Lazarus, Hillard M.

Abstract Abstract 3619 Extramedullary (EM) acute myeloid leukemia (AML) is generally associated with a poor prognosis. We evaluated the baseline characteristics, response and survival characteristics in a subset of patients age ≤ 60 years with de novo AML and EM manifestations at presentation, treated on the Eastern Cooperative Oncology Group E1900 protocol: daunorubicin 45 or 90 mg /m2 x3 days in conjunction with cytarabine 100 mg/m2 × 7 days followed by risk-stratified consolidation. (Fernandez et al New Engl J Med 2009) Methods: Patient baseline characteristics were compared using Fisher's exact test if they were categories and Wilcoxon rank sum tests if they were continuous. Logistic regression models were used for complete remission (CR) rates and Cox regression models were used for overall survival (OS) and disease-free survival (DFS). The univariate models included indication of whether patient had extramedullary disease involvement, adjusted by induction treatment. The multivariate models were further adjusted for age, gender, cytogenetic risk, ECOG PS, WBC, platelets, marrow blast, hemoglobin, peripheral blasts, and secondary AML. All P values were based on 2-sided tests. Results: 58 (8.9%) of 651 patients in the study presented with evidence of EM at diagnosis. Patients with EM disease were younger and presented with higher peripheral WBC counts and circulating blasts than those without. Immunophenotyping did not demonstrate a difference in baseline CD56 expression (p=0.77). Sites of EM involvement included gingival hypertrophy (n= 33), skin (n= 7), central nervous system (n= 6), lymphadenopathy (n=6), mediastinum (n=2) and other (n=6). 3 patients had multiple sites. Cytogenetic risk in the EM subgroup was favorable (8.6%), indeterminate (inadequate/missing) (34.5%), intermediate (37.9%) and unfavorable (19%) and did not differ statistically from those without EM disease. The complete remission (CR) rates were similar for patients with EM disease compared to those patient's without, regardless of the anthracycline dose (univariate model p= 0.93; multivariate model p=0.88. DFS (patients in CR) and OS of patients with EM disease was not significantly different in the univariate (p= 0.99, p=0.49) or multivariate models (p= 0.92, p=0.37), respectively. On multivariate modeling patients with EM AML who received the standard-dose of daunorubicin had a shorter OS (HR 1.86, 95% CI 1.20 to 2.91, p=0.006). OS was not improved in EM patients treated with high-dose daunorubicin (HR 0.62, 95% CI 0.34 to 1.14, p=0.12) (Table). There was a significant difference in OS for patients with EM treated with the 90 mg/m2 dose of daunorubicin compared to patients with EM treated with the 45 mg/m2 dose (multivariate model: HR 0.30, 95% CI 0.12 to 0.76, p=0.01). Conclusion: Younger patients with de novo EM AML are sensitive to higher doses of anthracycline in induction therapy and should be treated in a similar fashion as patients without EM involvement. For both groups the higher doses of anthracycline are recommended as CR rates, DFS and OS are improved. Further evaluation of immunophenotypic and molecular/ genetic characteristics should be undertaken in this subset of patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 493 The International MRC UKALL XII/ECOG E2993 trial for adults with newly diagnosed acute lymphoblastic leukemia (ALL) recruited 1,914 patients to the main part of the trial from 1995 up to its closure in 2006, of whom 100 were over the age of 55 years (median 57, range 55–65). Beginning in 2003 (MRC) or 2004 (ECOG), patients with Philadelphia chromosome positive (Ph+ve) disease were entered into an Imatinib sub-study. We report here baseline characteristics, treatment course and outcomes, and discuss implications for future management strategies. Direct comparison of the 100 patients over 55 yrs with 1,814 under 55 yrs showed that the groups are comparable for gender, immunophenotype and white cell count but there is an indication that more elderly patients had Ph+ve disease (28% aged ≥55 vs 17% aged <55 of those entered before the start of the Imatinib trial; p=0.02). All patients in this trial received a 2 stage induction regimen, consisting of Daunorubicin, Vincristine, Asparaginase and Steroid followed by Cyclophosphamide, Cytarabine, 6-Mercaptopurine and Methotrexate. CNS prophylaxis with IT Methotrexate and Cytarabine was given during both phases. There was a randomisation to autograft or chemotherapy, but only a small number of patients in this age group were randomised (13 autograft and 13 consolidation chemotherapy). Outcomes Complete remission (CR) rate, event-free survival (EFS) and overall survival (OS) were all worse in the over 55 age group, and even after achieving CR, the 5-year OS rate was reduced. There were more infections in phase I induction (67% vs 45%, p<0.0001) and more deaths during induction chemotherapy (18% vs 4% p<0.0001). Excluding those who died in induction, 47% had drug dose reductions in phase I or phase II vs 27% <55 yrs (P=0.0006). Of these, Asparaginase was the most common in those aged ≥55 years, usually due to hepatotoxicity. Age p-value <55 vs ≥55 <55 ≥55 Number 1814 100 CR No v Yes p<0.0001 No 131 (7%) 27 (27%) No (died in induction) 70 (4%) 18 (18%) No (but survived induction) 61 (3%) 9 (9%) Yes 1641 (90%) 70 (70%) Unknown 42 (2%) 3 (3%) Deaths 1112/1814 (61%) 78/100 (78%) Relapses 750/1683 (45%) 36/73 (49%) Overall survival at 5 years (95% CI) 41% (38–43%) 21% (12–29%) p<0.0001 Event free survival at 5 years (95% CI) 37% (34–39%) 19% (10–27%) p<0.0001 Relapse free survival at 5 years (95% CI) 50% (48–53%) 38% (25–52%) p=0.08 Overall survival at 5 years (95% CI) in those who achieved CR 44% (41–46%) 30% (18–41%) p=0.03 In those patients aged ≥55 years, baseline factors causing a significantly worse 5-yr EFS were Ph-positivity (0% vs 23%, p=0.005), unfavourable vs standard cytogenetic risk (7% vs 26%, p=0.02) and a presenting WCC >50 × 109/l (0% vs 25% for WCC between 10 and 49.9 × 109/l and 23% for WCC <10 × 109/l, p=0.003). Infection during induction chemotherapy predicted for worse EFS; this was especially significant in those who had infection in both phases of induction (6% vs 38%, p=0.007). In those patients who received chemotherapy and were not transplanted, the differences in outcome were smaller: 5-yr OS 25% in ≥55 years vs 38% in <55 years (p=0.06), 5-yr EFS 22% vs 32% (p>0.1). Conclusion Older adults fared significantly worse than younger adults both in terms of achieving an initial CR and long-term survival. This difference cannot be explained solely by a difference in disease characteristics, and the marked increase in infection and deaths during induction reflect the inability of many older patients to tolerate the intensive level of treatment. This is also supported by the large numbers of drug omissions or dose reductions seen. Our data show that this inability to tolerate induction chemotherapy is a major contributor to the poor outcomes seen in this age group. The less marked differences between age groups when transplant patients are excluded, indicates the significant mortality associated with these procedures in older patients. Alternative approaches to consider in this group include less intensive induction with a steroid and vinca alkaloid combination, in conjunction with targeted therapies (eg Rituximab in B-lineage CD20+ disease, Imatinib Mesylate in Ph+ disease). Even amongst those patients who do achieve CR however, the long-term outcome is worse. Reduced intensity allografts may play a role in carefully selected patients in this age group, and the emerging use of MRD monitoring may also assist in selecting patients for more or less intensive approaches. Disclosures: McMillan: EUSA: Honoraria. Goldstone: Roche: Honoraria, Speakers Bureau.

Abstract Abstract 1987 Background. MultiStem®, a multipotent adult progenitor cells (MAPC) collection, is an immune-modulatory, bone marrow-derived adult adherent allogeneic stromal cell product manufactured to large scale, assuring consistency of universal donor cell product during clinical evaluation. Pre-clinical studies showed safety of IV infusion and survival benefit in a haploidentical transplantation rat model of acute GVHD (Kovacsovics 2008, 2009). Methods. An open label Phase I clinical dose escalation study is being conducted with the primary goal to assess safety of MAPC as an adjunct treatment for human subjects undergoing myeloablative allogeneic HSCT for hematologic malignancies. Patients have been enrolled for MultiStem® administration as a single dose or in multiple weekly doses. Infusional toxicity and RRTs are assessed for 30 days following the last study drug dose administration. Secondary endpoints include incidence of acute GVHD, infection and survival through day 100. Dose escalation is guided by the Continual Reassessment Method (CRM). Results. In the single dose arm, 18 patients with AML (9), MDS (4), CML (3) and ALL (2) from 5 clinical centers were administered MultiStem® IV at 1, 5, or 10 million cells per kg at day 2 after allogeneic HSCT. There was no observed infusional toxicity. Two patients experienced Bearman RRTs (Gr 3 mucositis; Gr 3 renal & pulmonary failure) deemed unrelated to study product. Engraftment occurred in all 18 patients. The median time to neutrophil engraftment for related (n=7) and unrelated (n=11) HSCT was 15 days (range, 12–16 days) and 14 days (range, 11–25 days), respectively. The 100-day cumulative incidence of Grade II-IV and III-IV GVHD was 28% and 6% (n=18). In the highest MultiStem® dose group (n=9) there was no grade III-IV GVHD, and only one case of grade II GVHD, which subsequently resolved with treatment. 17/18 patients have been enrolled in the multidose arm. Results of safety endpoints and interim results of all secondary endpoints of repeated MultiStem® administrations following HSCT will be presented. Conclusion. Single dose administration of MultiStem® is well-tolerated, without observation of infusional toxicity or graft failure. Together with the observed low incidence of severe aGVHD, these findings are supportive of the concept that stromal stem cell therapy is safe and may be harnessed as an efficacious therapeutic option for acute GVHD prophylaxis following HSCT. Disclosures: Maziarz: Athersys, Inc: Patents & Royalties, Research Funding. Perry:Athersys, Inc.: Employment. Deans:Athersys, Inc: Employment. Van't Hof:Athersys, Inc.: Employment.

Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and the Medical Research Counsel, United Kingdom, and supported in part by Public Health Service Grants CA180820, CA180794, CA180790, CA189859, CA180853, CA180791, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Late relapse in acute leukemia is considered a relatively rare event. Patients with acute myeloid leukemia (AML) are often considered cured of the disease at 3 years, but information regarding adult acute lymphoblastic leukemia (ALL) patients is scarce. Data are presented from one of the largest prospective adult ALL studies, the MRC UKALLXII/ECOG E2993, to evaluate the rate and characteristics of late relapse in ALL. For this purpose, late relapse was defined, arbitrarily, as relapse 3 years post achievement of complete remission (CR) and very late relapse was defined as relapse > 5 years from CR. Methods: The UKALLXII/ECOG E2993 was an international ALL trial conducted jointly by the MRC in the United Kingdom and ECOG in the United States. All patients received identical induction therapy, followed by central nervous system prophylaxis. Patients with a sibling donor (or a matched unrelated donor in Philadelophia-chromosome-positive ALL) were assigned to receive an allogeneic hematopoietic stem cell transplant (HSCT); all others were randomized to undergo an autologous transplant or protracted standard consolidation/ maintenance therapy. The study accrued 2109 patients from 1993 to 2008. Following relapse, patients were followed for survival. For this report only patients registered before the tyrosine kinase inhibitors era are included in the analysis. Results: 1518 study patients were eligible for this analysis, 1208 (79.6%) Philadelphia-chromosome negative (Ph-neg) and 267 (17.5%) Philadelphia-chromosome positive (Ph-pos). 1381 (91%) of the patients achieved CR; 93% of the Ph-neg and 82% of the Ph-pos. 572 patients (37.7%) underwent allogeneic HSCT. The median duration of follow-up of patients who achieved CR was 10 years. Among the 1381 patients who achieved CR, 626 (45.3%) had a documented relapse; 566 (90.4%) relapsed within 3 years of CR and 60 (9.6%) relapsed beyond 3 years ('late relapse') (Figure 1). Among these 60 patients, 18(2.9%) relapsed after 5 years ('very late relapse'). Table. Patients n CR All relapses Relapses< 3 years Relapses≥ 3 years Relapses≥ 5 years All patients 1518 1381 (91%) 626 (45.3%) 566 (90.4%) 60 (9.6%) 18 (2.9%) Ph-neg 1208 (79.6%) 1123 (93%) 485 (40.1%) 429 (88.5%) 56 (11.5%) 17 (3.5%) Ph-pos 268 (17.5%) 219 (82%) 124 (56.6%) 122 (98.4%) 2 (1.6%) 1 (0.8%) Relapse beyond 3 years occurred in 4.3% of all who achieved CR, in 5% of Ph-neg and 0.01% of Ph-pos patients. Among the 60 late relapses, the median time to relapse was 46 months. 61.7% of the late-relapse patients were males, median age was 32 years, 88.3% were B-lineage ALL and the median white cell count at diagnosis was 6000/ul. 56.7% were in cytogenetic standard risk, 8.3% at high risk and the data of 35% are unknown. The median survival for the late relapse patients was longer than for those who relapsed within 3 years. The overall survival (OS) of the 56 Ph-neg patients who relapsed beyond 3 years is shown in Fig 2. Table.Relapse > 3 yearsRelapse > 3 yearsMedian survival from relapse (months)5.411.23-year OS from relapse6.5%29%5-year OS from relapse5.6%19% Conclusions: Late relapses in adults with Ph-neg ALL are not uncommon. About 10% of relapses occur beyond 3 years and 4.3% of all ALL patients who achieved a CR can expect to have a late relapse. These data are in contrast to AML where only 1% of patients relapse beyond 3 years (Watts JM et al, 2014). Most of the late relapse patients were at standard risk and appeared to have a relatively favorable outcome post relapse. Patients with ALL, particularly those who are Ph-neg, cannot be considered as cured at 3 years and need to be closely followed. Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Disclosures Rowe: Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Douer:Gilead: Consultancy.

