Antecedent Hematologic Disorder Research Articles

Phase 1/1b Study of RG7388, a Potent MDM2 Antagonist, in Acute Myelogenous Leukemia (AML) Patients (Pts)

Phase 1/1b Study of RG7388, a Potent MDM2 Antagonist, in Acute Myelogenous Leukemia (AML) Patients (Pts)

Pracinostat in Combination with Azacitidine Produces a High Rate and Rapid Onset of Disease Remission in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of <0.1µM, and the combination with azacitidine was synergistic (CI=0.44). A Phase I study of single agent pracinostat showed activity in AML and a pilot Phase II study of pracinostat in combination with azacitidine in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). We report initial results from a Phase II study of pracinostat with azacitidine in previously untreated, elderly AML.Methods: Eligibility includes previously untreated AML (≥ 20% bone marrow blasts), age ≥65 years, deemed inappropriate for intensive induction therapy, with intermediate or high risk cytogenetics based on SWOG criteria. De-novo, treatment-related, or AML evolved from an antecedent hematologic disorder (AHD) are allowed. Pracinostat is administered orally (60 mg) 3 days a week (e.g., Monday, Wednesday, Friday) for 3 weeks followed by a 1 week break. Azacitidine is administered subcutaneously or intravenously (75 mg/m2) day 1-7 or day 1-5 and 8-9 of each 28-day cycle. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) according to IWG criteria. Response assessments occur at the end of cycle 1 or 2 followed by every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, α=0.10, power=0.90. Transition from stage 1 to 2 requires ≥ 3/27 response events; the null hypothesis will be rejected if ≥ 7 response events are observed in the total planned sample of 40 patients.Results: As of August 01, 2014, 21 patients have been enrolled from 12 study sites and are evaluable for safety; 14 are evaluable for efficacy (Table 1), and 7 are 'too early’ for response assessment. Baseline disease characteristics include: median age 77 (range 69-84); 16 de novo AML, 4 evolved from AHD, 1 treatment related; 11 intermediate-risk, 8 high-risk cytogenetics, and 2 are pending; baseline bone marrow blast counts ranged from 22% to 89%. The primary endpoint of CR +CRi+MLFS was observed in 8 of 14 evaluable patients (57%), the majority after 1 or 2 cycles. No responders have progressed. The most common treatment emergent adverse events (TEAE) were neutropenia/neutropenic fever (n=15), thrombocytopenia (n=12), nausea (n=10), fatigue (n=8), and anemia (n=7). Serious adverse events include febrile neutropenia (n=6) and pulmonary infiltrate/pneumonia (n=2). Three patients discontinued study therapy due to a TEAE, including one each with cellulitis, bacteremia, and subdural hematoma after a fall. There have been 3 deaths on study: 1 bacteremia, 1 subdural hematoma, and 1 progressive disease.Abstract 947. Table 1Patient NumberDays on StudyBaseline BM Blast %1st On-Study BM Blast %Subsequent On-Study BM Blast %Best Response on Study2172+221 (C2)—CR3165+244 (C1)0 (C4)CRi5162+279 (C1)1 (C4)CRi6156+819 (C1)0 (C4)CRi7148+7844 (C1)17 (C3), 0 (C5)CR8114+894 (C1)—CR1086+453 (C1)—CRi1281+412 (C2)—CRi4902243 (C2)Off due to SAESD11563760 (C2)—PD152870—Patient Withdrew172860—PD12670—Off due to AE92638—Off due to AE+=Patients continue on study; C=cycle; SD=Stable Disease; PD=Progressive DiseaseConclusions: The study has achieved the primary goal of rejecting the null hypothesis. The CR+CRi +MLFS response rate estimate of 57% is high compared to historical results with hypomethylating agents alone in this population, and the responses occur rapidly, most within the first 2 cycles. The combination appears tolerable with no unexpected toxicities. Recruitment continues to the final planned sample size of 40 to further define the tolerability and efficacy of the regimen, including remission duration. Updated data will be presented at the meeting. DisclosuresGarcia-Manero:MEI Pharma, Inc.: Consultancy. Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Odenike:Sanofi-Aventis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Suneisis Pharmaceuticals : Honoraria, Membership on an entity’s Board of Directors or advisory committees. Medeiros:MEI Pharma, Inc: Research Funding. Cortes:Celgene: Research Funding. Esquibel:MEI Pharma, Inc.: Employment. Cha:MEI Pharma, Inc.: Employment. Khaled:Sequenom: Research Funding.

Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)

Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, has limited toxicity, and is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ³ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ² 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. In the phase I part of the study the first six pts received vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. This dose was well tolerated with no dose limiting toxicity identified and pts were then enrolled on phase II at this dose and schedule. However, due to mucositis in a few subsequent pts, the induction dose of vosaroxin was reduced to 70 mg /m2, starting with pt #25. The vosaroxin dose could be maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the overall response rate including complete response (CR) + CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 35 pts (32 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-78) have been enrolled; 34 (97%) pts were older than 60 years. They included 15 (43%) pts with diploid cytogenetics, 12 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 8 (23%) with other miscellaneous abnormalities. 13 (37%) pts with AML had antecedent hematological disorders (AHD) including 7 (20%) with MDS, 4 (11%) with myeloproliferative neoplasm and 2 (6%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 5 (15%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, median white blood cell, hemoglobin, &amp; platelet counts were 40% (9-97), 4.1 x 109/L (0.4-57.0), 9.4 g/dL (6.8-11.5), and 40 x 109/L (7-333), respectively. 34 pts were evaluable for response; 17 (50%) achieved CR, 6 (18%) CRp, and 3 (9%) CRi for an overall response rate of 77%. One pt is too early for response assessment. Responses by age, cytogenetic and molecular characteristics are shown in table 1. The median follow-up is 5.1 months (range, 0.9-11.0). Pts have received a median of 2 (1-6) treatment cycles with the median number of cycles to response being 1 (1-4). Three pts have relapsed and the median duration of CR/CRp/CRi has not been reached (0.5-9.9+ months). Four (12%) pts have proceeded to allogeneic stem cell transplant (ASCT). 4-week and 8-week mortality were 0% and 14%, respectively. The regimen is well tolerated with the main grade ³ 3 toxicity being mucositis in 9 (26%) pts and liver enzyme elevation in 3 (9%). Conclusion: Combination of vosaroxin and decitabine is effective and feasible in older pts with AML and high-risk MDS. Enrollment is ongoing. Table 1: Response by baseline characteristics Parameter Category N Overall response Too early to evaluate Age* 60-70 16 14/16 (88%) 0 &gt;70 18 12/17 (71%) 1 Cytogenetics Diploid 15 11/14 (79%) 1 -5/-7/other adverse 12 8/12 (67%) 0 Miscellaneous 8 5/8 (63%) 0 Mutation Status IDH2 7 7/7 (100%) 0 IDH1 5 1/4 (25%) 1 TP53 9 6/9 (67%) 0 RAS 9 4/9 (44%) 0 *1 pt below the age of 60 years was unsuitable for standard chemotherapy and was enrolled on study. Disclosures Naval: Sunesis: Advisory board membership Other, Research Funding. Off Label Use: Vosaroxin (Qinprezo) has not been approved for AML. In this clinical trial we are evaluating the efficacy and safety of vosaroxin (Qinprezo) in combination with decitabine in elderly patients with AML. . Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. Jabbour:Ariad, Novartis, BMS, Pfizer, and Teva: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Craig:Sunesis: Employment. Ravandi:Sunesis: Advisory board membership Other, Research Funding.

