agent A. Allo-SCT may offer PFS and OS superior to maintenance A, but confirmation of this trend requires more mature follow-up and multivariate analysis. Disclosures: Stilgenbauer: Genzyme: Consultancy, Honoraria, Research Funding. Ibach:WiSP CRO: Employment.

Abstract 2840 Background: Pomalidomide in a single arm phase-I/II study and one randomized four arm phase-II study in primary myelofibrosis (MF) and post-polycythemia vera/essential thrombocythemia (post-PV/ET) MF showed efficacy in particular with respect to improvement in anemia. To date, pomalidomide has been evaluated in MF at two dose levels, 0.5mg and 2.0 mg/day. Aims: To evaluate clinical efficacy of pomalidomide alone and in combination with prednisolone (PRED) in patients with primary or post-PV/ET MF and cytopenia. Methods: The main inclusion criteria for primary or post-PV/ET MF patients were red blood cell (RBC)-transfusion-dependence or hemoglobin =50 years were eligible. Treatment consisted of pomalidomide (POM) 2mg/day; prednisone (PRED) 30mg/day was added in patients who did not respond (≤ stable disease) within three months of therapy. The primary endpoint was response assessed by IWG criteria and extended by the criterion red blood cell transfusion-independence (Gale RP et al., Leuk Res. 2011). Concurrent hydroxyurea in patients with proliferative disease and aspirin 100 mg/d in patients with platelets between 50/nl and 1000/nl were administered. The statistical design of the study was based on the Simon optimal two-stage design. Here we report on the first stage of the study. Median follow-up according to the method of Korn was 18 months. Results: Thirty-eight patients were treated with POM 2 mg/d, the median age was 71 years (range 51–83), 34% were female. Twenty-seven had primary and 11 post-PV/ET MF. Disease stage at study-entry according to the DIPSS was high-risk in 13 (34%), intermediate-2 risk in 22 (58%) and intermediate-1 risk in 3 (8%). Incidence of high-risk cytogenetics, JAK2 V617F mutation and MPL W515L mutation were 29% (10/34), 55% (21/38) and 18% (7/38), respectively. Twenty-seven patients (71%) were RBC-transfusion- and 7 (18%) platelet-transfusion dependent. Median duration of treatment with POM was 11.4 months with 5 patients continue on treatment 24+ months. PRED was added after 3 months in 19 of 28 eligible patients. POM dose-reduction (n=8, 1mg/d; n=2, 0.5mg/d) was performed after a median time of 34 days (range 3–308 days) due to fatigue (n=2), thrombo- and/or neutropenia (n=7), rash (n=1). Seven patients with high risk characteristics (n=6 RBC-transfusion dependent, n=4 high risk cytogenetics) experienced transformation into blast phase (BP), the actuarial probability of transformation to BP measured from diagnosis was 6.0% (SE 4.1%) at 2 years and 22.4% (SE 8.4%) at 5 years. Response was observed in 14 patients (37%) after a median time of 4.8 months (n=1 complete remission, n=5 clinical improvement-platelets, n=3 clinical improvement-erythrocytes, n=5 red cell transfusion-independence); 8 responders received concomitant PRED and responded after a median of three months (range 0.8–11.7 months) of the addition of PRED. In 5 of 14 responders POM dose was reduced due to toxicity, notably before response occurred. Responses were observed within the first 3 months (n=4), between month 4 to 6 (n=4) and beyond month 6 (n=6) with the latest response seen at 12.7 months. There was no correlation between response and JAK2/MPL mutation status or cytogenetics. Basophilia defined as greater than 50% increase in absolute basophil count at month 3 was in trend associated with response (p=0.06). Conclusions: POM with or without PRED in patients with different risk groups of patients with primary and post-PV/ ET MF was effective with a response rate of 37%. Based on results of this first cohort the protocol was amended; i) POM dose has been adjusted to 0.5 mg/d, ii) up-front randomization of PRED at month 4 or month 7 in patients without response but stable disease to single agent POM was introduced. Disclosures: Schlenk: Celgene: Research Funding. Off Label Use: Pomalidomide is so far not approved for the treatment of primary and secondary myelofibrosis.

