Bennett, John M.

Abstract Results from clinical trials may change with time. Data presented in initial abstracts or early reports are often different from what appears in subsequent publications, sometimes due to a more rigorous analysis (as in initial response rates) or to maturity of data (as in reports of survival). Survival curves usually provide projected data based on Kaplan-Meier analyses. Such data may change with time when unexpected events occur (as, for example, relapse after T-cell depleted allogeneic transplants) or more patients advance to the initially projected time point. For AML, several groups have reported that there are very few relapses beyond 3 years. At issue is the optimal time for reporting these survival data. Table 1 reports data from 6 consecutive clinical trials addressing induction and post-remission questions in AML patients performed by ECOG. These data compare the 3-year overall survival (OS) and disease-free survival (DFS) for the identical cohorts of patients as presented at 1 year and at 3 years after completion of the study accrual. PC 486 was a phase II study of induction therapy followed by allogeneic or autologous transplant without prior consolidation. E 3489 was a US intergroup study in which patients received post-induction therapy using an allogeneic transplant (allo), an autologous transplant (auto) or chemotherapy (chemo). E1490 was a study in older adults of induction and consolidation with GM-CSF or placebo. E2491 was an intergroup study comparing ATRA induction versus standard chemotherapy in patients with APL. After consolidation, patients were randomized to maintenance with ATRA versus observation (obs). E3993 was a study in older adults comparing priming with GMCSF or placebo. E4995 was a phase II study of intensified induction and consolidation followed by an autologous transplant. For the same cohorts of patients the 3-year OS tends to decrease as the time from completion of study accrual increases. When looking at the DFS, while a decrease may also occur, in several studies there was an improved DFS with time (for example, in E2491, chemo to ATRA, or in E3993 with GM-CSF priming). There were no changes in either OS or DFS beyond 3 years (data not shown). Table 1: Three-year OS and DFS Presented at Different Time Points OS (%) DFS (%) Study One year Three years One year Three years PC 486 auto or allo HSCT 42 → 38 45 → 39 E 3489 allo HSCT 50 → 50 48 → 47 auto HSCT 47 → 46 39 → 39 chemo 56 → 51 36 → 36 E 1490 Induction / consolidation GM-CSF 23 → 22 23 → 24 placebo 15 → 12 16 → 15 E2491 APL induction+ maintenance ATRA + ATRA 87 → 84 72 → 73 ATRA + obs 83 → 80 61 → 60 chemo + ATRA 81 → 75 43 → 58 chemo + obs 54 → 45 16 → 18 E 3993 Induction/consolidation GM-CSF priming 13 → 11 5 → 10 placebo 14 → 14 9 → 9 E 4995 Induction / consolidation / auto HSCT 54 → 48 63 → 53 In conclusion: For large cooperative group studies, treatment results in AML presented one year from conclusion of study accrual are unlikely to dramatically alter the overall results. Nonetheless, some differences may occur, both in OS and DFS, warranting caution in interpreting the data and comparing with other published reports. Such differences are likely to be even greater if data are presented upon completion of study accrual, prior to one year - although, in a cooperative group setting, this should be balanced against the need to release data for future planning. Publication of interim data, before conclusion of the study accrual, may be misleading and are to be strongly discouraged. Three years appear to be the appropriate time for the publication of definitive survival data.

Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin <9.5 g/dL who were unresponsive to rhEpo treatment or were TD (>2 units/month) with serum Epo >500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a >2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients (<4U RBC/8 wks). Arm A non-responders were offered cross-over to combined therapy. Results: Among 205 patients randomized, 14 were excluded from the primary analysis due to a 4 month interruption in drug supply. Among the 195 evaluable patients, 96 were assigned to Arm A and 99 to Arm B. Baseline characteristics were well balanced between arms with 85% of patients heavily TD, receiving a median of 4 units/8 weeks. Overall, 93% of patients received prior treatment with Epo and 18% azanucleosides. In an intent to treat analysis, 28/99 patients (28.3%) in Arm B achieved MER compared to 11/96 (11.5%) in Arm A (P=0.004). Among 136 patients who completed 16 weeks of study treatment, 28/72 (38.9%) and 10/64 (15.6%) achieved MER, respectively (P=0.004). Forty-four Arm A non-responders crossed over to combination-therapy with 11 patients (25%) experiencing a MER. Multivariable logistic regression analysis identified only treatment with LEN + EA as an independent covariate for erythroid response (P=0.01). Responses were durable with MER median duration of 23.8 months in Arm B compared to 13 months in Arm A. There was no significant difference in the frequency or distribution of >Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

