Advani, Anjali S.

Background: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate composed of anti-CD22 antibody conjugated to the cytotoxic agent calicheamicin, which is approved for relapsed/ refractory (RR) B-cell acute lymphocytic leukemia (ALL), based on efficacy demonstrated in a randomized control trial. We sought to investigate the safety and efficacy of InO in the "real world" setting. Methods: We conducted a retrospective multicenter study in collaboration with 11 U.S. academic institutions, and evaluated the outcome of patients (pts) with RR B-cell ALL, who received InO outside of clinical trials. These pts were evaluated for response to InO, duration of response, overall survival (OS) and toxicity. Demographic and disease characteristics were summarized using descriptive statistics. Survival curves were estimated using the Kaplan-Meier method and compared via log-rank test. Duration of response was estimated among pts who achieve complete remission (CR)/CR with incomplete count recovery (CRi). Results: From June 2016 to May 2019, 84 pts with RR-B cell ALL were identified. Baseline characteristics are summarized in Table 1. The median age of pts at InO initiation was 50 years (yrs) (range, 20-87). Twenty-two (27.5%) pts had t(9;22) (Ph+ve) and 6 (7.5%) pts had t(4;11) (MLL gene) chromosomal abnormalities. Nine (11%) and 20 (25%) pts had CNS disease at diagnosis and at relapse, respectively. Median number of therapies prior to InO was 2 (range, 0-7), 40 (48%) pts had ≥ 3 therapies and 23 (27%) pts had allogeneic stem cell transplantation (allo-HCT) prior to InO. Forty (48%) pts received blinatumomab prior to InO. Fourteen (17%) pts received InO in combination with chemotherapy and/ or tyrosine kinase inhibitor (TKI). Overall response rate (CR/CRi) was 63%; 44% had CR with minimal residual disease (MRD) negativity by flow cytometry. Response rate in Ph+ve B-cell ALL was 73%. Twenty-three (27%) pts were successfully bridged to allo-HCT. Median response duration with InO was 11.5 months (mo); 32.5% had sustained response at 2 yrs (Fig. 1a). Median response duration post InO, censored at allo-HCT was not reached (NR) (51% in remission at 2 yrs) (Fig. 1b). Median OS after InO was 11.6 mo and 32% were alive at 2 yrs (Fig. 1c). Median OS post InO, censored at of allo-HCT was 13.6 mo (Fig. 1d). Median OS after InO in Ph+ve pts was NR (71% alive at 1 yr). Forty-nine percent, 27%, 6% and 5% of pts discontinued InO due to progression, allo-HCT, adverse events and maintenance therapy, respectively. Nineteen (30%) pts had dose interruptions. In terms of toxicities, 14 (17%) and 7 (8%) pts had grade (G)1-2 and G3 transaminases secondary to InO, respectively. One pt each had G2 and G3 pancreatitis, respectively. One (1%) and 2 (2%) pts had G2 and G4 veno-occlusive disease secondary to InO, respectively. Two of these pts were treated with defibrotide. Two (2%) pts died due to InO toxicity. A complete description of adverse events are summarized in Table 1. Conclusion: Our real-world data obtained by multicenter collaboration suggest that InO was well tolerated and had significant efficacy in this heavily treated patient population of RR B-cell ALL. Disclosures Liedtke: Celator: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria; AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Curran:Incyte: Research Funding; Merck: Research Funding; Gilead: Research Funding. Podoltsev:Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Advani:Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Abbvie: Research Funding. Atallah:Takeda: Consultancy, Research Funding; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy.