Abstract 433 Novel gene mutations have been found in CLL by next generation sequencing including mutations of NOTCH1 and SF3B1 in 5–20% of cases. In initial studies, both have been associated with advanced disease and poor outcome. We assessed the incidence and impact of gene mutations in the CLL8 trial (1st line FC vs. FCR, n=817). TP53 (exons 2–11) was analyzed by a re-sequencing chip (Amplichip, Roche Molecular Systems) with confirmatory Sanger sequencing. NOTCH1 was analyzed by Sanger sequencing exon 34, chr9:139,390,619–139,391,290 (PEST domain). SF3B1 (exons 13–16) was analyzed by DHPLC (WAVE® 3500HT, Transgenomic Inc.) with subsequent Sanger sequencing. Baseline samples were available for analysis of genetic markers in 619 (75.8%) to 645 (78.9%) patients. All markers were available for 573 (70.1%) patients and this cohort was representative of the full trial population. Mutations (mut) were found in TP53, NOTCH1, and SF3B1 in 11.5%, 10.0%, and 18.4%, respectively. At least one mutation was identified in 35.2% patients, while 30.6% had one, 4.4% had two and 0.2% had three mutations. Concurrent NOTCH1mut and SF3B1mut were found in only 0.5% patients. TP53mut was observed in 16.7% of NOTCH1mut cases (p=.528) and in 14.5% of SF3B1mut patients (p=.472). Regarding baseline characteristics, there were significant associations of TP53mut with CIRS>1, unmutated IGHV and 17p-; of NOTCH1mut with Binet A/B, no B-symptoms, unmutated IGHV, and 17p-; and of SF3B1mut with TK>10, and no +12. Regarding response to therapy, TP53mut was significantly associated with refractory disease in both arms (FCR: 25.0% vs. 1.8%, p At extended follow-up (median 69.97 months), FCR resulted into significantly improved PFS (HR 0.586, p To evaluate the independent prognostic impact, we performed multivariable analyses by Cox regression for PFS and OS including the following variables: treatment, age, sex, stage, ECOG status, B-symptoms, WBC, TK, β2-MG, 11q-, +12, 13q-, 17p-, IGHV, TP53, NOTCH1 and SF3B1. Regarding PFS, the following independent prognostic factors were identified: FCR (HR 0.510, p10 (HR 1.367, p=.019), IGHV0 (HR 2.202, p10 (HR 2.707, p To identify a predictive impact of gene mutations for a specific treatment effect by the addition of rituximab, we performed multivariable analyses including the treatment arms, the gene mutations and the interaction of both. Regarding PFS, FCR (HR 0.544, p In conclusion, gene mutations show independent prognostic value for PFS (TP53, SF3B1) and OS (TP53) in patients receiving 1st line FC and FCR treatment. Of note, NOTCH1mut appears to identify a subset of CLL patients that does not benefit from the addition of rituximab to FC. Disclosures: Stilgenbauer: Roche: Consultancy, Honoraria, Research Funding. Patten:Roche: Employment. Wenger:Roche: Employment. Mendila:Roche: Employment. Hallek:Roche: Consultancy, Honoraria, Research Funding.