Abstract Introduction: High-dose cytarabine consolidation chemotherapy for acute myeloid leukemia (AML) induces profound transient myelosuppression. Thrombocytopenia is a limiting factor in chemotherapy administration for maintaining dose intensity and schedule as thrombocytopenic-related hemorrhage may contribute to significant morbidity and mortality. Therapeutic and prophylactic platelet (plt) transfusions remain the treatment of choice but the benefits typically last only 3-7 days, are expensive, time consuming, and may induce alloimmunization and transmit infection. PrE0901 was a phase I multi-center study to evaluate the safety and toxicity of eltrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, for plt recovery in AML patients (pts) receiving consolidation therapy. Methods: The primary objectives were to determine the safety, tolerability, and optimal dosing of eltrombopag while describing the kinetics of plt recovery in AML pts receiving intensive consolidation. Plt recovery was defined as a sustained plt count of ≥ 20 x 109/L following the nadir with no plt transfusions in prior 7 days or a continued upward trend in plt count for at least 2 successive measurements despite no plt transfusions in 48 hours. We used a standard 3+3 design utilizing a novel dose escalation/de-escalation strategy for pts in either first or second complete remission, ≥18 and ≤70 years of age, who had an ECOG performance status of 0-2. Cytarabine was administered at 3 g/m2 (1.5 g/m2 for pts >60 years) IV over 3 hours twice daily on days 1,3,5. Eltrombopag at assigned dose was administered with a first cycle of cytarabine only. Planned eltrombopag dose levels -2, -1, 1, 2, 3, 4, and 5 were 50, 100, 150, 150, 150, 200, and 300 mg, respectively (Table 1). Eltrombopag was to start on days X, X, 3, -1, -5, -5, and -5 relative to day of cytarabine start and levels -2, -1, 1, 2, 3, 4, and 5, respectively, with day X being variable depending on timing of observed dose limiting toxicities (DLTs). The eltrombopag was continued until plt recovery or for up to 35 consecutive days, whichever occurred first. An exploratory objective was to determine if eltrombopag had an effect on TPO and EPO blood concentrations in this setting. Results: Accrual began on July 31, 2012 and the trial closed on January 8, 2016 upon recommendation after an independent Data and Monitoring Committee reviewed a separate trial of eltrombopag therapy in MDS which demonstrated futility. 104 pts were screened. 54 declined participation and 35 were deemed medically ineligible. A total of 15 eligible pts were enrolled; 14 were treated on study with one pt being withdrawn prior to starting treatment due to infection. Three pts were treated at each of dose levels 1-4 and two were treated on dose level 5. No DLTs were observed. Median time to plt recovery of all pts treated on study was 22.5 (range 16-43) days. Pts in cohort 1 dosed with eltrombopag 150 mg daily starting on day 3 of consolidation demonstrated the fastest plt recovery (median =19 days; range 19, 19, 19) compared to cohort 2 who received 150 mg daily starting on day -1 of consolidation and recovered the slowest (median 23 days; range 16, 23, 43). Dose escalation in terms of starting eltrombopag further in advance of chemotherapy exposure as within cohort 3 (150 mg starting day -5) was associated with a median plt recovery of 27 (range 22, 27, 27) days. Eltrombopag dose intensification with cohort 4 at 200 mg daily and cohort 5 at 300 mg daily was associated with median plt recoveries of 24 (range 18, 24, 26) and 23 (range 19, 27) days, respectively. Kinetics of plt recovery for all cohorts are represented in Figure 1 and duration of eltrombopag exposure for each individual patient is represented in Table 2. Conclusions: Endogenous cytokine (TPO and EPO) levels varied inversely with plt and hematocrit values and did not appear to be affected by eltrombopag dose / schedule (details to be provided at ASH Annual Mtg). Unusually high screen fail numbers warrant examination to guide future trial design in the post-remission setting. The addition of eltrombopag to high-dose cytarabine consolidation therapy was well-tolerated and no DLTs were observed. The results for cohort 1 [eltrombopag 150 mg daily starting on day 3 of consolidation] demonstrated the fastest plt recovery. Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding.