Background Blinatumomab is a bispecific T cell antibody construct, that binds and allows CD-3 positive cytotoxic T cells to recognize and eradicate CD19-positive acute lymphocytic leukemia (ALL) blasts. The drug is approved for patient (pts) with relapsed/ refractory (RR) B-cell ALL and those with minimal residual disease (MRD) based on efficacy in clinical trials. We sought to evaluate the safety and efficacy of blinatumomab in the "real world" setting. Methods We conducted a retrospective multicenter study in collaboration with 11 U.S. academic institutions, and evaluated the outcome of RR B-cell ALL pts, who received blinatumomab outside of clinical trials. These pts were evaluated for response, duration of response (DOR), overall survival (OS) from the time of blinatumomab initiation and toxicity. DOR was estimated among pts who had achieved complete remission (CR)/CR with incomplete count recovery (CRi). Survival curves were estimated using the Kaplan-Meier method and compared via log-rank test. Results From December 2014 to May 2019, 239 pts with B-cell ALL were identified. Baseline characteristics are summarized in Table 1. The median age of pts at blinatumomab initiation was 48 years (yrs) (range, 18-85). Sixty-one (26%) pts had Philadelphia chromosome [t(9;22)] positive (Ph+ve) disease. Sixty-one (26%) pts had ≥ 3 prior therapies and 46 (19%) pts had allogeneic stem cell transplantation (allo-HCT) prior to blinatumomab. Twenty-two (9%) pts received inotuzumab ozagamicin prior to blinatumomab. Twenty-nine (12%) pts received blinatumomab in combination with tyrosine kinase inhibitor (TKI). Twelve (5%) pts received blinatumomab for MRD. Response rate (CR/CRi) in pts with RR disease was 61%; 44% had CR with MRD negativity by flow cytometry. Rate of CR/CRi in Ph+ve B-cell ALL was 74.5%. Among 12 pts who received Blinatumomab for MRD, 9 (75%) pts achieved MRD negativity. Overall 113 (48%) pts were successfully bridged to allo-HCT. Median DOR in pts with RR disease was 32.1 months (95% CI; 9.5-not reached [NR]) (Fig. 1a) and when censored at allo-HCT was 14.8 months (95% CI; 5.2-NR) (Fig. 1b). Median OS in pts with RR disease after blinatumomab was 12.7 months (95% CI; 9.2 -17.9) (Fig. 1c) and when censored at allo-HCT was 8.6 months (95% CI; 6.4-11.6) (Fig.1d). Median OS after blinatumomab in RR B-cell ALL Ph+ve pts was NR (59% alive at 2 yr). Among pts who received blinatumomab for MRD, median DOR was NR and 54% sustained MRD negativity at 2 yrs. Median OS was 34.7 months (95% CI; 8.8-34.7) in group of pts who received blinatumomab for MRD. Seven (3%) pts discontinued blinatumomab due to adverse events and 40 (21%) pts had dose interruptions. Cytokine release syndrome (CRS) of any grade (G) was reported in higher number of pts (93 [39%]) compared to clinical trials, though G3-4 CRS appears to be similar (G1-2 [36%], G3-4 [3%]). Forty-four (44%) pts were treated with steroids and 8 (8%) pts required tocilizumab with steroids for CRS. Ninety-three percent of pts had complete resolution of CRS. CNS toxicities were observed in 31 (13%) pts, among them 60% (n= 19) had G3-4 toxicities. Hepatic toxicities were observed in 84 (35%) pts as outlined in Table 1. Six (2.5%) pts died due to blinatumomab induced toxicities. Conclusion: Our real-world data with multicenter collaboration suggest that overall blinatumomab was well tolerated and had led to significant response in pts with RR B-cell ALL. Disclosures Advani: Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Aldoss:AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; Agios: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau. Podoltsev:Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding. Curran:Incyte: Research Funding; Merck: Research Funding; Gilead: Research Funding. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah:Helsinn: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Jazz: Consultancy.