Heatshock Protein (HSP) Family Expression Is Dichotomous and Prognostic in Acute Myelogenous Leukemia (AML)

Background. Heat shock family proteins (HSP) are induced by cellular stress, and act as molecular chaperones regulating protein folding, conformation and proteosomal degradation, thereby affecting cell stability, cycling, and apoptosis. High levels of some HSP have been observed in AML and high HSP90 is prognostically adverse. Cell line studies show that HSP protects AML cells against chemotherapy or other stresses and that inhibition of HSP 27, 70 or 90 has antileukemic activity. HSP proteins have typically been studied individually, and in small series. Interactions with multiple signaling and functional pathways are suspected, but the actual relationship in primary AML samples is unknown. We therefore investigated the protein expression of members of the HSPA, B and C groups, HSP 70, 27 and 90, Hugo Names HSPA1A_L, HSPB1 and HSP90AA1_B1, respectively, in a large series of 511 AML patients and compared expression to 228 other simultaneously measured proteins.Methods. We made a reverse phase protein array (RPPA) with protein from leukemia enriched cells from 511 new AML patients. Both bone marrow (BM, n=387) and peripheral blood (PB, n=283) samples were used, with 140 cases having both. The RPPA was probed with 231 strictly validated antibodies, including antibodies against HSP27, 70 and 90. Expression was compared to that of normal bone marrow derived CD34+ cells. Interaction networks with the other 228 proteins were generated from the RPPA data using glasso and supplemented by the literature of known interactions.Results: A heatmap of HSP27, 70 and 90 expression was generated and hierarchical k-and means clustering performed (Fig 1A). Using the “Prototype Clustering” method an optimal division into two clusters C1) characterized by High HSP27 and 70 but low HSP90 and C2) characterized by High HSP90 and low HSP27 and 70 expression. Patients with high HSP90 had significantly higher % BM Blasts (63.6% vs. 42%), WBC (40.8K vs 16.9K), %PB blasts (44 vs. 17%), LDH levels, concurrent infection 34% vs. 12%), FLT3-ITD (25 vs. 13%) or FLT3-D835 mutation (8% vs. 4%) (all P < 0.00001) compared to those with High HSP27 & 70. HSP90 High patients were less likely to have an antecedent hematological disorder (26 vs. 47%, P < 0.00001). Other clinical features, age, gender, cytogenetics, RAS mutation, NPM1 mutation did not differ. Overall survival for all patients (Fig D) was inferior for those with High HSP90 (42 vs. 60 weeks, p = 0.04), but this was based solely on those with intermediate cytogenetics (Fig E) (48 vs. 91 weeks p =< 0.00001), whether FLT-3 mutant (Fig G) (30 vs. 78 weeks, p=0.025) or Wildtype (Fig H, p = 0.037). This was seen in NPM1-WT/FLT3- WT (p=0.03), NPM1-Mut/FLT3 -Mut (fig I, p=0.006) and NPM1-Mut/FLT3 WT (fig J, p=0.08). High HSP90 patients also had inferior remission duration (Fig F, 39 vs. 84 weeks, p=0.025). Networks (Fig B & C) of proteins with expression strongly (p <.00001) correlated with the HSP in the literature (dashed spoke) or the dataset (solid spoke) are shown. Differential expression between the two groups are shown in Fig C (*). Among those with differential expression, levels were higher in the HSP90 high group for histone methylation associated proteins ASH2L, SIRT1, hnRNPK, Nucleolin, proliferation regulators Myc, EIF2S1, EIF2AK2, EIF4E, and for apoptosis/autophagy proteins Beclin1, Park7, MDM2 and BCL2. In contrast protein levels were lower in HSP90 High for : AKT1.pT308, BIRC2, CDKN1A, CDKN2A, CDK4, EGFR 7 pEGFR, ERBB2, HIF1α, IGF1R, LCK PKCα, SRC & pSRC.Conclusions. AML is characterized by dichotomous expression of HSP proteins 27, 70 and 90. HSP expression pattern is associated with FLT3 mutation but not cytogenetics. HSP90 expression is prognostically adverse, exclusively among those with intermediate cytogenetics. High HSP90 expression is associated with higher WBC and PB and BM blast percentages, suggesting a proliferative advantage. This may arise through the effects of Myc and through increased gene expression arising from increased histone3K4 trimethylation from ASH2L and decreased histone 3 acetylation due to increased Sirt1 levels. Therapeutics directed at interfering with HSP function will need to consider which HSP pattern a patient exhibits to target the correct family members. [Display omitted] DisclosuresBorthakur:Tetralogic Pharmaceuticals: Research Funding.

Feasibility Trial of Individualized Therapy for Relapsed or Refractory Acute Myeloid Leukemia Based on a High Throughput in Vitro Drug Sensitivity Assay

Introduction. Resistance to therapy, rather than treatment-related mortality, is the usual cause of failure to cure AML. Typically all patients receive the same therapy despite great inter-patient variation in the mutations that underlie the disease. Thus an individualized approach to therapy might be more productive. To this end, we developed a high-throughput sensitivity assay for 160 drugs; 45 are FDA approved and 115 investigational, encompassing a wide range of targets and mechanisms of action. We previously validated the assay in 30 primary patient blast samples and 14 acute leukemia cell lines. Here we report a clinical trial (NCT01872819 at clinicaltrials.gov) utilizing this assay to select drugs for patients with refractory AML.Method. The primary objectives were to obtain assay results within 10 days and initiate treatment within 21 days. The secondary objective was to achieve a response (cytoreduction or at least partial response) greater that that expected for comparable refractory populations with other therapies. Mononuclear cells from marrow or peripheral blood were obtained by density centrifugation and enriched for blasts using magnetic bead separation if the initial sample contained < 80% blasts. Cells were incubated in coated 384 well plates overnight, then drugs were added at 8 concentrations spanning 4 log orders of magnitude, in duplicate. After 4 days, live cells were detected with CellTiter-Glo® (Promega). XLfit (idbs) was used to plot survival curves (4 parameter logistic dose fit) and to calculate EC50s. Individual drugs were chosen on the basis of EC50 and drug availability, and patients received the single agents at the accepted maximal tolerated dose.Results. Fifteen patients were enrolled. Ten had unfavorable cytogenetics, and 3 had the Flt3ITD and 1 the Flt3D835 mutation. Eight patients had antecedent hematologic disorder. They had received an average of 5 prior therapies (range 3-6). The average time from sample procurement to assay result was 5.1 days (range 4-8). Within an average of 11.6 (median 9, range 4-28) days, 13 patients received single drugs to which their cells appeared to be sensitive with an EC50 range of 0.026 - 0.175 μmol/L , including cladribine, mitoxantrone, bortezomib, or vinblastine. For the patient with the Flt3ITD mutation, the blasts exhibited sensitivity to 6 Flt3 inhibitors in the high throughput assay. Although only FDA approved drugs were able to be procured, as the pharmaceutical companies denied requests for individual patient use, most patients received a drug they had not previously received. All patients exhibited a decline in blast number after receipt of the indicated drug, on average, by 92.6% (range 80.5-99.8%). Toxicity was as expected if the patients had received standard investigational protocols for relapsed/refractory AML. Median overall survival was 88 (range 7-276) days from start of treatment.For one patient without circulating blasts, the marrow blast percent declined from 27% by flow to 0% at day 15 and also 0% at day 51. 6 of 9 evaluable participants exhibited a reduction in bone marrow blasts by flow cytometry on a day 14-21 marrow. There were also 2 patients whose day 14-21 marrows were severely hypocellular. Moreover, 1 patient achieved CR, and 2 patients, CRp, that occurred after additional cycles of combination chemotherapy regimens for 2 of the 3 patients, that included drugs identified by the high throughput assay.Conclusion. In vitro high throughput testing to guide individual treatment choice is feasible and warrants further evaluation in larger clinical trials, with panels that include investigational drugs. DisclosuresOff Label Use: Cladribine is indicated for the treatment of hairy cell leukemia. Vinblastine is indicated for the treatment of Hodgkin’s disease and testicular cancer, and some other cancers. Bortezomib is indicated for the treatment of multiple myeloma and mantle cell lymphoma.

Preliminary Evidence That ODSH (2-O, 3-O Desulfated Heparin) Is Safe and Enhances Count Recovery in Patients Treated with Intensive Therapy for Acute Myeloid Leukemia – Results of a Pilot Study