Abstract 710 Genetic alterations play a major role in stratifying prognostic risk groups in chronic lymphocytic leukemia (CLL). Recently, next generation sequencing strategies revealed novel recurrent mutations in genes such as NOTCH1 and SF3B1 in CLL. Correlations have been reported for SF3B1 mutations (SF3B1mut) with deletion 11q and for NOTCH1 mutations (NOTCH1mut) with trisomy 12. Both mutations have been associated with unmutated IGHV, refractory disease and inferior outcome in heterogeneous cohorts outside clinical trials. We assessed the incidence and prognostic impact of NOTCH1, SF3B1 and TP53 mutations in the CLL2H trial of the GCLLSG, a multicenter phase II trial of subcutaneous alemtuzumab (3 × 30mg/week, max. 12 weeks, n=103, NCT00274976) for fludarabine-refractory CLL patients. Genetic studies were performed in the central reference laboratory of the GCLLSG on 97/103 (94%) trial patients based on availability of DNA. NOTCH1 was analyzed by Sanger sequencing of a PCR fragment from the PEST domain (exon 34, chr9:139,390,619–139,391,290), while SF3B1 (exons 13–16) and TP53 (exons 2–11) were analyzed by DHPLC (WAVE® 3500HT, Transgenomic Inc.) followed by sequencing of aberrant fragments. NOTCH1 mut were found in 13/97 (13.4%), SF3B1mut in 17/97 (17.5%), and TP53mut in 37/99 (37.4%) cases. Two different types of NOTCH1mut (c.7541_7542delCT, n=11; c.7444delC, n=2) and 13 different point mutations of SF3B1 were identified. All SF3B1mut were heterozygous missense mutations resulting into 11 different amino acid changes in exons 14, 15 and 16. Of note, in none of the 97 cases concurrent NOTCH1mut and SF3B1mut was found. IGHV was unmutated in 71/90 (79%) cases overall, in 100% of NOTCH1mut (p=.062) and in 60.0% of SF3B1mut (p=.078). Moreover, SF3B1mut was associated with 11q deletion (p=.042), but we observed no significant correlation of NOTCH1mut with trisomy 12 (p=.321). TP53 mut was found together with NOTCH1mut in 3/12 (25%, p=.349) and with SF3B1mut in 7/17 (41%, p=1.000) cases. The overall response rates (ORR) among the 97 cases was 34% (3% CR and 31% PR). After a median follow-up time of 33.9 months, the median progression-free survival (PFS) was 7.7 months, and the median overall survival (OS) was 18.3 months. The ORR was not significantly different when comparing the groups with or without mutations (50.0% vs. 34.2% for NOTCH1, p=.341 and 41.2% vs. 35.1 % for SF3B1, p=.781, respectively). PFS in NOTCH1mut cases was significantly superior as compared to wild type cases (median 15.47 months vs. 6.74 months, p=.025, see Figure) but there was no significant difference in OS (median not reached vs. 18.3 months, p=.181). For SF3B1mut, we found no significant difference between mutated and wild type cases in PFS (median 4.76 vs. 7.72, p=.974) and OS (median 29.0 vs. 17.1, p=.243). Multivariate analysis of PFS and OS was performed including age, ECOG performance status, WBC, thymidine kinase, β2-microglobulin, IGHV status, 11q deletion, 17p deletion, NOTCH1mut, SF3B1mut and TP53mut as potential factors. Regarding PFS, ECOG performance status > 1 (HR 2.080, p=.057), increased thymidine kinase (cont.) (HR 1.479, p=.007) and elevated β2-microglobulin (cont.) (HR 1.188, p=.0003) emerged as independent unfavorable prognostic factors, whereas NOTCH1mut (HR 0.375, p=.049) was a favorable marker. Regarding OS, none of the gene mutations showed significant prognostic impact, whereas age at increments of 10 years (HR 1.035, p=.024), ECOG performance status > 1 (HR 2.575, p=.017) and increased thymidine kinase (HR 1.568, p=.002) were identified as independent unfavorable factors. In summary, our analysis performed in a multicenter trial of fludarabine-refractory CLL patients showed NOTCH1mut in 13.4%, SF3B1mut in 17.5% and TP53mut in 37.4% cases, with NOTCH1mut and SF3B1mut being mutually exclusive. As compared to non-refractory CLL cohorts, the incidence of NOTCH1mut and SF3B1mut do not appear to be increased which is in contrast to TP53mut. NOTCH1mut was found as a favorable prognostic marker for PFS, but none of the mutations impacted OS in this trial. Figure: Figure:. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding. Stilgenbauer:Genzyme: Consultancy, Honoraria, Research Funding.

Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

Abstract 185 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy Background: Treatment options in AML patients older than 60 years are limited. In our previous randomized AML HD98B trial, the addition of all-trans retinoic acid (ATRA) to intensive chemotherapy resulted in an increased complete remission (CR) rate, event-free (EFS) and overall survival (OS). Recent reports indicated a synergistic action of the histone deacetylase inhibitor, valproic acid (VPA), and ATRA as differentiating agents. A synergic effect of VPA in combination with cytarabine and anthracyclines was also observed in vitro. Aims: To evaluate VPA in combination with intensive induction therapy and ATRA in older patients with newly diagnosed AML. Methods: Between August 2004 and February 2006 186 patients were randomized (standard arm, n=93; investigational arm, n=93) in the AMLSG 06-04 study (ClinicalTrials.gov Identifier: NCT00151255); median age was 68 years (60-84). The first 77 were randomized to receive 2 induction cycles (idarubicin 12 mg/m2 i.v. days 1–3, cytarabine 100 mg/m2 cont. i.v. days 1–5, ATRA 45 mg/m2 days 3–5 and 15 mg/m2 days 6–28) with or without VPA (days 1–28; started at 400 mg twice a day iv for 2 days and then adapted after day 2 po in order to obtain a serum level of 60–150 mg/l). After an interim analysis the study was amended; for the following 109 patients idarubicin was dose-reduced to day 1 and 3 and VPA only added during the first induction cycle. All patients were intended for consolidation. Results: CR rates after double induction were in trend higher in the standard arm (standard, 51%; investigational, 40%; p=0.18), whereas rates of early death (ED) were significantly higher in the investigational arm (8% versus 24%; p=0.004) of the study. The increased rates of ED in the investigational arm were present before (p=0.06) and after the amendment (p=0.05). The main observed toxicities attributed to VPA were grade 3/4 infections and delayed hematologic recovery, with differences between the two arms exclusively seen in the second induction cycle and only in the cohort treated before the amendment: grade 3/4 infections 33.3% versus 53% (p=0.0001); median time to WBC count >1.000 /μ L 21 days versus 26 days (p= 0.02); median time to neutrophil count >500/μ L 24 days versus 30 days (p=0.002); median time to platelet count >20.000/μ L, 19 days versus 28 days (p=0.009) in the standard and investigational arm, respectively. Pharmacokinetic studies revealed that the aimed VPA-serum level of above 60mg/l was achieved in only half of the patients at day 8 of treatment. The interrelationship between VPA-dosage and serum level was weak (Spearman's coefficient, 0.35). The correlation between total VPA-serum level and free VPA-serum level evaluated in a subset of patients adjusted for albumin level was strong (p The median follow up was 47 months; OS and EFS were not significantly different (3-year OS; standard, 16.3%; investigational, 13.2% (p=0.33); EFS; standard, 4.6%; investigational, 8.6% (p=0.77). The cumulative incidence of relapse (CIR) and death at 3 years was 79% and 10% for the standard arm as well as 68% and 5% for the investigational arm (p=0.16, p=0.73), respectively. Multivariate Cox regression analysis on OS revealed a negative impact of age above 70 years (HR, 1.76; p=0.003), high log10(WBC) (HR, 1.59; p=0.0006), adverse cytogenetics (HR, 2.05; p=0.0009) and in trend wild type NPM1 (HR, 1.58; p=0.06), whereas treatment arm was not significant (HR, 1.21; p=0.29). Conclusion: In older patients with AML, the addition of VPA to standard induction treatment did not improve clinical outcome. VPA was associated with an increased rate ED due to infections and delayed hematologic recovery. Disclosures: Döhner: Pfizer: Research Funding. Schlenk:Celgene, Pfizer, Novartis, Cephalon, Amgen:.