Abstract The prognosis of elderly patients (pts) with acute lymphoblastic leukemia (ALL) remains poor, and novel therapeutic approaches are clearly needed. CD19 is expressed on the majority of precursor-B ALLs and represents an attractive therapeutic target. The anti-CD19 bi-specific engager antibody blinatumomab has demonstrated significant activity in both relapsed/refractory ALL and minimal residual disease (MRD) positive ALL. Therefore, we evaluated blinatumomab as a single agent in the upfront treatment of newly diagnosed elderly pts with Philadelphia chromosome (Ph) negative B-lineage ALL to determine response rates and overall survival (OS). Methods: Pts were treated at National Clinical Trial Network sites from June 2015 to September 2017. The primary objective of the study was to estimate 3-year OS. An IND was approved by the FDA and the protocol was approved by a central institutional review board. Eligibility: age > 65 years, newly diagnosed Ph negative B-lineage ALL with adequate organ function and no evidence of central nervous system (CNS) disease. Pts received blinatumomab for induction at standard dosing for 1-2 cycles until attainment of complete response (CR) or CR with incomplete count recovery (CRi) (defined below). Pts then received 3 cycles of blinatumomab post-remission therapy followed by 18 months of maintenance POMP (prednisone, vincristine, 6-mercaptopurine, methotrexate). A total of 8 doses of intrathecal methotrexate were administered as CNS prophylaxis. Cytogenetic risk was ascribed by NCCN 2018 criteria and bone marrow samples were analyzed for the presence of the Ph-like signature. MRD was assessed centrally by 8 color flow cytometry pre-treatment, on Day 35 of induction cycle 1, and on Day 35 of re-induction (if applicable). Response was assessed at the completion of 1-2 cycles of blinatumomab. CR was defined as < 5% marrow blasts with no evidence of extramedullary disease and recovery of counts [absolute neutrophil count (ANC) > 1000/uL, platelets >100,000/uL]. CRi was defined the same as CR but ANC < 1000/ uL and/ or platelets ≤ 100,000/ uL. OS was measured from day of registration on trial until the date of death. Disease-free survival (DFS) was measured from the date the pt achieved CR/ CRi until relapse or death. Toxicities were graded according to NCI CTCAE version 4.0. Results: Of 31 pts enrolled, 29 were eligible. The median age was 75 years (range 66 - 84), 22 (76%) were male, median baseline white blood count was 3.7 x 103/uL (range 0.3 - 7,100), and median bone marrow blast count percentage was 86.5% (range 30-100). Three pts received hydroxyurea or steroids prior to treatment initiation. Cytogenetic risk at diagnosis was: poor (34% of pts; n=10), standard (55% of pts; n=16), good (3% of pts; n=1) and unknown (7% of pts, n=2). Testing for the Ph-like signature is being completed. The most common Grade 3-5 non-hematologic toxicities related to treatment during induction were hyperglycemia (14%), dyspnea (10%), febrile neutropenia (10%), hypertension (10%), and lung infection (7%). One pt developed Grade 3 cytokine release syndrome and 1 developed Grade 3 neurotoxicity. No pts died during the first 28 days of treatment. The overall response rate (CR + CRi) was 66% (all CRs). Thirteen of the 19 responders have available MRD data post-treatment. Of these, 12 pts (92%) achieved MRD negativity, all at Cycle 1 Day 35. One pt required 2 cycles of blinatumomab to achieve CR. One pt proceeded to allogeneic hematopoietic stem cell transplant. The median follow-up time is 1 year and median duration on trial is 170 days (6 pts are still on maintenance therapy). OS estimated by Kaplan Meier at 6 months is 79% (95% CI 58%-90%) and at 1 year is 65% (95% CI 43%-80%). DFS estimated at 6 months is 68% (95% CI 43%-84%) and at 1 year is 56% (95% CI 31%-75%). No baseline features including CD19 expression (by percentage or mean-fluorescent intensity) or presence of a CD19 negative subpopulation were associated with response. Conclusions: Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph negative B-lineage ALL. Further follow up will determine the durability of these responses. Disclosures Advani: Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. Wieduwilt:Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Park:Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Erba:Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Jazz: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Agios: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; MacroGenics: Consultancy; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; MacroGenics: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau.