Abstract Abstract 524 The International UKALLXII/E2993 trial enrolled 2091 pts with newly diagnosed adult ALL between 1993 and 2006. Patients received 2 months of combination induction chemotherapy followed by an intensification course of high dose methotrexate and L-asparaginase after which pts were randomized to autologous hematopoietic stem cell transplant (HSCT) or consolidation and maintenance chemotherapy. Patients <55 years of age with a matched sibling donor were assigned myeloablative allogeneic HSCT (Goldstone, et al, Blood 2008; 111:1827). Here we report a detailed analysis of 1,229 pts from this trial with B-ALL, excluding Philadelphia-chromosome-positive patients. The median age was 30 years (range 14–65) and 59% were male. The median WBC was 9.2×109/L (range 0.1–930) and 73% of pts had a WBC <30 × 109/L. CNS involvement was present in 4% of pts at diagnosis. Comprehensive centralized immunophenotyping was performed in 372 of the 409 (91%) ECOG pts enrolled and initial analysis demonstrated pro-B/pre-pre-B in 17%, early pre-B in 52%, pre-B in 14%, either early pre-B or pre-B in 6%, mature B in 2% and B-lineage, not otherwise specified, in 9%. Outcomes were similar between patients with immunophenotyping data and those without. The complete remission (CR) rate was 93% and there were 4% induction deaths. The overall survival (OS), event-free survival (EFS), relapse risk (RR) and non-relapse mortality (NRM) at 5 years for the overall group is shown in the table. There were no significant differences in CR rate, OS, EFS, RR or NRM for the immunophenotypic subgroups. There was better OS and EFS with less relapse and similar risk of NRM for pts randomized to chemotherapy as compared with autologous HSCT (Figure 1). In the matched sibling donor-no donor comparison, OS and EFS were improved, RR was less and NRM was higher in the donor group (Figure 2). Cytogenetic analysis confirmed that patients with t(4;11) (n=77, 8% total), t(8;14) (n=19, 2% total), a complex karyotype (≥5 abnormalities in the absence of an established chromosomal abnormality) (n=38, 5% total), or low hypoploidy/near triploidy (n=41, 5% total) had an inferior OS and patients with high hyperdiploidy had a superior OS when compared to other patients. In conclusion, this is the largest series of B-ALL in uniformly treated adults ever reported and confirms the superior outcome of patients randomized to chemotherapy as compared with autologous HSCT and shows that patients with a matched sibling donor have an improved survival over patients without a donor. No difference in CR rates or outcome was noted for patients with different immunophenotypic subtypes of B-ALL. Future improvements in outcome of pts with B-ALL will rely on the addition of new agents such as B cell monoclonal antibodies and improvements in allogeneic HCT.Table.Outcomes at 5 years of follow-upnCR rate (%)OSEFSRRNRMOverall12299342375021Pro-B/pre-pre-B639236345421Early pre-B/pre-B2689340345421Age ≤ 35 years746 (61%)9653454516Chi square p<0.0001<0.0001<0.0001<0.0001<0.0001Age >35 years483 (39%)8932265930Randomized to autologous HSCT15735316610Log rank p0.030.010.01NSRandomized to chemotherapy1694742558Matched sib donor34452483032Chi square p0.050.03<0.001<0.001No Donor47445415510Values are % except n and p values. CR=complete remission, OS=overall survival, EFS=event-free survival, RR=relapse risk, NRM=non-relapse mortality NS=not significant. The p values represent the difference between age groups for the first comparison, randomized to autologous HSCT versus chemotherapy for the second comparison and between matched sibling donor and no donor for the third comparison. Overall survival by randomized allocation at 10 years Overall survival by donor availability at 10 years Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 579 Background: In AML, age and cytogenetics remain among the major prognostic factors. Age above 55 years and a complex karyotype (CK; ≥ 3 abnormal clones) or the presence of monosomy 7 (M7) are universally associated with unfavorable prognosis. Recent data from HOVON-SAKK (J Clin Onc 26: 4791) suggest that in patients under the age of 60 years, subgroups with poor risk versus very poor risk can be delineated based on the presence of a MK. MK was defined as either the presence of at least two autosomal monosomies or one monosomy plus at least one structural abnormality. Limited data exists regarding the impact of MK in AML patients over the age of 55 years. Methods: Data from 935 AML patients above age 55 enrolled on three prospective ECOG therapeutic clinical trials (E1490, E3993, E3999) between 1990 and 2005 were retrospectively reviewed to identify those with MK with single and/or multiple monosomies, MK in the presence or absence of a CK, CK with/without MK, MK with/without M7, and normal karyotype (CN). CK was defined as ≥ 3 clonal abnormalities for the purposes of this study. Complete remission (CR), disease-free survival (DFS), and overall survival (OS) were assessed. Results: The median age of evaluable patients was 68 years (range 