IntroductionIntensive treatment of acute myeloid leukemia (AML) is associated with severe pancytopenia. Thrombopoietic agents have so far failed to mitigate treatment-associated thrombocytopenia. Platelet factor 4 (PF4) is a potent negative regulator of megakaryopoeisis and its levels correlate with platelet transfusion requirements in children treated for acute lymphoblastic leukemia. Anti-PF4 antibodies diminish chemotherapy-induced thrombocytopenia in mice. ODSH (2-O, 3-O Desulfated Heparin), a heparin derivative with low anticoagulant activity, is a potent inhibitor of PF4, mitigates heparin-induced thrombocytopenia and, like other heparins, may inhibit the CXCL12/CXCR4 axis. The purpose of this pilot study was to obtain preliminary data on the effect of ODSH when combined with intensive AML treatment.MethodsAdult patients with newly diagnosed untreated AML (excluding acute promyelocytic and acute megakaryoblastic leukemia) were enrolled. Induction therapy consisted of cytarabine (100 mg/m2 as a continuous 24-hour infusion on days 1 – 7) and idarubicin (12 mg/m2 by intravenous bolus on days 1 – 3). During induction cycles, ODSH was given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 7. Patients 60 or older received further post-induction therapy off study. Patients younger than 60 received consolidation therapy with high dose cytarabine (3 g/m2 every 12 hours on days 1, 3, and 5) along with ODSH given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 5. Patients received transfusion and antibiotic support per standard guidelines. Patients did not receive growth factor support during induction cycles.Primary endpoints were to determine the safety and tolerability of ODSH combined with intensive AML therapy, and to obtain preliminary data on the effect of ODSH on platelet count recovery. Secondary endpoints included obtaining preliminary data on the effect of ODSH on complete remission rate and tolerability of chemotherapy. Data presented here are for induction cycles. Data for consolidation cycles will be presented at the meeting.ResultsTen patients were enrolled. Two patients did not complete the full induction cycle due to complications unrelated to ODSH therapy and are not included in the analysis. The median age of the 8 patients (3 women) who completed the full induction cycle and were analyzed was 55 (range: 22 – 74). There were no ODSH-associated adverse events. Based on cytogenetic, molecular, or antecedent hematologic disorder, 1, 5, and 2 patients fell into the better, intermediate, and poor risk categories, respectively. Day 14 bone marrow biopsies were obtained on all 8 patients and were aplastic without detectable leukemia in all. Seven out of 8 patients who completed induction had evidence of a morphologic complete remission upon count recovery using IWG criteria. One of the 7 patients in morphologic remission had evidence of minimal residual disease by flow cytometry and cytogenetics. It is noteworthy that the 2 patients who did not receive a full course of induction therapy (treatment discontinued on Day 3 and Day 5 of the induction cycle, respectively) achieved a complete remission upon count recovery using IWG criteria with evidence of minimal residual disease by molecular testing.All 8 patients who received a full course of induction therapy were evaluable for platelet count recovery. Among those patients, the median day to obtain a sustained platelet count above 20,000/ml without transfusion was day 20 (range: 16 – 22). Five of the 8 patients who received a full course of induction therapy were evaluable for neutrophil count recovery. Among those patients, the median day to a neutrophil count above 1,000/mL was day 23 (range: 21 – 27).ConclusionWe conclude that ODSH is well tolerated when combined with aggressive therapy for the treatment of AML. Results from this pilot study show that ODSH may enhance count recovery and treatment efficacy. These results justify further study of this strategy in a randomized trial. DisclosuresKennedy:Cantex Pharmaceuticals: Equity Ownership. Bavisotto:Cantex Pharmaceuticals: Consultancy. Marcus:Cantex Pharmaceuticals: Employment, Equity Ownership. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Lone Star Thiotherapies: Equity Ownership; Cantex Pharmaceuticals: Research Funding.

A Randomized Phase II Study of Tosedostat in Combination with Either Cytarabine or Decitabine in Newly Diagnosed Older Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Background: Tosedostat is an oral aminopeptidase inhibitor that has anti-neoplastic activity in a variety of malignancies. Pre-clinical assays have demonstrated synergy between tosedostat and both cytarabine and hypomethylating agents. We performed a randomized, open-label Phase II trial to determine the rates of complete remission (CR) and 4 month overall survival using tosedostat in combination with intermediate-dose cytarabine or decitabine in patients with untreated AML or high-risk MDS.Methods: Patients ≥60 years old were randomized in a 1:1 fashion to receive tosedostat 120 mg daily by mouth days 1-21 with either 5 days of intravenous cytarabine 1 g/m2/day or decitabine 20 mg/m2/day delivered every 35 days for up to three cycles. Eight patients received 180 mg tosedostat daily continuously. Patients who obtained a CR or CR with incomplete blood count recovery (CRi) after 3 cycles of therapy were eligible to receive up to 2 additional cycles (maximum of 5).Results: Thirty-four patients with a median age of 70 (range, 60-83) years were treated, with 17 each receiving either tosedostat/cytarabine or tosedostat/decitabine. Twenty-nine patients (85%) had AML and 5 (15%) had MDS RAEB-2. Nineteen patients (56%) had cytogenetics with intermediate-risk, 14 (41%) adverse-risk, and 1 (3%) favorable-risk by European Leukemia Net criteria. Seven patients had FLT3/ITD mutations with normal cytogenetics. Fifteen patients (44%) had secondary AML/MDS or antecedent hematologic disorder. The median duration of treatment was 3 months. The overall CR/CRi rate was 53% (9 in each arm), with 14 patients (41%) achieving a CR and 4 patients (12%) a CRi. CR/CRi was attained in 6 patients with adverse cytogenetics and 4 additional patients with FLT3 mutations. Fourteen patients (41%) were taken off study after a median of 2 cycles due to lack of response or disease progression. With a median follow-up of 11.2 months (range, 0.5-22.3 months), the median overall survival was 11.5 months (95% CI, 5.2-16.7). Twenty-three patients (67.6%) were treated as outpatients and 10 of these patients (44%) required hospitalization during treatment for febrile neutropenia. There were no Grade 3-4 non-hematologic toxicities requiring withdrawal from the study.Conclusions: Tosedostat in combination with cytarabine or decitabine likely provides a CR/CRi rate of >50% with acceptable toxicity in older patients with untreated AML/ MDS. This approach delivered predominantly as outpatient therapy suggests that further study in a larger, controlled trial may be warranted. DisclosuresOff Label Use: Pravastatin is not FDA approved for treatment of AML. Wang:CTI Biopharma: Employment. Singer:CTI BioPharma, Corp: Employment, Equity Ownership.

Secondary Acute Myeloid Leukemia Is an Heterogeneous Subgroup of Elderly AML Where Patient’s Fitness Criteria and ELN Prognostic Stratification Can be Applied to Guide Treatment Decisions: An Analysis of 127 Patients By the Network Rete Ematologica Lombarda (REL)

Background: According to the WHO classification, secondary acute myeloid leukemia (s-AML) includes cases occurring in patients (pts) receiving prior antineoplastic treatments as well as cases developing in pts with a history of previous hematology disorders, such as a myelodysplastic syndrome (MDS) or a chronic myeloproliferative disease (MPD).Outcomes for this large group of pts, which has a high median age and a high frequency of unfavourable cytogenetics, has been traditionally considered very poor, compared to AML developing “de novo”, and treatment with intensive chemotherapy (iCT) is not standardized in elderly pts. Indeed pts with s-AML have been excluded from molecular and cytogenetic prognostic stratification defined by the ELN criteria.Aim: Since patients with s-AML actually represent an heterogeneous subgroup of pts a multicenter retrospective study was performed to analyse their outcome in relationship to age, fitness and ELN risk stratification, in order to potentially identify subgroups at different prognosis.Patients and Methods: We evaluated 127 pts, representing 35% of a population-based series of elderly AML, aged > 65 years (y), diagnosed at five Hematology Centers of the Hematological Network of Lombardy in Northern Italy from January 2008 to May 2014. Thirteen pts (10%) had t-AML and 114 (90%) had AML secondary to previous hematological disorders (89 MDS and 25 MPD). Median age was 74 y (range 65-94 y). Performance status (PS) was evaluable in 122 pts (96%) and PS ECOG was >3 in 32 pts (26%). According to “fitness criteria”, (Ferrara et al, Leukemia, 2013), 126 pts (99%) were evaluable: 54 pts (42.5%) were fit to i-CT (FIT), 55 (43.3%) unfit to i-CT (UNFIT), 17 (13.4%) unfit to ni-CT (FRAIL). Intensive CT was given to 34 (27%), ni-CT (low-dose arac, azacytidine or experimental non-myelotoxic drugs) to 26 (20%) and best supportive care (BSC) to 67 pts (53%). Overall concordance between the fitness and the treatment actually received was 78%.The ELN prognostic criteria were applicable in 69 pts (54%), because of lack of complete molecular and cytogenetic data in the others. Six pts (8.5%, all NPM1+) were at low, 14 (20%) at intermediate-1, 11 (16%) at intermediate-2 and 38 (55%) at high risk.Results: The median OS according to fitness was 9,6, 4 and 3 months (ms), in FIT, UNFIT and FRAIL pts, respectively (p=0.0021) (Figure 1). Both the treatment received (i-CT or ni-CT vs BSC) and the risk ELN classification were related to OS (p< 0.0001 and p=0.0089, respectively). In FIT pts the median OS was 8 ms in pts treated with i-CT, 11 ms with ni-CT, and 3 ms with BSC (p<0.0001) (i-CT vs ni-CT : p=0.6) (Figure2).The achievement of CR was related to outcome (median OS 12.7 ms vs 5 ms) (p= 0.0035). AML with antecedent hematological disorder (53.8%) or with t-AML (50%) had similar CR rate (53,8% vs 50%) as well as OS (median OS 11 ms vs 7 ms) (p =0.5).According to ELN risk, OS was better in LR/Int-1/int2 vs HR (median OS 11,4 vs 5 ms, p=0.0035) (Figure 2).Moreover, also the achievement of CR was related to ELN risk: 100% in LR, 57% in Int1/Int2, 14% in HR (p= 0.012), and percentages differed from de novo AML only in HR pts. Prognosis of the subgroup of 34 ELN low/Int1 risk pts treated with i-CT was fair with CR rate of 53%, and 2 y OS 40% compared to 10% in similarly treated Int2/HR pts (p=0.07).Conclusion: Elderly pts with s-AML are an heterogeneous subgroup both according to fitness and to ELN risk stratification and these parameters are significantly related to clinical outcome. Overall prognosis of elderly patients with s-AML is not exceedingly worse than in elderly with de novo AML. Outcome was better using i-CT or ni-CT compared to BSC, with no differences between the two treatment modalities. ELN risk stratification merits to be applied also to patients with s-AML and its integration with fitness criteria can identify a subgroup of patients which may benefit from intensive CT. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Transplantation in First Remission Improves Outcome in Secondary Acute Myeloid Leukemia