Abstract Introduction Population level data about the survival outcomes of patients with hematologic malignancies occurring as second cancers is limited. We undertook one of the largest analyses of second hematologic malignancies (SHM) using the Surveillance, Epidemiology & End Results (SEER) registry to identify factors associated with survival. Methods SEER 9 &13 registries were queried to identify adult patients (pts>18 years) diagnosed with SHM that comprised of Acute Myeloid Leukemia (AML), Acute Lymphoid Leukemia (ALL), Myelodysplastic Syndromes (MDS), Chronic Myeloid Leukemia (CML) & Other Acute Leukemias (OAL, biphenotypic leukemias, myeloid sarcomas & leukemias NOS) > 1 year (yr) after diagnosis of a primary unrelated cancer, using ICD-O-3 codes over a 40 yr period (1973-2012). Data on demographics, follow up, primary tumor & survival were abstracted. Univariate & multivariate analyses were performed to identify factors influencing survival of SHM & compared with hematologic malignancies occurring as first cancers. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported & significance was set at p< 0.01. Results SHM cases included 4665 AML, 3569 MDS, 1140 OAL, 1076 CML & 536 ALL pts. Median age at diagnosis of SHM was 73 yrs (range, 18-100) for AML, 79 yrs (18-100) for MDS, 74 yrs(20-99) for OAL, 74 yrs(18-98) for CML & 70 yrs(19-97) for ALL. Pts>60 yrs comprised 79.2% of AML, 92% of MDS, 88.7% of OAL, 82.9% of CML & 75.2% of ALL cases. Gender distribution was similar across all categories, with females comprising 48.5% of AML, 42.2% of MDS, 45.3% of OAL, 42.8% of CML & 50.2% of ALL cases. More than 85% of pts in each group were Caucasians. While the majority of pts had one primary unrelated cancer (82-89%), 14% of AML pts, 17.8% of MDS pts, 13.8% of OAL, 15.3% of CML pts& 10.6% of ALL pts had >1 primary unrelated cancer. Most common primary sites were prostate (19.1-29.6%), breast (16.1-21.9%) & colorectal (9.3-14.5%). Median survival (range) was as follows: AML 0.2 yrs (0-28.2); MDS 1.5 yrs (0-14); OAL 0.2 yrs (0-29.1); CML 2.5 yrs (0-27.1); & ALL 0.7 yrs (0-28.8). Median latency periods (range) for secondary cancers were as follows: AML 5.2 yrs (1.0-24.2); MDS 7.6 yrs (1.0-35.5); OAL 5.7 yrs (1.0-=34.3); CML 5.2 yrs (1.0-31.6); & ALL 6.2 yrs (1.0-35.5). In univariable analyses, age <60 yrs predicted for better survival (p<0.0001) for all SHM, as did diagnosis in recent yrs (2001-2012) (p< 0.0001 for AML, OAL, CML & ALL). Effect of time period on survival for MDS was not done, as it became formally reportable in 2001. Having >2 primaries was associated with an unfavorable outcome for subsequent AML (HR=1.15; 1.08-1.23; p < 0.0001), MDS (HR=1.13; 1.05-1.22: p=0.001) & CML (HR=1.30; 1.13-1.48: p=0.0002). In multivariable analyses, advancing age was an independent adverse prognostic factor for all secondary leukemias & MDS, both as a continuous variable & when categorized as <60 yrs vs. >60 yrs (p<0.001). Race & gender did not impact survival. Using breast cancer as a referent primary, AML pts had worse outcomes following colorectal (HR=1.31; 1.14-1.5; p=0.0002) or lung (HR=1.46; 1.22-1.74; p< 0.0001) primaries, while MDS pts fared worse with prior lung (HR=1.61; 1.22-2.12; p=0.0007) or Non-Hodgkin lymphoma (HR=1.58; 1.3-1.92: p< 0.0001). Of all 2ndCML cases, those after colorectal cancer had worst survival (HR=1.54; 1.12-2.13; p=0.008). Among SHM pts, MDS pts had better survival than those with AML (HR=0.42; 0.4-0.44: p< 0.0001), as did pts with CML (HR=0.37; 0.35-0.41: p< 0.0001) & ALL (HR=0.64; 0.58-0.70; p< 0.0001). Out OAL had similar outcomes compared to AML (HR=0.99; 0.92-1.05; p=0.66). Pts with CML fared better than MDS (HR=0.47; 0.41-0.54; p< 0.0001) & OAL (HR=0.37; 0.34-0.41: p< 0.0001). Pts with ALL had worse survival than CML (HR=1.8; 1.6-2.03: p< 0.0001) & MDS (HR=1.28; 1.11-1.48: p=0.0005), but better than OAL (HR=0.65; 0.58-0.73: p< 0.0001). (Figure 1) Patients with all SHM, except CML, had worse outcomes compared to those with primary hematologic cancers (Figure 2). Conclusion The prolonged latencies for SHM in this study suggest that they are likely therapy-related. Our findings show that type & number of primary cancers influence survival