56 – 93) with a male/female ratio of 391/299. Cytogenetic data were evaluable in 690 (74%) subjects. Clonal cytogenetic abnormalities occurred in 399 (58%). Core-binding factor (CBF) abnormalities accounted for 16/399 (4%) whereas CK was detected in 181/399 (45%). MK was present in 172 (25%) evaluable cases, predominantly in the setting of CK (140/172, 81%). Overall CR was 44%. CR was achieved in 49% MK−, 29% MK+, 31% CK+, and 49% of CK−. Data for the combinations of MK and CK are presented in Table 1. Median follow-up for survivors was 5.0 years. OS at 4-years was 9% for all evaluable patients and 4y-DFS was 12% in those achieving CR. Median OS of MK+/CK+ (0.3y) was significantly worse (p<0.001) than MK+/CK−(0.6y), MK−/CK+ (0.8y), and MK−/CK−(0.9y). Median DFS of MK+/CK+ (0.3y) was also significantly poorer (p<0.001) than MK+/CK− (0.9y), MK−/CK+ (0.8y), and MK−/CK− (0.9y). M7 was present in 82 (13%) enrolled patients with 98% (80/82) of M7 occurring within a MK. CR was achieved in 31% of MK+/M7+ and 27% of MK+/M7−. Neither median OS nor DFS were significantly impacted by M7 status as noted in Table 2. Conclusions: AML patients above the age of 55 years have an unfavorable prognosis with the majority of patients harboring adverse clonal cytogenetic abnormalities and failing to achieve a CR. Fewer than 10% survive 4-years from diagnosis. Results from the ECOG experience demonstrate the prognostic predictive value of MK in older AML patients. In contrast to the data presented by the HOVAN-SAKK group, the prognostic value of MK in patients over 55 years is limited to those with MK in combination with CK. These results also demonstrate the failure of monosomy 7 to provide prognostic value in the setting of MK. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3405 Poster Board III-293 Background: Autologous hematopoietic cell transplantation (AutoHCT) as consolidation has been an alternative to standard intensive chemotherapy and/or allogeneic HCT for younger patients with acute myeloid leukemia (AML) in first complete remission (CR). However concerns about toxicity and true benefits in long-term outcome have hampered its use. Methods: We present the follow-up of younger patients with de novo AML treated on ECOG study E1900, on an intention-to-treat (ITT) and per protocol (PP) analysis. DFS and OS were measured from the time of registration to consolidation therapy. Results: 657 patients younger than 61 years were initially randomized to standard-dose cytarabine and either standard- or high-dose daunorubicin in a 7+3 approach. Of the 352 patients who entered consolidation phase, 307 patients, 68 with favorable-risk cytogenetics (FRC), 128 with intermediate-risk cytogenetics (IRC), 90 with indeterminate cytogenetics (IDT) and 21 with unfavorable-risk cytogenetics (URC), were allocated to AutoHCT. Patients in these cohorts were treated with high-dose cytarabine 3g/m2 x 6 doses in 5 days, for two cycles. Peripheral blood cells were collected after the second cycle. Initially patients were randomized to receive gemtuzumab ozogamicin (GO) or not; however, no benefit was derived from GO therapy and the randomization was closed. 156 patients did not receive the planned AutoHCT due to disease progression, alternative therapy, failure to collect, insurance denial, toxicity and other reasons. 151 patients (33 FRC, 64 IRC, 47 IDT and 7 URC) were conditioned with IV busulfan 0.8 mg/kg daily x 16 doses (without dose adjustment) and cyclophosphamide 60 mg/kg x 2 days. Autologous cells were infused on day 0 and patients were supported with sargramostim until ANC recovery > 500/μL. Veno-occlusive disease occurred in three patients. Treatment-related mortality (TRM) of AutoHCT was 1.3% (2/151) at 30 days. Median follow-up was 31.8 months. In the ITT analysis, median disease-free survival (DFS) was 21.1 months and overall survival (OS) was 31.8 months. For patients treated PP, median DFS and OS were 29.8 months and 39.7 months, respectively. Median DFS by cytogenetics was, 20.5 months for IRC and 22.4 months for IDT; not reached for the FRC group (p=0.10) and median OS was 32.8 months for IRC and 34.4 months for IDT; not reached for the FRC group (p=0.06). For FRC patients treated with high dose daunorubicin induction and AutoHCT the DFS and OS was ≥ 80% at 4 years based on K-M estimates. Patients who were FLT3-positive (n=27) demonstrated a trend towards worse DFS (16.2 vs. 30.3 months) and OS (20.0 vs.39.7 months) than those who were FLT3-negative (n=113) (p=0.12 and 0.10, respectively). Conclusions: Auto HCT is a safe consolidation approach with a low TRM in younger patients with de novo AML in first remission. Results are excellent in respect to DFS and OS particularly for the FRC patients on the high-dose daunorubicin arm. Due to small numbers, we could not demonstrate a negative outcome in FLT3-positive patients receiving AutoHCT. Further study, however, with a larger number of patients is warranted. Disclosures: Fernandez: Otsuka: Honoraria. Off Label Use: IV busulfan in the treatment of acute myeliod leukemia .