Abstract 2184 Background: Treatment outcome in patients with cytogenetically and/or molecularly defined high-risk acute myeloid leukemia (AML) is dismal with low complete remission (CR) rates after intensive induction therapy and 5-year overall survival of about 25% in patients 60 years and younger and far below 5% in patients above the age of 60 years. In younger patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched related or unrelated donors results in significantly better clinical outcome especially if patients are transplanted early in first CR (Schlenk et al., J. Clin. Oncol. 2010, in press). Azacitidine is a demethylating agent showing promising results as a single agent in AML patients with bone marrow blast counts between 20 and 30%. Therefore, the randomized AMLSG 12-09 trial will evaluate the combination of idarubicin/etoposide chemotherapy combined with azacitidine instead of cytarabine as compared to induction with idarubicin/etoposide/cytarabine (ICE) in an attempt to increase CR rates in these high-risk patients. Aim: To evaluate feasibility of the investigational induction therapy with idarubicin and etoposide in combination with sequentially or concurrently administered subcutaneous (sc) azacitidine. Methods: Patients were treated according to the investigational treatment schedules of the AMLSG 12-09 protocol. Patients received idarubicin 12 mg/sqm on days 1, 3 and 5 and etoposide 100 mg/sqm on days 1, 2 and 3 (patients above the age of 65 years received idarubicin 12 mg/sqm and etoposide 100 mg/sqm only on days 1 and 3, respectively). Azacitidine 100 mg/sqm sc was added on days -5 to -1 in 7 patients (schedule A), days 1 to 5 in 6 patients (schedule B), and days 4 to 8 in 5 patients (schedule C). Results: 18 patients have been treated (13 males and 5 females). Median age was 62.5 years (range, 28–76). The cytogenetic and molecular risk profile of the 18 AML was as follows: Eight AML had MDS-related cytogenetic changes (WHO 2008) including five exhibiting a complex karyotype and two had 3q abnormalities; three AML had balanced t(v;11q23), and six exhibited a normal karyotype together with triple negative genotype (NPM1-wt, FLT3-wt and CEBPA-wt). In one case, there were no metaphases available, however molecularly NPM1-wt, FLT3-wt, CEBPA-wt, no core binding factor AML, no t(15;17) and or t(9;11) were present. Median WBC was 4.6/nl (range, 0–6-75/nl). Overall response to induction therapy was CR n=7, partial remission (PR) n=3, refractory disease (RD) n=7 and one patient died during induction therapy (ED). Moreover, two patients with RD achieved CR after additional cycles of single agent azacitidine treatment. Overall response rates (CR and PR) according to treatment schedule were 43% (3/7), 67% (4/6) and 80% (4/5) for schedules A, B and C, respectively. Most common azacitidine-related toxicity was local reactions at injection site not exceeding CTC-grade 2. As expected, fever in neutropenia was the most common severe toxicity (83%). In addition, one patient with history of epilepsy had seizures during induction therapy and one patient with history of Crohn‘s disease had mucositis CTC-grade 3. Allo-HSCT has been performed in three patients and is planned in five. After a median time of 7.5 months, 16 of 18 patients are alive. Conclusion: Azacitidine administered sc can be given safely either sequentially or concurrently in combination with idarubicine/etoposide induction chemotherapy. Response rate of this high-risk population appears promising and the toxicity profile was favorable. The question which schedule is the most effective will be addressed in the randomized AMLSG trial (NCT01180322) Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Döhner: Pfizer: Research Funding. Schlenk: Celgene, Pfizer, Novartis, Cephalon, Amgen: Research Funding.