of subsequent leukemias & MDS. SHM have worse survival compared to those with primary hematologic malignancies except CML where non-separation of survival curves suggest that CML as SHM does not behave like a therapy-related neoplasm. Disclosures Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: The incidence of thyroid cancers has been rising in the United States primarily due to the increased detection of well differentiated thyroid cancers (WDTC). Radioactive iodine (RAI), which is frequently used to treat WDTC, can be considered a circulating radiation emitter with the potential for mutagenic effects on hematopoietic stem cells. With a growing number of WDTC patients (pts) surviving long term following RAI therapy, establishing the risk of developing a myelodysplastic syndrome (MDS) in this cohort has important clinical implications. Methods: A novel R program, SEERaBomb (Radiat Environ Biophys. 2014;53(1):55-63) was used to query all 18 Surveillance Epidemiology and End Results (SEER) registries to identify WDTC cases treated with RAI and MDS as second cancers. SEERaBomb allows merging of all 18 SEER registries - a function not permitted by the SEER*Stat MP-SIR that limits researchers to use to one of two datasets (SEER 9 or SEER 13), thereby significantly increasing the capture of MDS cases (Figure 1). WDTC includes papillary and follicular thyroid histologies. WDTC survivor person-years at risk for developing MDS was based on age at diagnosis of WDTC, survival time, and age at diagnosis of MDS. Relative risks (RR) for developing MDS were then based on observed/expected cases between the cohorts receiving surgery alone (control), surgery combined with RAI as well as those receiving external beam radiation therapy (EBRT) and surgery with or without (+/-) RAI. Mean radiation exposure to bone marrow was compared between RAI and prostate cancer (as example) treated with other radiation modalities - brachytherapy (seeds), EBRT (3D, IMRT and VMRT). Results: In total 132,157 WDTC patients were identified from 1973-2011, of whom 69,975 (53%) received surgery alone, 59,015 (45%) underwent surgery + RAI and 3167 (2%) underwent EBRT [combined with surgery+/- adjuvant RAI]. Mean age at the time of WDTC diagnosis was: 49.4 years (yrs, range, 2-105) in the surgery group; 46.7 yrs (2-99) in the surgery + RAI group and 55.1 yrs (10-101) in the EBRT group. Median person years of follow up after WDTC diagnosis was: 6.1 yrs (2.5-11.6) in pts undergoing thyroidectomy; 5.4 yrs (2.4-9.7) in the surgery + RAI group and 5.9 yrs (1.7-11) in the EBRT group. A total of 55 patients developed MDS; 24 had surgery alone, 27 received surgery + RAI and 4 had EBRT. Median time to development of MDS after WDTM diagnosis (25-75 interquartile range) was: 6.4 yrs (4-15) in pts receiving surgery alone; 4 yrs (1.7-6.7) in the surgery + RAI group and 3.6 yrs (2.4-7.9) in the EBRT group. MDS cases were classified as RA (n=11), RARS (n=2), RCMD (n=3), RAEB (n=9), MDS with 5q deletion syndrome (n=1), and MDS-U (n=29). Compared to patients definitively treated with surgery, those who additionally received RAI (+/- EBRT) had a statistically significantly increased risk of developing MDS within the first two years of exposure (RR=1.9; 95% CI, 0.43-5.61 vs. RR=5.8; 95% CI, 2.84-12.22). Beyond 2 years, the risk for MDS drops to baseline rates, and a trend observed beyond 12 years, which did not reach statistical significance (Figure 2). Conclusion: WDTC pts undergoing RAI treatment appear to have an increased risk of developing MDS within the first two years of exposure to RAI. It is difficult to determine whether this early excess risk is true risk or an effect of ascertainment bias (RAI pts followed more closely), as the kinetics of RAI indicate a lower magnitude of bone marrow exposure compared to other radiation modalities (Figure 3). Considering the long latency of MDS seen in atomic bomb cohorts, relative young age of WDTC pts, current trend towards overdiagnosis and overtreatment of WDTCÕs, MDS rates are likely to continue to rise. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Retrospective analyses have demonstrated significantly improved survival for AYA ALL patients (pts) aged 16-21 years (yrs) when treated on pediatric versus adult U.S. NCI Cooperative group regimens where 2-yr event-free survivals (EFS) have been only 35-40%. The purpose of C10403, a large prospective US intergroup trial, was to evaluate the feasibility and effectiveness [with EFS as a primary endpoint), of treating AYA ALL pts (ages 16-39 yrs) using the standard arm of the successful Children's Oncology Group regimen (COG AALL0232) . Methods: Newly diagnosed AYA patients with B-precursor (B-ALL) or T-precursor (T-ALL) ALL were eligible to enroll on C10403. Burkitt type and Ph+ ALL were excluded. The regimen was identical to the Capizzi methotrexate arm of COG AALL0232 (Larsen E. JCO 2011; 29 suppl:3) and consisted of four intensive courses: remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy. Pts with M2 marrow response (>5% but < 25% lymphoblasts) after remission induction received an extended remission induction course of therapy. Events were defined as induction failure (M3 [³25% blasts] day 29 of induction or M2 day 43 of extended induction), death, relapse, or second malignancy. Key correlative science studies in a subset of the total accrued population included assessment of Minimal Residual Disease (MRD) using quantitative real-time PCR of clonal IgH or TCR gene rearrangements as well as Low Density Microarray (LDA) assays designed to detect a previously validated gene expression profile (Harvey, R; ASH 2013, abstract 826) which can prospectively identify ALL pts with Ph-like (BCR-ABL1-like) ALL. Results: 318 pts were enrolled on C10403 from 11/2007 to 8/2012; 22 withdrew prior to therapy. Of 296 evaluable pts, the median age at diagnosis was 24 yrs (range: 17 to 39): 25% were 17-20 yrs, 53% were 21-29 yrs, and 22% were 30-39 yrs. The majority had B-ALL (76%) and were male ( 61%). Approximately 25% were non-Caucasian and 15% were Hispanic or Latino. 32% of pts were obese (BMI³30). There were 5 (2%) treatment-related deaths during protocol therapy: liver failure (n=2, both during induction), infection (1 in induction, 1 in consolidation), and ventricular arrhythmia (1 in induction). Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia for C10403 pts, as reported previously (Advani A, ASH 2013, abstract 303). To date, 70 deaths have been reported and 87 pts remain on protocol therapy. With a median follow-up of 28 months for surviving pts, 105 events have been observed. The median EFS overall is 59.4 months (95% CI: 38.4 to NR) and the 2-yr EFS rate overall is 66% (95% CI: 60 – 72%) [Fig 1a] with similar 2-yr EFS rates for B and T- ALL pts (65%, and 68%). The 2-yr OS rate is 78% (95% CI: 72 – 83%)[Fig 1b], which is similar for B (78%, 95% CI: 72 – 84%) and T-ALL, (80%, 95% CI: 70 – 91%). These results allow rejection of the null hypothesis of this Phase II trial that the true median EFS is, at most, 32 months. In multivariable analysis of presenting clinical features, age > 20 years and initial WBC count ³ 30k/microliter were significantly associated with worse EFS and OS. Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Notably, absence of detectable MRD noted in 22/58 [38%] evaluable pts at day 28 of induction was associated with 100% EFS (p=0.0006). The Ph-like like signature was detected in 28% of pts tested on C10403 and the 2 yr EFS for these patients was only 52%, compared to 81% for those without Ph-like disease (p = 0.04). Conclusions: This large prospective US adult intergroup trial (C10403) for pts 16-39 years old employing an intensive pediatric regimen demonstrates a significant improvement (compared to historical controls) in AYA EFS and OS and validates this approach for treatment of AYA with ALL by adult hematologists. The improved clinical outcomes and the predictive value of the correlative studies in this trial lay the foundation for the design of future trials, where incorporation of novel agents to eradicate MRD, and/or use of tyrosine kinase inhibitors to target the frequently detected Ph-like ALL in AYA pts may further improve survival for young adults with ALL. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Stock: Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Sigma Tau: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding.