Allogeneic stem cell transplantation (SCT) is widely used as post-remission treatment in younger patients with poor or intermediate risk AML. Transplant decisions are mainly based on cytogenetic and molecular risk group, age, comorbidity and on the availability of a suitable donor. Secondary AML, including therapy-related AML (t-AML) and AML after an antecedent hematological disorder (AHD-AML), constitutes more than one fourth of the AML cases and is a predictor of a poor outcome. However, the extent to which SCT improves outcome of this patient group is poorly studied.In this study, we set out to investigate the role of SCT for the survival of secondary AML patients within the population-based Swedish Adult Acute Leukemia Registry. In total, 5881 patients with AML diagnosed during the period 1997 – 2013 were included in the study. Of these, 4233 (72%) were de novo AML, 1098 (19%) AHD-AML and 550 (9%) t-AML. The median age at diagnosis was 70 in de novo AML, 73 in AHD-AML and 70 in t-AML. The gender distribution was equal in de novo AML (51% males). In AHD-AML, there was a male predominance of 57% whereas in t-AML, there was a female predominance of 56%. The proportion of patients who underwent SCT in first remission (CR1) was 10% in de novo AML, 5% in AHD-AML and 8% in t-AML (de novo vs AHD-AML p < 0.001, de novo vs t-AML p = 0.068, AHD-AML vs t-AML p = 0.081; Fisher’s exact test). In patients aged 65 or below, the proportion of SCT in CR1 was 24%, 21% and 20%, respectively. The median age of SCT patients was 48 (range 17 – 71) in de novo AML, 57 (27 – 76) in AHD-AML and 49.5 (18 – 68) in t-AML. In de novo AML, the distribution of genetic risk groups among SCT patients was 3% low risk, 55% intermediate risk and 42% high risk. Corresponding figures for AHD-AML was 0%, 34% and 66% and for t-AML 5%, 45% and 50% respectively (de novo vs AHD-AML p = 0.004, de novo vs t-AML p = 0.299, AHD-AML vs t-AML p = 0.124; Fisher’s exact test).The estimated median survival after the date of SCT in CR1 was 15 months in AHD-AML and 22 months in t-AML but not reached in de novo AML (95% lower confidence limit 107 months). Among patients <65 years who had been in CR for 3 months (genetic low risk excluded), those with secondary AML had a greater benefit from consolidation with SCT than those with de novo AML (Figure 1). The projected 7-year survival in de novo AML was 60% with SCT and 44% with conventional post remission therapy (CPRT) as compared to 46% and 21%, respectively, in secondary AML. The survival hazard with SCT was 0.45 in secondary AML (95% CI 0.28-0.72) as compared to 0.66 in de novo AML (CI 0.53 – 0.82), by multivariable Cox regression adjusting for type of secondary AML, age, sex, and cytogenetic risk group. To refine the analysis correcting for major confounding factors, a matched pair analysis was performed in patients with CR longer than 3 months. Matching criteria were type of secondary AML (AHD or t-AML), cytogenetic risk group and age (+/- 3 years). Remission of the patient with CPRT was at least as long as the time between CR1 and transplantation for the matched patient undergoing SCT. The projected 7-year survival rate was 43% in the SCT and 8% in the CPRT group (p = 0.01; log-rank test, Figure 2) further indicating a benefit for SCT as post remission therapy in secondary AML. We conclude that SCT improves survival in patients with secondary AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase II Feasibility Study of Prophylactic White Cell Transfusions for the Prevention of Infection in AML Patients Undergoing Induction Therapy

▪Patients with acute myeloid leukemia (AML) experience sustained and profound neutropenia during induction chemotherapy; infections remain the leading cause of morbidity and mortality in myelosuppressed leukemia patients. The current standard of care is to provide patients with broad-spectrum antibiotic, antifungal and antiviral therapy; however resistance to available anti-infective agents is increasing. Transfusion of functional non-irradiated allogeneic granulocytes to neutropenic leukemia patients may treat, delay or prevent infections in patients with leukemia, and importantly may also have anti-leukemia benefits.Patients treated at MD Anderson Cancer Center with a diagnosis of AML undergoing front-line AML therapy were eligible. Patients were required to be free of signs and symptoms of infection at the time of study entry, and have sufficient volunteer donors to administer prophylactic white cell transfusions approximately twice a week for six weeks. Allogeneic white cell transfusions (≥ 4 x 10¹⁰ cells per transfusion) were administered every 3-4 days during the induction chemotherapy cycle, so long as patients remained neutropenic with an absolute neutrophil count < 500. Prophylactic transfusions continued until the time of sustained ANC recovery, initiation of a new treatment regimen, or after the completion of 6 weeks on protocol.Herein we provide the results of the first 21 patients. Median age was 67 (range 23-78); 12 patients were male and 9 were female. All patients were enrolled at the time of initiation of AML induction therapy. Seven patients had a diagnosis of therapy-related AML (6 with an antecedent hematologic disorder and 1 with prior solid malignancy). Various treatment regimens were administered and are displayed in Table 1, along with cytogenetic and MD Anderson prognostic model classification.Patients received a median of 5 transfusions (range 0 – 11). Of 21 patients, 1 withdrew consent prior to the first transfusion, and 3 patients discontinued transfusions prior to the end of study (due to a diagnosis of pneumonia in one with potential concern for increased pulmonary toxicity with continued transfusions, and two at patient requests due to fevers and myalgias post transfusions).Median time to ANC recovery was 38 days (range 14 – 137) and platelet recovery 29 days (range 12 – 160), consistent with the elderly population and the allotted treatment regimens. All patients experienced at least one neutropenic fever, often within 48 hours of white cell administration. Documented infections included 2 instances of bacteremia (1 streptococcal and 1 E. coli), 2 urinary tract infections (both coagulase negative staphylococci), 8 cases of pneumonia (1 documented E. coli, 7 culture-negative and presumed fungal pneumonia per imaging). There was one patient with neutropenic colitis per imaging. There were no induction-related deaths. 8-week mortality was 5% (n=1) and 12-week mortality was 20% (n=4). With a median follow-up time on study of 20.3 weeks, overall survival is 67% with a median survival which has not yet been reached (Figure 1). Overall response to initial induction chemotherapy was 67% (9 CR, 1 CRi, 4 PR). A total of 15 patients (71%) ultimately attained a CR (after the first cycle or with additional cycles of therapy), and 4 patients received a stem cell transplant at the time of CR/CRi.In conclusion, prophylactic transfusion of allogeneic non-irradiated white blood cells for newly diagnosed AML patients during induction chemotherapy was associated with a decreased incidence of life-threatening infections, decreased induction mortality (6-week OS of 100%), and may also lead to improved remission rates and overall survival. This feasibility study has been expanded to enroll a total of 50 patients, with updated results to be provided at the annual meeting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Risk Older AML Patients May be Benefited from the Treatment of Decitabine Combined Wih CAG Regimens