Abstract We studied the prognostic significance of plasmablastic (PB) multiple myeloma (MM) in Eastern Cooperative Oncology Group Phase III trial E9486. Two reviewers independently reviewed 453 cases. They agreed on 37 PB (8.2%) cases and 416 non-PB cases, achieving an 85% concordance (P < .0001). These PB cases had significantly lower hemoglobin and serum albumin levels, higher calcium and β 2-microglobuin levels, and higher percentage BM plasma cells (PC) by immunofluorescence. They had higher bone marrow PC labeling indices, higher serum soluble interleukin-6 receptor (sIL-6R) levels, and a higher probability of ras mutations. Three treatment regimens were used: vincristine, bis-chloro-ethyl nitrosourea (BCNU) melphalan, cyclophosphamide, and prednisone (VBMCP) alone; VBMCP with added cyclophosphamide (HiCy); or recombinant interferon α 2 (rIFNα2). Although the numbers are low, patients with PB had a significantly lower response rate versus non-PB MM when treated with VBMCP (treated, 47.1% v nontreated, 66.5% [P = .015]). Patients with nonresponding PB had a significantly higher progression rate than non-PB cases (30.6%v 11.8% [P < .0001]), especially with VBMCP alone (35.3% v 15.8% [P = .002]), and with added HiCy (37.5% v 9.8% [P < .0001]), but not with added rIFNα2. Event-free and overall survival of PB MM was shorter (median years, 1.1 v 2.7 and 1.9 v 3.7, respectively [P < .0001 for both]). In multivariate analysis, PB classification was also highly prognostic. There is no survival difference between the patients who were classified as PB by both reviewers versus patients classified as PB by only one reviewer. We conclude that PB MM is a discrete entity associated with more aggressive disease and shortened survival. Tumor cell rasmutations and increased sIL-6R may contribute to a higher proliferation rate and reduced survival. There were significant improvements in response and progression with the addition of HiCy and rIFNα2 to VBMCP, but the numbers were small and improved survival could not be shown.

We studied the prognostic significance of plasmablastic (PB) multiple myeloma (MM) in Eastern Cooperative Oncology Group Phase III trial E9486. Two reviewers independently reviewed 453 cases. They agreed on 37 PB (8.2%) cases and 416 non-PB cases, achieving an 85% concordance (P < .0001). These PB cases had significantly lower hemoglobin and serum albumin levels, higher calcium and β 2-microglobuin levels, and higher percentage BM plasma cells (PC) by immunofluorescence. They had higher bone marrow PC labeling indices, higher serum soluble interleukin-6 receptor (sIL-6R) levels, and a higher probability of ras mutations. Three treatment regimens were used: vincristine, bis-chloro-ethyl nitrosourea (BCNU) melphalan, cyclophosphamide, and prednisone (VBMCP) alone; VBMCP with added cyclophosphamide (HiCy); or recombinant interferon α 2 (rIFNα2). Although the numbers are low, patients with PB had a significantly lower response rate versus non-PB MM when treated with VBMCP (treated, 47.1% v nontreated, 66.5% [P = .015]). Patients with nonresponding PB had a significantly higher progression rate than non-PB cases (30.6%v 11.8% [P < .0001]), especially with VBMCP alone (35.3% v 15.8% [P = .002]), and with added HiCy (37.5% v 9.8% [P < .0001]), but not with added rIFNα2. Event-free and overall survival of PB MM was shorter (median years, 1.1 v 2.7 and 1.9 v 3.7, respectively [P < .0001 for both]). In multivariate analysis, PB classification was also highly prognostic. There is no survival difference between the patients who were classified as PB by both reviewers versus patients classified as PB by only one reviewer. We conclude that PB MM is a discrete entity associated with more aggressive disease and shortened survival. Tumor cell rasmutations and increased sIL-6R may contribute to a higher proliferation rate and reduced survival. There were significant improvements in response and progression with the addition of HiCy and rIFNα2 to VBMCP, but the numbers were small and improved survival could not be shown.