Abstract 920 CLL refractory to purine analogues (e.g. fludarabine, F) or with 17p- is associated with very poor prognosis. Alemtuzumab is active in F-refractory CLL, and has proven efficacy in patients (pts) with 17p-. However, outcome of F-refractory CLL is still poor in terms of remission rate and duration of remission. The multinational, multicenter CLL2O trial aims at achieving a higher remission rate by adding high-dose dexamethasone to alemtuzumab, and prolongation of remission duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (allo-SCT). Pts with CLL refractory (no PR/CR or PR/CR < 6 months) to F-based (e.g. FR, FC, FCR) or similar chemotherapy (i.e. pentostatin, cladribine, bendamustine), or exhibiting 17p- (untreated or at relapse) were eligible if they had “active disease”. Treatment was with subcutaneous alemtuzumab 30 mg weekly × 3 for 28 days, combined with oral dexamethasone 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or alemtuzumab maintenance with 30mg weekly every 14 days for up to 2 years (yrs). Decision for one of the two consolidation options was at discretion of patient and physician. From January 2008 to July 2010, 80 pts were enrolled at 22 centers and 79 were eligible; F-refractory (n=31), 17p- without prior therapy (n=31), and 17p- in relapse (n=17). Median age was 65 yrs in the F-refractory (range 38–76) and 17p- 1st-line group (36-76), and 60 yrs for the 17p- relapse group (54-73) with male predominance (F-refractory 74%, 17p- 1st-line 71%, 17p- relapse 82%). In the 17p- 1st-line and relapse groups, 52% and 50% were stage Binet C and exhibit reduced performance status (ECOG 1–2), compared to 81% Binet C and 60% ECOG 1–2 for the F-refractory cohort. Pretreated pts had received a median of 2 prior lines (F-refractory 1–6; 17p- relapse 1–5), and 5 pts had received prior SCT. In the F-refractory group, 16% of pts had 11q- and 52% had 17p-. IGHV was unmutated in 64% of 17p- groups and 72% in the F-refractory group. The median levels of ß2-MG / TK were 4.35 / 35.40 in the 17p- groups and 4.12 / 22.65 in the F-refractory group. Treatment data are currently available for 50 pts who completed induction therapy; F-refractory (n=19),17p- 1st-line (n=22), 17p- relapse (n=9). Full treatment duration (12 weeks) could be achieved in 47% F-refractory, 67% 17p- relapsed and 82% 17p- 1st-line pts. In the latter cohort, early stop of therapy was mainly correlated with CR, while in the F-refractory cohort with disease progression (n=2) and infections (n=5, 4 with no documented response). Response rates (ORR / CR) were 47% / 0% in the F-refractory cohort, 78% / 0% in the 17p- relapsed, and 100% / 23% in the 17p- 1st-line cohorts (as compared to this, ORR / CR was 71.4% / 4.8% with FCR in the 17p- 1st-line group of CLL8). Adverse events during treatment were mostly grade 1/2 apart from hematotoxicity. Grade 3/4 non-CMV infection occurred in 35% of F-refractory, 12% of 17p- relapsed, and 16% of 17p- 1st-line pts. CMV reactivation was observed in 32 % of the 17p- 1st-line pts, and less for the pretreated groups (F-refractory 16%, 17p- relapsed 18%). All CMV episodes were successfully treated, and there was no CMV-related death. Among 18 pts documented to receive alemtuzumab maintenance treatment, so far 3 SAEs have been reported: ITP (n=1, twice in the same pt), and fever / diarrhea / thyroiditis (n=1). At a median follow-up of 41.9 weeks (maintenance 54.7 weeks, allo-SCT 29 weeks), there were 7 (37%) deaths in the in the F-refractory cohort, 2 due to disease progression, and 5 due to infection. For the 17p- relapsed group, 3 progressions and 3 deaths were reported, with one case in each treatment option (SCT/maintenance), and one pt in salvage therapy. In the 17p- 1st-line cohort, 4 progressions occurred, 2 pts died, both in maintenance therapy. At 12 months, estimated overall survival was 54%, 66% and 100% in the F-refractory, 17p- relapse, and 17p- 1st-line cohorts, respectively. Accrual is currently ongoing with a target enrolment of 122 pts and updated results will be presented at the meeting. Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Off Label Use: off-label use of diagnostic tests and therapeutic agents. Leblond:ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Choquet:ROCHE : Consultancy. Hallek:Roche: Honoraria, Research Funding. Döhner:Pfizer: Research Funding.