Patients over age 60 maked up more than 50% of newly diagnosed patients with acute myeloid leukemia (AML). Futhermore, with an aging population, more and more older AML patients were diagnosed in China. But the treatment approaches of this disease were variable, with many uncertainties and controversies. Treatment options for older patients with adverse prognostic features, such as poor performance status, unfavorable cytogenetics or an antecedent hematologic disorder were limited, and outcomes were poor. Aggres­sive induction chemotherapy had a high mortality and relatively low efficacy in this population. There were several new therapeutic schemes for older patients with AML. CAG regimens consisting of low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor for the treatment of older patients with AML showed higher rates of CR (42-68%). Decitabine, a DNA-hypomethylating agent induces differentiation and apoptosis of leukemic cells. The current National Comprehensive Cancer Care guidelines suggested decitabine as alterative options for older patients with AML. Previous studies have shown that decitabine demonstrated efficacy in a phase II multicenter study of older patients with AML, with a CR rate of 25%, 30-day mortality of 7%, median overall survival 7.7 months and little extramedullary toxicity. In our study, decitabine(15 mg/m2/d, d1-5) combined with CAG regimens (aclarubicin 20 mg/d, d3-6, Ara-C 10 mg/m2, q12h, d3-9, G-CSF 300ug, qd, d1-9) treated 27 older patients with AML, repeated every 4 weeks. Effectiveness and safety were assessed.27 older patients with newly diagnosed AML who were in Tianjin First Central Hospital of China from January 2011 to December 2013 were enrolled in our study. They were all treated with decitabine combined with CAG regimens. The characteristics of the 27 patients were described in Table I. The study population included 15 males and 12 females, with a median age of 68 years (range 60-79 years). All patients had Eastern Cooperative Oncology Group (ECOG) performance status of <3. Cytogenetics were classified according to criteria of the Cancer and Leukemia Group B(CALGB), and were adverse in 11 patients (40.7%) and intermediate in 16 patients (59.3%). No patient had favorable cytogenetics. 12 patients (44.4%) had secondary AML or an antecedent MDS or myeloproliferative disorder. Molecular diagnostics with mutations of FLT3-ITD in 6 patients (22.2%), NPM1 in 7 patients (25.9%) patients and JAK-2 in 4 patients (14.8%). Clinical responses, survival and adverse events of all 27 patients were analyzed. The median treatment cycle was 4 cycles. Rate of complete remission, overall response rate and a 30-day mortality rate were 40.1%, 66.7%, 7.4%, respectively. The median overall survival and median recurrence-free survival were 13.0months (95%CI, 7.0-18.0 months ) and 7.0 months (95%CI, 3.0-11.0 months), respectively. Adverse events in the regimens were mainly included myelosuppression, infection, nausea, vomiting and liver dysfunction. The adverse events could be well tolerated after managements.In conclusion, the treatment of decitabine combined with CAG regimens was found to be feasible and useful in high-risk older patients with AML. This regimen was a well-tolerated therapeutic alternative, was effective in producing remissions lasting several months or disease stabilization in high-risk older patients with AML.Table 1The characteristics of newly diagnosed patients with AMLTotal number of patients n=27median age(range)68 years(60-79 years)Male/female15/12 (1.25/1)ECOG performance status, n (%)05 (18.5%)110 (37.0%)212 (44.4%)Cytogenetics, n (%)Adverse 11 (40.7%)Intermediate16 (59.3%)secondary AML, n (%)MDS6 (22.2%)myeloproliferative5 (18.5%)Other tumors1 (3.7%)Molecular mutations, n (%)FLT3-ITD6 (22.2%)NPM17 (25.9%)JAK-24 (14.8%) DisclosuresNo relevant conflicts of interest to declare.

Bortezomib + MEC (Mitoxantrone, Etoposide, Cytarabine) for Relapsed/ Refractory Acute Myeloid Leukemia: Final Results of an Expanded Phase 1 Trial

MEC (mitoxantrone, etoposide, cytarabine) is a standard regimen for relapsed/ refractory (R/R) acute myeloid leukemia (AML), but outcomes remain poor. The overexpression of proteasomes and constitutive activation of NF-KB in AML cells suggest that proteasome inhibitors (PI) such as bortezomib (Bz) may be effective anti-leukemia therapy. PI or a decoy NF-KB oligonucleotide increase chemosensitivity to both anthracyclines and cytarabine. To test the hypothesis that PI may improve the efficacy of MEC, we conducted a phase 1 trial of Bz in combination with MEC. Here, we present final results of this trial: response rate, toxicity, and correlation of outcomes with mutation analysis. As CD74 expression may identify a subset NF-KB-dependent AML with predicted increased sensitivity to PI (Clin Can Res 2008; 14: 1446-54), we also explored this correlation.Methods: All pts were treated at the Cleveland Clinic from Aug 2010-Mar 2014. This protocol was approved by the institution’s review board. Eligibility included: age 18-70 yrs, R/R AML, cardiac ejection fraction ≥ 45%. CD74 was assessed by flow cytometry using CD45 PE (BD Biosciences San Jose, CA) and CD74-Alexa 488 (AbD Serotec Raleigh, NC). A myeloid panel mutational analysis was performed on extracted DNA in pts with banked samples (n=26). All pts received 1 cycle of MEC: mitoxantrone (6 mg/m2/d), etoposide (80 mg/ m2), and cytarabine (1000 mg/ m2) Days 1-6. Bz was administered IV on Days 1, 4, 8, and 11. Dose was escalated using a standard 3 x 3 design. Dose levels (DL) were: -1 (0.40 mg/ m2), 1 (0.70 mg/ m2), 2 (1.0 mg/ m2), and 3 (1.3 mg/m2). Response was defined by IWG criteria (Cheson, 2006). The maximum tolerated dose (MTD) of Bz with MEC was 1.0 mg/m2 (Advani et al, ASH 2012, Abstract 3595).Results: Of 35 pts enrolled, the median age was 55 yrs (range 33-69), 13 (38%) were male, and median baseline WBC was 4.0 K/ µL (range 0.82-84.7). The median time from initial diagnosis of AML to enrollment was 8.4 months (range 1.1-88.2) and 6 pts (17%) had an antecedent hematologic disorder. Salvage status (S) at enrollment: S1 (24 pts, 69%), S2 (7 pts, 20%), S4 (4 pts, 11%). Nine pts (26%) were refractory to all prior therapies, and 3 pts (9%) had received prior allogeneic hematopoietic cell transplant (AHCT). Adverse cytogenetics per CALGB/ Alliance 8461 criteria occurred in 19% of pts at study entry and 15 of 26 pts (58%) had poor-risk molecular mutations (RUNX1, ASXL1, TET2, p53, IDH1, MECOM, FLT3 ITD). Ten pts were enrolled on DL1, 13 pts on DL2, 11 pts on DL3, and 1 pt died prior to treatment. Overall, 3 pts (9%) died during induction. In addition to febrile neutropenia and Gr 4 hematologic toxicity, the most commonly reported adverse events (AEs) were metabolic, constitutional, gastrointestinal (GI), and dermatologic, with the majority of these being Gr 1 or 2. GI toxicity was the only reported AE attributable to Bz: 12 pts had constipation or ileus (10: Gr 1 or 2; 2: Gr 3 or 4). Seventeen of the 33 evaluable pts (52%) have achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi); with 1 pt inevaluable due to donor lymphocyte infusion. The estimated median overall survival was 7.2 months; median duration of response was 10.3 months. DL did not correlate with response. Eleven pts (32%) went on to receive AHCT. Among pts with poor-risk molecular mutations, 64% achieved CR/ CRi. Inhibition of NF-KB signaling in leukemia cells with mutated RUNX1 efficiently blocks growth and development of leukemia (Blood 2011; 118: 6626-37). Of the 5 pts with RUNX1 mutations, 3 (60%) achieved CR/ CRi, suggesting that Bz may have promising clinical benefit in this difficult subset of pts. Among the 17 pts with CD74 expression testing who were evaluable for response, the mean CD74 expression trended higher in non-responding pts (32.6%) than in responders (11.1%) (p=0.14).Conclusions: The combination of MEC/Bz was well-tolerated and resulted in high response rates, even within a molecularly-defined poor risk population of pts with R/R AML. Our data do not confirm the expectation that higher CD74 expression would correlate with response in this R/ R AML cohort, but larger pt numbers are needed. These results, especially in pts with poor-risk mutations, support development of a randomized study to address the benefit of adding Bz to MEC in the treatment of R/R AML. DisclosuresAdvani:Takeda: Research Funding. Carew:Takeda: Research Funding. Sekeres:Celgene Corp.: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity’s Board of Directors or advisory committees.