Abstract Abstract 924 Background: Therapy-related myeloid neoplasia (t-MN), including myelodysplastic syndrome and acute myeloid leukemia, has been reported at a higher frequency with chlorambucil + fludarabine as compared to fludarabine alone, but has not been rigorously studied in the context of cyclophosphamide as an alkylator agent. The intergroup prospective randomized Phase 3 trial, E2997, compared FC with F alone as initial therapy for patients (pt) with chronic lymphocytic leukemia (CLL). FC therapy led to higher complete and overall response rates and longer progression-free survival at the initial analysis (Flinn et al JCO 2007). One rationale for combining F with C is that F can inhibit repair of DNA damage induced by C. FC did cause more myelosuppression that could lead to more long-term effects on myeloid hematopoietic function, including t-MN. Methods: E2997 enrolled 278 pts, 141 on FC and 137 on F. These cases were assessed for t-MN by required reporting of these events. Baseline genetic and molecular features of CLL were available through a companion lab correlative trial for 235 pts, 122 on FC and 113 on F. Results: With median follow-up of 6.4 yrs, there have been 13 (4.7%) reported cases of t-MN, 9 after FC and 4 after F. By cumulative incidence methodology, adjusting for the competing risk of death, the rates of t-MN at 7 yr are 8.2% after FC and 4.6% after F (p=0.18 by the Gray test). Median age at study entry of the t-MN pts was 60 (range 45–80) yrs vs 61 (range 33–86) yrs among those not reported to have t-MN. Median time from initial therapy to diagnosis of t-MN was 5 (range 0.7–8) yrs and did not differ between FC and F. Ten of 13 affected pts received 6 chemotherapy cycles. Additional therapy prior to occurrence of t-MN was given to only 2 of 9 FC pts, in contrast to 3 of 4 F pts. Thus, t-MN occurred in only 1 pt treated with F and no further therapy vs 7 who received FC and no further therapy. Ten of 12 pts with available cytogenetics at diagnosis of t-MN had an abnormality of chromosome 5 and/or 7, common to alkylating agent-induced t-MN, usually (n=8) with complex karyotype. Of the 9 pts with t-MN after FC, all 7 with available CLL data had lower risk IgVH mutated disease, in contrast to 1 of 4 with t-MN after F and 44% in the entire cohort. Conclusion: Our analysis suggests that a higher incidence of t-MN has occurred after FC than after F. t-MN after FC occurred most often without additional therapy and in IgVH mutated CLL which is associated with more favorable outcome. The increased incidence of t-MN after FC in this study, usually in the absence of additional treatment, suggests that FC is more leukemogenic than F. This finding emphasizes a need for longer follow-up of toxicity and survival before concluding that FC is preferable to F as the chemotherapy backbone for initial therapy of both low and high risk CLL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 702 Background: Large granular lymphocyte (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells. Prominent clinical features include neutropenia, anemia, and rheumatoid arthritis. The terminal effector memory phenotype (CD3+/CD8+/CD57+/CD45RA+/CD62L-) of leukemic LGL suggest a pivotal chronic antigen driven immune response. LGL survival is then promoted by PDGF and IL-15 (Proc Natl Acad Sci USA 105:16308, 2008), resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced death (Blood 112:770, 2008). These pathogenic features explain why treatment of LGL leukemia is based on immunosuppression therapy. However, no standard therapy has been established due to the absence of large prospective trials. Methods: Eligibility criteria included increased number of LGL (CD3+CD57+ cells > 400/ul or CD8+ cells >650/ul) plus evidence of clonal rearrangement of T cell receptor gene. Treatment indications included the following categories: a) severe neutropenia (ANC < 500/ul); b) neutropenia associated with recurrent infections; c) symptomatic anemia; and, d) transfusion-dependent anemia. Initial Treatment: (Step 1) consisted of methotrexate (MTX) at 10 mg/m2 po in divided doses once weekly. Prednisone was given at 1 mg/kg po × 30 days and then tapered off in the subsequent 24 days. Patients not responding to MTX received cyclophosphamide (CY) at 100 mg po daily with the same prednisone schedule (Step 2). Treatment response was assessed after four months of therapy as: complete remission (CR): normal CBC (ANC ≥ 1,500/ul, lymphocyte count <4,000/ul, hemoglobin ≥ 11 g/dl, and platelet count > 100,000/ul. In addition, LGL counts needed to be within normal range. Partial response (PR) was defined as improvement in hematologic parameters in the absence of CR: 1) ANC > 500, as long as this represented 50% increase (category a); 2) improvement in ANC ≥ 50% over baseline (category b); 3) increase in hemoglobin by ≥ 1 g/dl for at least four months duration (category c); and, 4) decrease in monthly transfusion requirement of > 50% for at least four months (category d). Progressive disease (PD) was defined as worsening of hematologic parameters in patients previously achieving PR/CR. No response (NR) was defined as lack of CR/PR. Results: Response data are shown for Step 1 (Table 1) and for Step 2 (Table 2). Overall response rate (CR/PR) for MTX was 37%. In patients failing MTX, the overall response to CY was 64%. There were two infectious deaths during Step 1 therapy. Conclusion: Data documenting efficacy of immunosuppressive therapies commonly utilized in LGL leukemia (MTX, CY, Cyclosporine) are limited to 300 patients published primarily as small retrospective studies. Such data show an overall response rate to MTX of 58% (56/96 patients). Here in the only large prospective trial we observed an overall response rate of 37%. Overall response rate of 64% for CY was not statistically different than MTX. However, given that CY response rate was observed in MTX failures, future studies should consider evaluation of CY as initial therapy. Disclosures: Off Label Use: Immunosuppressive therapies for LGL leukemia including Methotrexate and Cyclophosphamide.