Abstract Introduction: Surveillance, Epidemiology, and End Results (SEER) registry captures data on acute leukemias (AL) that morphologically do not conform to well characterized acute leukemic entities in the established French-American-British (FAB) nomenclature. Not much is known about population level outcomes of these rare AL. We performed a comprehensive survival analysis of these rare AL over a forty-year period using the SEER registry. Methods: SEER 18 dataset was queried to identify adult patients (pts > 18 years) diagnosed with Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL) and rare AL from 1973-2012. Rare AL cases were identified using ICD-O-3 morphology codes and included Leukemias, Not Otherwise Specified (NOS) (9800-01, 9860) and myeloid sarcoma (9930). Data on demographics,follow up and survival was abstracted. Univariate and multivariate analysis was performed to identify factors influencing survival of rare AL and survival patterns were compared to AML and ALL. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Results: We identified 61,550 AML pts, 13,457 ALL pts, 525 myeloid sarcoma pts and 13,446 pts with leukemia NOS. Median age at diagnosis was 68 years (yrs, range 18-100) for AML, 54 yrs (18-100) for ALL, 65 yrs (18-95) for myeloid sarcoma and 76 yrs (18-100) for leukemia NOS. Gender distribution was similar with females comprising 45.9% of AML, 43% of ALL, 42.3% of myeloid sarcoma and 47.2% of leukemia NOS cases. Over 80% pts in all categories were Caucasian. Median survival was as follows: 0.4 (0-40) yrs for AML; 1.4 (0-39.8) yrs for ALL; 0.7 (0-32.9) yrs for Myeloid Sarcoma; and 0.3 (0-38.9) yrs for leukemia NOS. In univariable analysis, younger age predicted for better survival for both myeloid sarcoma and leukemia NOS (p<0.0001). Improvement in survival over time period was observed for pts with leukemia NOS (p < 0.0001). In multivariable analysis, advancing age was an independent prognostic factor for rare AL, both as a continuous variable and when categorized as older vs. younger pts using age cutoff of 60 yrs. Compared to younger pts, HR for pts > 60 yrs with rare AL was as follows: 2.68 (2.13-3.37; p <0.0001) for myeloid sarcoma; and 2.18 (2.07-2.31; p<0.0001) for leukemia NOS. No difference in survival over time was seen for myeloid sarcoma. Pts with leukemia, NOS diagnosed in yrs 2006-2012 (HR=0.87; 0.82-0.92; p < 0.0001) had better survival compared to the referent years 1973-80. Race and gender did not impact survival. In multivariable analysis, pts with leukemia NOS did worse overall compared to AML (HR=1.13; 1.11-1.53; p<0.0001) and ALL (HR=1.86; 1.81-1.91; p<0.0001). Interestingly, younger pts had a poorer outcome than AML (HR=1.10; 1.04-1.16; p=0.0003), but pts > 60 yrs had a better outcome (HR=0.93; 0.91-0.95; p<0.0001). Both younger (HR=1.33; 1.26-1.41; p<0.0001) and older pts (HR=1.45, 1.40-1.50: p<0.0001) compared unfavorably to ALL (Figure 1). Pts with myeloid sarcoma had a better survival compared to AML pts (HR=0.77; 0.7-0.85; p<0.0001) (Figure 2). This was uniform for pts <60 yrs (HR=0.77; 0.64-0.93; p=0.006) and > 60 yrs (HR= 0.77; 0.69-0.87; p<0.0001). Conclusion: Pts with leukemias NOS have poor outcomes compared to AML and ALL but prognosis has improved in recent years. The most probable explanation is identification of prognostic molecular mutations that has allowed accurate risk-stratification of pts using the WHO classification and in turn better selection of treatment strategies. Several reasons have limited our understanding of these rare AL - small numbers, exclusion from clinical trials and wide variability in treatment options used. Efforts at better molecular characterization of these AL holds the most promise for improving outcomes. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 788 FLT3 mutations are common in AML and are associated with poor prognosis. Lestaurtinib is a multi-targeted kinase inhibitor with potent activity against FLT3. In an attempt to definitively establish whether or not there is clinical benefit for FLT3 inhibition in the relapse setting, we conducted a randomized trial of chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Patients were randomized to receive either chemotherapy alone, consisting of mitoxantrone, etoposide, and cytarabine (MEC) or high-dose cytarabine (HiDAc) depending on the duration of CR1) or chemotherapy followed by 80 mg lestaurtinib