Time to Complete Remission As a Function of Kinetics of White Blood Cell Elimination and Recovery in Acute Myeloid Leukemia Patients Undergoing Remission Induction Chemotherapy

Background: While achieving complete remission (CR) is a major treatment milestone in acute myeloid leukemia (AML) patients (pts) undergoing induction chemotherapy (IC), it is the time to achieve CR (Tc) that has greater prognostic value in predicting subsequent survival. We are particularly interested in seeing whether trends in white blood cell (WBC) count elimination and recovery during induction phase can aid in prediction of Tc, thus enabling real-time prognostication.Methods: Adult pts diagnosed with AML (excluding acute promyelocytic leukemia) at the Cleveland Clinic from 10/08 - 11/12 who underwent IC with 7+3 (cytarabine and anthracycline) and achieved CR were included. Pretreatment variables including age, gender, race, smoking status, body mass index at dx, peripheral blood counts at diagnosis (dx), peripheral and marrow blasts at dx, disease classification and metaphase cytogenetics (per CALGB/Alliance 8461 criteria) were assessed. For mapping WBC elimination and recovery kinetics, we collected data on total WBC, absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) at several different time points after IC – day 1, day 7, day 14 (range, 13-17), day 21, day 35 (range 30-45) and the day CR was achieved. Time intervals selected for analysis included time taken for clearance of peripheral circulating blasts; time to reach nadirs for WBC, ANC and ALC; and time to ANC recovery (from ANC nadir to > 500/µL). Tc was assessed as a function of WBC, ANC and ALC measurements (at the above predefined time points); time intervals; and magnitude of drop and rise in WBC, ANC and ALC (log reductions and improvements in counts) using multivariable logistic and Cox proportional hazards models and stepwise regression using Akaike’s Information Criterion (AIC) for model selection. Due to multiple testing, parameters are reported as significant if p<0.01. Cell counts and time interval metrics were also analyzed as a function of pretreatment covariates using standard linear regression.Results: Of 80 pts, 58% (n=46) were female, 79% (n=63) were Caucasian, 68% (n=54) were younger than 60 years, the median age at treatment was 53.5 years (range, 19 to 77) & 18% (n=14) received 2 cycles of induction therapy. Twenty one pts (26%) had secondary AML. Disease characteristics (per WHO classification) were – AML with recurrent cytogenetic abnormalities 31% (n=25), secondary AML 27% (n=22), therapy-related AML 6% (n=5), AML not otherwise specified 34% (n=26), myeloid sarcoma 1% (n=1) and unknown 1% (n=1). Cytogenetic risk groups per CALGB 8461 were – favorable 19% (n=15), intermediate 53% (n=42), unfavorable 23% (n=18), & unknown cytogenetics (n=5). In the final model of a multivariable stepwise regression analysis, none of the cell counts at the defined time points of IC predicted for Tc. Of pretreatment covariates, only male sex correlated slightly with longer Tc (p=.04). Longer times to reach ANC (p=.01) and ALC (p=.03) nadirs had borderline correlations with longer Tc. In contrast, longer times to reach ANC > 500/µL was significantly associated with delayed Tc (p<<.001). Greater fold change drop and rise in ANC counts correlated with Tc but was not significant at the p<.01 level.Conclusions: In this study the only WBC cell kinetic parameter post IC that independently predicted Tc was time to ANC recovery, which seems intuitive. Biologically, this could represent resiliency of the underlying hematopoietic stem cell reserve which is a function of age, prior therapies or antecedent hematologic disorder. Interestingly, in our series, WBC kinetics did not correlate with the number of induction cycles required (1 vs. 2), age (using age cut-offs of 60 and 70 years) or body mass index. Although the concept of using WBC kinetics during IC as a clinical surrogate for chemotherapy responsiveness or toxicity (overdosing vs. underdosing) is appealing, it is not supported by our data. DisclosuresSekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen Corp: Membership on an entity’s Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity’s Board of Directors or advisory committees. Mukherjee:GlaxoSmithKline: Research Funding.

Results of a Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients (Pts) with Activating FLT3 Mutations

IntroductionFLT3-ITD (Internal tandem duplication) and FLT3-TKD (tyrosine kinase domain, D835) mutations are frequently seen in AML; FLT3-ITDs are associated with inferior survival. Development of FLT3-TKD mutation during FLT3 inhibitor-therapy is seen in up to 22% of patients and associated with FLT3 tyrosine kinase inhibitor (TKI) treatment failure (Cancer 2014). Crenolanib besylate is an orally bioavailable TKI with activity against both FLT3-ITD and FLT3-TKD mutations. We evaluated the clinical efficacy of crenolanib in relapsed/refractory AML pts with activating FLT3 mutations.MethodsThis was a single center phase II open label study of crenolanib administered at 200 mg/m2/day three times a day continuously in 28 day cycles. FLT3 mutated pts (either FT3-ITD or FLT3-TKD) with primary AML, therapy-related AML and AML following an antecedent hematological disorder were included. Pts were ≥18 years of age with ECOG PS of 0-2. Pts with CNS disease were excluded. Pts relapsing post-allogeneic stem cell transplant could be included if they were >30 days post-transplant. 38 pts enrolled in 2 parallel cohorts of which 34 were evaluable, 13 in cohort A (FLT3 TKI-naïve) and 21 in cohort B (progressed on prior FLT3 TKI).ResultsMedian age was 61 (30 – 87). Patients had undergone a median of 3.5 prior therapies (range 1 – 8); 38% of pts had diploid and 23% complex cytogenetics. Among patients with available information, NPM1 mutation was identified in 62% (10/16) and DNMT3A in 57% (8/14). Median baseline marrow blast % was 58% (7 – 97%). Of cohort B patients, prior therapy was sorafenib in 57%, quizartinib in 14%, PLX3397 in 5% and midostaurin in 10%. 9% and 5% had received 2 and 3 FLT3 TKIs, respectively. 10 enrolled patients had progressed post-transplant (SCT) (3 allogeneic in cohort A; 6 allogeneic, 1 autologous in cohort B). Median duration of study therapy was 9 wks (range 5 – 24), 2 pts remain on study. Reasons for study cessation were disease progression in 66%, no response in 16%, toxicity in 6%, clinical deterioration due to other co-morbidities in 6%, 3% lost to follow up and 3% to receive SCT. At a median follow up of 14 weeks (wks), ORR was 47%: 12% achieved complete response with incomplete count recovery (CRi), 32% hematological improvement (Hi) (85% of them with >50% decrease in blast count) and 3% morphologic leukemia-free state (MLFS). 21% had progressive disease and 32% no response.The median event-free survival (EFS) was 8 wks and overall survival (OS) was 19 wks for the whole cohort. The response by cohort was:TableFLT3 TKI naïvePrior FLT3 TherapyResponse %CRi235MLFS80Hi3133NR3133PD829Median OS55 wks13 wks (p=0.027)Median EFS13 wks7 wks (p<0.001)Pts achieving marrow response (CRi and MLFS) had superior EFS (median 22 wks vs 8 wks for non-responders, p=0.003), with a trend toward superior OS for the marrow responders (median 55 weeks versus 15 wks, p=0.166). 2 of the 4 pts with FLT3-TKD in cohort A responded (CRi, Hi). Among pts with both mutations, 1/1 pt in cohort A achieved CRi and 5/6 pts in cohort B achieved Hi.EFS and OS were not influenced by complex cytogenetics, number of prior therapies or the presence of NPM1 or DNMT3A mutations. OS and EFS were, for patients with ITD (19 wks; 7 wks), D835 (6 wks; 8 wks) or both FLT3 mutations (12 wks; 9 wks), p=0.908; 0.391 respectively.The main grade 3 toxicities were GI side effects (abdominal pain and nausea). There was no death attributed to treatment related toxicity.ConclusionsCrenolanib is a well-tolerated FLT3 TKI with clinical efficacy in heavily pre-treated, relapsed/refractory FLT3 mutated AML patients. The superior results in FLT3 inhibitor-naïve patients suggests that on-target FLT3 inhibition is likely primarily responsible for drug efficacy. Combination therapy (e.g., with chemotherapy or hypomethylating agents) could potentially provide additive efficacy in both treatment-naïve and relapsed/refractory pts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Phase I Trial of Targeted Alpha-Particle Therapy Using Actinium-225 (225Ac)-Lintuzumab (Anti-CD33) in Combination with Low-Dose Cytarabine (LDAC) for Older Patients with Untreated Acute Myeloid Leukemia (AML)