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 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 Background: MDSs are clonal hematopoietic stem cell malignancies characterized by cytopenias resulting from ineffective hematopoiesis. A phase 2 study of lenalidomide (MDS-002) demonstrated hematological improvement in patients with MDS without an associated deletion 5q cytogenetic abnormality (List AF, et al. Haematologica2006;91[suppl1]:379[abst 1032]). We now report multicenter results after 〉2 yrs follow-up. Methods: A total of 214 pts with transfusion-dependent anemia were categorized into the following IPSS MDS risk groups after central review of bone marrow morphology, karyotype, and peripheral blood findings: Low/Int-1 (168 [78%]); Int-2/High (8 [4%]); and unclassified (38 [18%]). Patients were unclassified for missing or inadequate marrow studies for central review (morphology [29] or cytogenetic [7]) or other diagnoses (AML [1], atypical CML [1]). Patients were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI) (IWG criteria), hemoglobin (Hgb) response, and safety. The starting dose of lenalidomide was 10 mg (daily or daily × 3 wks q28d cycle). Results: Overall, 56 (26%) of 214 enrolled patients achieved RBC-TI. Median time to RBC-TI was 5 wks, median duration of RBC-TI response was 41.0 wks (range, 8.0–136.4), and median Hgb increase achieved during RBC-TI was 3.2 g/dL (range, 1.0–9.8). An additional 36 patients experienced a ≥ 50% reduction in RBC transfusions (overall hematological improvement in 92 [43%] patients). Overall, 47 (22%) patients had an abnormal karyotype at baseline and 9 (19%) patients achieved a cytogenetic response (4 complete). The most common drug-related grade 3/4 adverse events (AEs) were neutropenia and thrombocytopenia (25% and 20%, respectively). Deep vein thrombosis occurred in only 2 (1%) patients. The duration of RBC-TI was ≥ 52 weeks in 21 (38%) patients. Among these 21 patients, 14 (67%) did not require a lenalidomide dose reduction during the first 52 weeks of treatment. Analyses of response variables will be presented. Dose-limiting neutropenia/thrombocytopenia was not reported after 52 weeks. The most commonly reported AEs after 52 weeks were mild-moderate diarrhea and fatigue (38% and 29%, respectively). Conclusion: Lenalidomide is an active, well-tolerated treatment in MDS patients with transfusion-dependent anemia that is not associated with a deletion 5q abnormality. The rate of erythroid hematologic improvement and duration of RBC-TI is encouraging and offers a possible alternative to cytokine therapy.

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.