Abstract Abstract 2463 The treatment of relapsed/refractory B-Chronic Lymphocytic Leukemia (CLL) is difficult in terms of both inducing meaningful responses and being able to predict clinical outcome. In an attempt to address the latter aspect, we analyzed a battery of prognostic parameters obtained from a cohort of relapsed/refractory CLL patients entered onto ECOG trial E2903. This protocol included 2 steps: an induction phase (step 1) with pentostatin (4 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) given every 3 weeks for 6 cycles and a consolidation phase (step 2) where complete responders (CR) were given 4 weeks of subcutaneous (sc) alemtuzumab (30 mg/m2, 3 times a week) or patients attaining partial response (PR), stable or progressive disease were given 18 weeks of sc alemtuzumab. Sixty-five eligible patients were enrolled; median age was 63 yr; male to female ratio of 4:1; median (range) number of prior therapies was 3 (1–7); and there were 16, 7, and 40 patients in Rai 0–1, Rai 2; and Rai 3–4 stages respectively. The median serum β-2 microglobulin was 4 (1–28). The overall response rate for step 1 in this cohort was 46% with 1 complete and 29 partial responses and 38.5% judged as having stable disease. Strict CR criteria, including CT imaging were utilized, demonstrating the infrequency of total response using CT scans. For traditional prognostic parameters, we found that age over 70 yr and high Rai risk stage (3–4) did not preclude a clinical response, but there was a significant difference between responders and non-responders in serum β-2 microglobulin levels (p=0.03). For molecular prognostic parameters, we found that the immunoglobulin variable heavy chain region (IGVH) mutational status did not preclude a lack of clinical response. However, for patients who were ZAP70 negative (−) or CD38 negative (−) these factors were positively associated with clinical response (p=0.046, 0.0005, respectively). The sensitivity in predicting a clinical response was 82% in ZAP70- and 73% in CD38-. In multivariable logistic regression analysis, only CD38 was significantly associated with response (Odds Ratio: 41, p=0.002). When patients were segregated into low (13q- or normal), intermediate (Trisomy 12) and high risk FISH (17p-,) there was no association with clinical outcome. In addition, if patients' CLL cells were unmutated and high risk FISH, there was no reduced clinical response. Of 65 patients included in this analysis, the 2-year overall survival (OS) was 55% (±7%) and the 2-year progression-free survival (PFS) is 25% (± 6.6%). The median follow-up time amongst survivors was 23 (range 6–60) months. The univariable analysis for PFS revealed that the IGVH mutated (2-yr PFS 53% for mutated vs. 18% for unmutated, p=0.037, Figure) and low risk FISH (2-yr PFS 42% for low risk vs. 23% for high risk, p=0.04) were significant. However, only IGVH mutated was significant (HR 0.33, p=0.027) for PFS in multivariable Cox model. In univariable analysis for OS, the combination of age <70 yr and β-2 microglobulin<2 upper limits [UL] was significant (2-yr OS: 68% vs. 39%, p=0.048), whereas only β-2 microglobulin was significant (HR 3.45 for >=2UL vs. <2UL, p=0.02) in multivariable Cox model. A total of 24 patients entered onto step 2 of the consolidation phase, receiving alemtuzumab; 17 patients who were responders from step 1 entered onto the 4 weeks of step 2; and 7 of the non-responders went onto the 18 weeks of step 2. The 2-year OS of these 24 patients was 62% from the date of consolidation phase: 61% for 17 responding patients to PCR and 60% for non responders to PCR (p=0.87). Current conclusions of this study are: (1) heavily pretreated high risk CLL patients may still have a respectable survival with the PCR combination; (2) β-2 microglobulin, ZAP70, and CD38 were important factors associated with response to PCR; (3) both IGVH mutated and FISH were prognostic markers associated with PFS; (4) addition of alemtuzumab may confer comparable survival rates for PCR non responders to the responders; (5) β-2 microglobulin was the only prognostic factor significant for OS. In total this study shows that both traditional and molecular markers can be used to predict clinical outcome for high risk relapsed/ refractory CLL patients treated with chemoimmunotherapy. We anticipate further valuable prognostic information to come from this still accruing study. Progression Free Survival post PCR for IGVH patients as separated by Unmutated (UM) or Mutated cohorts Progression Free Survival post PCR for IGVH patients as separated by Unmutated (UM) or Mutated cohorts Disclosures: Rosen: Genentech: Speakers Bureau.

Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180794, CA180820, CA180795, CA180791, CA189859, CA180790, CA180853, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Relapse after achieving a complete remission (CR) in AML portends for a poor prognosis and allogeneic transplant after achieving a second remission is the only chance for cure. Patients who undergo a transplant have a 30-40% chance of long term survival. This is a follow-up of a report published 10 years ago (Rowe JM, ASH 2005, abstract 546) and includes contemporary studies and longer follow-up. The study examines the long term overall survival (OS) of AML patients who relapsed after achieving first CR in 9 successive ECOG-ACRIN trials for newly-diagnosed AML patients (E3483, E3489, PC486, E3993, E4995, E1490, E3997, E1900 and E3999) from March 1984 to November 2008. Methods: OS was defined as time from first relapse to death from any cause. Kaplan-Meier estimates were used to estimate the event-time distributions for OS. Multivariate model stratified on protocol and treatment were used to examine whether the following factors are prognostic for OS from relapse: age, gender, cytogenetic risk, ECOG performance status, WBC, platelets, hemoglobin, marrow blasts, peripheral blasts, and duration of CR. All P values were based on 2-sided tests. Results: A total of 3160 patients were enrolled in the 9 studies. The median follow-up on patients still alive was 10.0 years. Among those 3160 patients enrolled, 1864 (58.9%) achieved first CR of which 1086 (58.2%) had documented relapse. The median age at diagnosis of the relapsed patients was 50 (range: 16-84) and 50.6% were males. Fifty percent of the patients had reliable cytogenetic results. Of those, 13.5% had favorable cytogenetics, 55.8% - intermediate and 30.6% had unfavorable baseline results. The median OS from relapse was 0.5 years. The 2- and 5-year OS were 16(±1)% and 10(±1)%, respectively. This is true in even the most contemporary studies (E1900 and E3999) with median OS of 0.6 and 0.4 years, respectively. By age stratification (< or ≥ 55), 5-year OS was 13(±1)% and 5(±1)%, respectively (figure 1). Among patients<55, those with unfavorable cytogenetics had the poorest prognosis (median OS of 0.4 years and 5-year OS of 6(±3)%. Those with favorable and intermediate cytogenetics had similar OS with 0.7 and 0.6 years median OS and 5-year OS of 16(±5)% and 17(±3)%, respectively (figure 2). Multivariate analysis was perfomed on 517 patients who had enough baseline information, including cytogenetics. Factors that were significantly associated with OS from relapse included: age (p<0.001), ECOG performance status (p=0.04), hemoglobin (p=0.03), cytogenetics (p=0.045) at baseline and duration of CR (p<0.001). Conclusions: The short- and long-term OS of AML patients post-relapse is dismal (<10%). Although age<55 and favorable cytogenetics at diagnosis are relatively good prognostic factors, the general survival of even these patients is very poor. Disappointingly, these data are also applicable to the most contemporary studies. Long-term survival was possible only in the minority of patients who survived the relapse, achieved a second CR and then successfully underwent an allogeneic transplant. These data are crucial when considering post-remission strategy, and suggest that offering a therapy most likely to lead to cure in CR1 is the preferred option. Figure 1. Probability of OS from relapse by age group Figure 1. Probability of OS from relapse by age group Figure 2. Probability of OS from relapse by cytogenetic risk for patients age <55 Figure 2. Probability of OS from relapse by cytogenetic risk for patients age <55 Disclosures Douer: Gilead: Consultancy. Rowe:BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy; Amgen: Consultancy.