Background: Lintuzumab, a humanized anti-CD33 monoclonal antibody, targets myeloid leukemia cells but has only modest activity in AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity of β-emitting isotopes, 225Ac (t½=10 d), a radiometal that yields 4 α-particles, was conjugated to lintuzumab. A phase I trial showed that 225Ac-lintuzumab is safe at doses ≤ 3 µCi/kg and has anti-leukemic activity across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose-escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC.Patients and Methods: Patients ≥ 60 yrs who had untreated AML with poor prognostic factors, e.g., an antecedent hematologic disorder, unfavorable cytogenetic or molecular abnormalities, and significant comorbidities, were eligible. Patients received LDAC 20 mg twice daily for 10 d every 4-6 wks for up to 12 cycles. During Cycle 1, beginning 4-7 days after completion of LDAC, two doses of 225Ac-lintuzumab were given approximately one week apart. To prevent radiation-induced nephrotoxicity, patients were given furosemide while receiving 225Ac-lintuzumab and spironolactone for one year afterward.Results: Nine patients (median age, 76 yrs; range, 73-81 yrs) were treated. Seven patients (78%) had a history of myelodysplastic syndromes (MDS), for which five (56%) received prior therapy with hypomethylating agents (n=4) or allogeneic hematopoietic cell transplantation (n=1). One patient (11%) had chronic myeloid leukemia in a molecularly undetectable state at the time of AML diagnosis. Six patients (67%) had intermediate-risk cytogenetics, and three (33%) had unfavorable cytogenetics. The median CD33 expression was 76% (range, 45-100%). Patients received 225Ac-lintuzumab at doses of 0.5 (n=3) or 1 (n=6) μCi/kg/fraction. Total administered activity ranged from 68-199 μCi. The median number of cycles administered was 2 (range, 1-4). Dose-limiting toxicity was seen in one patient receiving 1 µCi/kg/fraction who had grade 4 thrombocytopenia with bone marrow aplasia persisting > 6 wks after receiving 225Ac-lintuzumab. Hematologic toxicities included grade 4 neutropenia (n=1) and thrombocytopenia (n=3). Grade 3/4 non-hematologic toxicities included febrile neutropenia (n=6), pneumonia (n=2), bacteremia (n=1), cellulitis (n=1), transient increase in creatinine (n=1), hypokalemia (n=1), and generalized weakness (n=1). Bone marrow blast reductions were seen in 5 of 7 patients (71%) evaluated after Cycle 1. Mean blast reduction was 61% (range, 34-100%). Three of the 7 patients (43%) had marrow blast reductions of ≥ 50%; however, no remissions were observed. Median progression-free survival (PFS) was 2.5 mos (range, 1.7-15.7+ mos). Median overall survival (OS) from study entry was 5.4 mos (range, 2.2-24 mos). For the 7 patients with prior MDS, median OS was 9.1 mos (range 2.3-24 mos).Conclusions: Fractionated-dose 225Ac-linutuzmab in combination with LDAC is feasible, safe, and has anti-leukemic activity. Dose escalation continues to define the MTD, with planned doses up to 2 µCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, PFS, and OS. DisclosuresRavandi:Actinium Pharmaceuticals, Inc.: Research Funding. Pagel:Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding. Park:Actinium Pharmaceuticals, Inc.: Research Funding. Wahl:Actinium Pharmaceuticals, Inc.: Research Funding. Earle:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Equity Ownership, Research Funding.

A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Background: Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Although cytarabine arabinoside (AraC) is the most active drug, constituting the backbone of a majority of r/r regimens, the benchmark response to therapy remains a dismal 17 to 20% (Burnett, Wetzler et al. JCO, 2011.). The immunomodulatory drug lenalidomide (Len), is approved by the Food and Drug Administration for multiple myeloma and myelodysplasia and has demonstrated activity as a single agent in AML at doses as high as 50 mg for 21 days (d) of a 28 d cycle (Blum et al, JCO, 2010.). Based upon this activity profile we developed a phase I study to evaluate the safety and tolerability of Len in combination with AraC in patients with r/r AML.Methods: Eligible patients were older than 18 years(y), had r/r AML with an Eastern Cooperative Oncology Group performance status better than 2 and adequate renal and hepatic function. Patients were excluded for active CNS disease, uncontrolled infections, congestive heart failure, adrenal insufficiency, anti-cancer therapy within 14 d of enrollment, or prior exposure to Len. All enrolled patients had to practice appropriate contraception. Patients received AraC 1.5 g/m2/d over 3 hours on d 1-5 of a 28 day cycle, with a plan for standard 3+3 Len dose escalation. Initial patients received Len 25 mg on d 6-10 (n= 3), subsequent patients received doses between 25 and 10 mg (dose de-escalation) on d 6-26 with 2 d of rest prior to the next cycle. Following induction, patients who had residual AML (>5%) could receive a second identical course of therapy, provided they demonstrated an improvement in blast percentage relative to baseline. Patients who achieved CR received maintenance with Len 10 mg/d continuously. A 12 patient expanded cohort was enrolled at the maximum tolerated dose (MTD) to assess efficacy. Responses were assessed by International Working Group Criteria for AML (Cheson B et al. JCO, 2003.).Patient Characteristics: Fifty-one patients were consented and 45 were treated on study, 32 of these were evaluable for response, all patients were evaluated for toxicity. Approximately half the patients were female (20/45). The median age was 66 y (range 33-82) and median WBC 2.42x109/L (range 0.18-63.15). Four patients (8%) had an antecedent hematological disorder. By European LeukemiaNet criteria 2 patients (4%) had favorable risk disease, 8 (18%) were Int-1, 12(27%) were Int-2 and 11 (24%) were adverse risk; 12(27%) patients were not evaluable by ELN due to lack of karyotype or molecular data from diagnosis. Twelve patients had primary refractory AML.Results: The MTD for Len given on d 6-26 in combination with AraC at 1.5 g/m2/d x 5 d was 10 mg. Dose de-escalation from the starting dose of 25 mg on this schedule was required due to excess toxicity. The most commonly observed non-hematologic drug related adverse events seen on the study (all < grade 2 unless indicated) were nausea, increased liver function tests (>grade 3), rash (grade >3), hypokalemia (> grade 3) and fatigue. At the 25 mg dose level the dose limiting toxicity was rash, while patients enrolled at the 15 mg dose level experienced dose limiting elevation in LFTs, fatigue and bleeding. Five patients achieved a CR (16%), 5 demonstrated CRi (16%) and there were 3 hematological improvements (HI) for an overall response rate (CR+Cri+HI) of 41% (13/32). The median overall survival (OS) (95% confidence interval) for patients treated on study was 5.8 (2.5, 10.6) months and disease free survival was 3.4 (2.3, 6.2) months.Conclusions: Although prior interesting data support the activity of single agent high dose Len in r/r AML, our single institute phase I study of intermediate dose AraC followed by Len was associated with marked skin and other toxicities at the Len 25 mg dose level, precluding dose escalation to the historically more active 50 mg dose. The CR rate in this study was not dissimilar to previously reported responses with single agent or combination AraC based regimens. Issues of dose and schedule for this combination may have had a significant impact on the potential benefit for these two drugs in combination. Nevertheless, the overall low CR rate from this study does not suggest any superiority for this combination in comparison with the historical single agent response rate for intermediate dose AraC in r/r AML. DisclosuresGriffiths:Celgene, Incyte and Alexion: Honoraria; Astex Pharmaceuticals: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Other. Wetzler:MedPace: Consultancy; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Plexus: Consultancy; Celgene: Research Funding.