orally BID. Patients on the chemotherapy only arm were eligible for crossover if they were refractory to therapy. Patients on the lestaurtinib arm received the drug for up to 112 days on study (they could continue to receive the drug through a separate extension protocol). The primary objective was complete remission (CR/CRp). Secondary objectives included overall survival (OS), safety, and tolerability. From January 2004 through December 2008, 224 patients at 52 different centers were enrolled and randomized, with 220 patients actually receiving therapy. Blood samples from patients on the lestaurtinib arm were obtained at baseline, on Day 15, and on Day 42 for pK studies and for determination of in vivo FLT3 inhibition and measurement of plasma FLT3 ligand (FL) and alpha-1 acid glycoprotein (AGP) levels. The median age for all patients enrolled was 55 years (53.5 in the control arm, 58.5 in the lestaurtinib arm), with 88% having FLT3/ITD mutations, 8% having D835 mutations, and 4% having both. The duration of CR1 was less than 6 months in 47% of patients in each arm. On the lestaurtinib arm, 107 patients received at least 1 week of lestaurtinib (mean 60.1 days, range 8-418), with 17 of these patients receiving drug on the extension protocol. On the chemotherapy only arm, 7 patients crossed over to receive lestaurtinib, and 31 patients went on to receive lestaurtinib on the extension protocol after outcome evaluation. Lestaurtinib was generally well tolerated following chemotherapy, with 104 Grade 3/4 adverse events in the lestaurtinib arm versus 99 in the control arm. There were 61 serious adverse events in the lestaurtinib arm versus 49 in the control arm. Early death (by Day 42) occurred in 22 lestaurtinib patients (2 progressive leukemia, 14 infectious, 6 organ failure) and16 control patients (6 progressive leukemia, 5 infectious, 5 organ failure). By intention to treat analysis, there were 29 CR/CRp in the lestaurtinib arm and 23 in the control arm (26% versus 21%; p = 0.35), with no difference in OS (4.73 months versus 4.57 months) between the two arms. Blood samples from 79 of the 107 lestaurtinib-treated patients obtained on Day 15 were analyzed for FLT3 inhibitory activity (plasma inhibitory activity [PIA] assay), as well as FLT3 ligand (FL), lestaurtinib, and AGP concentrations. Mean lestaurtinib plasma concentration was 12 uM at Day 15 and fell to 7.5 uM on Day 42. Mean lestaurtinib concentration at Day 15 was 13.3 uM in patients achieving CR/CRp and 11.5uM in non-responders. A target of >85% inhibition of FLT3 maintained at trough (pre-dose) was defined from previous studies. Of the 79 patients tested, 46 (58%) achieved this degree of FLT3 inhibition on Day 15. FL concentrations rose from baseline (15.6 pg/mL) to Day 15 (1148 pg/mL), and AGP concentrations rose by an average of 52% over the same period, both of which may have reduced the degree of FLT3 inhibition. Of the 46 patients with target FLT3 inhibition on Day 15, 18 (39%) achieved CR/CRp, while only 3 (9%) of the 32 patients with below target FLT3 inhibition achieved CR/CRp. Thus, in patients with FLT3 mutant AML at first relapse, pharmacokinetic factors and possible physiologic factors (FL and AGP) limit lestaurtinib's ability to effectively inhibit FLT3. FLT3 inhibition by lestaurtinib, when achieved, correlates with better CR rates, but in this trial that benefit was negated by a poor CR rate in those patients for whom the drug did not reach the target level of FLT3 inhibition. Overall, lestaurtinib treatment following re-induction chemotherapy failed to increase response rates or prolong survival of patients with FLT3 mutant AML in first relapse. Disclosures: Levis: Cephalon: Clinical Advisory Board member. Ravandi:Cephalon: Honoraria, Member, clinical advisory board, Research Funding. Erba:Cephalon: Research Funding, Speakers Bureau. Baccarani:Novartis Pharma, Bristol Myers Squibb, Merck Sharp & Dome, Pfizer: Consultancy, Speakers Bureau. Stone:Cephalon: ad hoc consultancy; Novartis: Research Funding, ad hoc consultancy. Advani:Cephalon: Research Funding. Douer:Cephalon: Honoraria, Research Funding, Speakers Bureau. Litzow:Cephalon: Research Funding. Tremmel:Cephalon: Employment, Equity Ownership. Bensen-Kennedy:cephalon: Employment. Smith:Cephalon: Research Funding.

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

Abstract Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.