Chemotherapy in Elderly Patients with Acute Myeloid Leukemia (AML): Analysis of Socioeconomic Factors Using National Cancer Data Base (NCDB)

Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults, accounting for approximately 35% of leukemia in United States (CA Cancer J Clin 2014;64(1):9-29). The use of chemotherapy is associated with significant survival benefit in AML, particularly young and fit individuals. Although survival rates have improved remarkably in the younger age group, the prognosis in older patients continues to be poor. The receipt of chemotherapy has a potential to alter the prognosis in elderly AML patients, however, many older patients may not be able to receive chemotherapy. We analyzed the trend in chemotherapy use in AML patients ³60 years using NCDB to understand the socioeconomic determinants of chemotherapy use.Methods: This is a retrospective study of AML patients (n= 99,664) diagnosed between 2000 and 2011 in the NCDB hospitals. NCDB contains approximately 70% of new cancer diagnosis in the United States and Puerto Rico. Chi-square test was used to determine any differences in characteristics of AML patients 60 years or above who did or did not receive systemic therapy.Results: Nearly 61% of AML patients were 60 years or above (n= 60,477), however, chemotherapy use was significantly lower in these patients than those below 60 years (57% vs 70%, p < .0001). In patients 60 years or above, males were more likely to receive chemotherapy than females (59% vs 55%; p < .0001) (Table 1). While their use was higher at academic vs. non-academic hospitals (67% vs 51%; p < .0001), presence or absence of other comorbidities in these patients also determined its use (55% vs 60%, p < .0001). However, race, education or household income did not significantly affect chemotherapy use in the elderly population.Conclusions: AML predominantly affects patients more than 60 years of age (Cancer. 2006;107(9):2099-107). The factors negatively influencing treatment outcomes, including poor performance status, the presence of comorbidities, adverse cytogenetics and antecedent hematologic disorders are more common in this subset of population (Blood research. 2014;49(2):95-9). The management of elderly AML patients is complex and requires good understanding of risks and benefits of chemotherapy in individual patient. Our study demonstrates that the chemotherapy use in elderly patients is lower than younger patients and differ by patients’ gender, type of hospital and the presesnce of comorbidties. Understanding the health care disparities can help individualize and optimize cancer treatment leading to better quality of care in patients expected to have poorer outcomes.Table 1Pattern of chemotherapy use in patients 60 years or above with AMLParameterPercent of cases receiving chemotherapyp-valueGender<.0001Male59Female55Race0.3677White57Black57Hispanics59Education (% with high school degree)0.8611³ 88%5770-88%57< 69%57Income0.0909< $28,00056$28,000 to $48,99957³ $49,00058Comorbidity<.0001None60³ 155Treatment Facility<.0001Academic Hospital67Other Hospitals51 DisclosuresNo relevant conflicts of interest to declare.

Phase II Study of Cladribine and Low-Dose Cytarabine (AraC) Alternating with Decitabine in Older Patients with Acute Myeloid Leukemia (AML)

BackgroundIntensive chemotherapy is associated with poor tolerability and high early mortality in the treatment of AML in older patients. Lower intensity approaches using hypomethylating agents have been developed in patients with lower bone marrow (BM) blast counts, but more effective therapies are needed, particularly in those with higher BM blasts. Cladribine, which itself may have hypomethylating properties, has single-agent activity in AML. Cladribine has also been shown to improve survival in AML in combination with standard-dose araC (Holowiecki JCO 2012).MethodsWe developed a low-intensity, prolonged-maintenance treatment protocol studying the combination of cladribine and low-dose araC (LDAC) alternating with decitabine in patients aged ≥ 60. Patients with adequate organ function and newly diagnosed AML (except APL), including secondary- (s-AML) and therapy-related AML (t-AML), and high risk MDS were eligible. Induction consisted of cladribine 5 mg/m2 IV over 30 minutes on days 1-5 followed by araC 20mg SQ BID on days 1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV over 30 minutes on days 1-3 + araC 20 mg SQ BID on days 1-10 alternating with 2 cycles of decitabine 20 mg/m2 on days 1-5, for a maximum of 18 cycles. One cycle was 4 weeks and up to 2 cycles of induction were allowed.ResultsA total of 74 patients have been enrolled with a median age of 69 years (range, 49-85), including 33 pts (45%) ≥ age 70. 41 pts (55%) had secondary- (s-AML) or therapy-related AML (t-AML) and 14 pts (19%) had therapy for an antecedent hematologic disorder. Patient characteristics are listed in table 1. Of the 74 pts evaluable for response, there were 42 CR (57%), 6 CRp (8%), and 3 PR (4%) for an overall response rate of 69% (51/74). 43 patients (58%) had BM blasts ≥ 30%, and they had a CR/CRp rate of 67%. Of the 43 patients who achieved a CR/CRp and had minimal residual disease testing (MRD) by flow cytometry, 28 patients (65%), achieved MRD negativity at the time of CR or later. AML mutation screening was performed prior to treatment. Ten of 10 patients (100%) with FLT3-mutated AML and 13/13 (100%) pts with an NPM1 mutation achieved a CR/CRp. With a median follow-up of 11+ months, the median OS is 12.7 months and the median CR duration is 13.1 months. (Figure 1) The 1-year OS estimate is 57%. The regimen was very well tolerated, with 1% 4-week mortality. There were no treatment-related grade 3/4 non-hematologic adverse events (AEs). Most common non-hematologic AEs were elevated bilirubin, nausea/vomiting, rash/itching, diarrhea and mucositis.ConclusionThe low intensity program of cladribine + LDAC alternating with decitabine is a highly effective, well-tolerated ambulatory regimen for older patients, including those with unfavorable-risk features. Patient samples are being analyzed for methylation changes on treatment.Table 1Patient Characteristics (N=74)CharacteristicN (%)Median age [Range]69 [49-85]CytogeneticsDiploid21 (28)Adverse30 (41)-5/-723 (31)Complex without -5/-77 (9)Misc. other17 (23)Insufficient6 (8)MutationsNPM113/69 (19)FLT3-ITD8/69 (12)RAS15/69 (22)Median BM Blast [Range]32 [8-95]Median WBC [Range]2.5 [0.5-72.3]Median Platelets [Range]40 [4-772]Median Peripheral Blasts [Range]6 [0-88]Median LDH [Range]742 [301-8425]Median Creatinine [Range]0.91 [0.46-1.94]Median Bilirubin [Range]0.6 [0.2-2] [Display omitted] DisclosuresKantarjian:ARIAD, Pfizer, Amgen: Research Funding.

Hypocellular acute leukemia: study of clinical and hematological features

Hypocellular acute leukemia was previously referred to as smoldering leukemia. This is currently defined as having ≥20 % blasts in peripheral blood or bone marrow with cellularity of less than 20 % in bone marrow biopsy at presentation. Hypocellular variants of acute myeloid leukemia (AML) are commoner than that of acute lymphoid leukemia (ALL). They may pose a diagnostic challenge to the treating clinician and pathologist as they can simulate hypoplastic myelodysplastic syndrome and aplastic anemia. It is of utmost importance to distinguish these overlapping disorders as treatment modalities differ. Details of clinical features, complete blood counts, bone marrow aspirate findings, percentage cellularity, pattern of infiltration in trephine biopsies, and immunophenotyping by flow cytometry or immunohistochemistry were analyzed in cases diagnosed as hypocellular acute leukemia. Hypocellular acute leukemia constituted 2.5 % (8/316) of all diagnosed cases of acute leukemia during the study period. Seven of the eight cases of hypocellular acute leukemia were hypocellular AML while one was hypocellular ALL. Median age of patients was 45 years, with a male:female ratio of 1.7:1. Mean duration of symptoms was 1.2 months, with most common presenting feature being fever. None of the patients except one had an antecedent hematologic disorder or chemotherapy or radiotherapy. Hypocellular acute leukemia is important to recognize from other overlapping disorders. Clinical parameters and laboratory data including immunophenotyping can aid in distinguishing them.

Abstract CT307: Phase I/II study of vosaroxin and decitabine in older patients (pts) with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS)

Abstract Background: Vosaroxin (formerly voreloxin), is a quinolone derived DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein and has limited toxicity; it is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ≥ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. The treatment regimen included vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. Vosaroxin dose was reduced to 70 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the complete remission (CR) rate. Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 12 pts (9 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-76) have been enrolled; 11 were older than 60 years. They included 6 (50%) pts with diploid cytogenetics, 4 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 2 (16%) with other miscellaneous abnormalities. 4 (34%) pts with AML had antecedent hematological disorders (AHD) including 1 (8%) with MDS, 1 (8%) with myeloproliferative neoplasm and 2 (17%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1) and lenalidomide (n=1). RAS mutations were identified in 4 (34%) and IDH2 mutations in 2 (16%) pts. Median bone marrow blast %, median white blood cell, hemoglobin, &amp; platelet counts were 29% (11-73), 3.7 x 109/L (1.0-127.1), 9.5 g/dL (8.2-10.8), and 92 x 109/L (11-361), respectively. 9 pts were evaluable for response; 5 (42%) achieved CR, 1 (8%) CRp, and 2 (17%) CRi, for an overall response rate of 89%. 1 pt had no response after cycle 1 and is currently undergoing re-induction. Three are too early for response assessment. Pts have received a median of 2 (1-3) treatment cycles with median number of cycles to response being 1 (1-2) and median time to achieving response, 26 days (21-74 days). The median duration of CR/CRp/CRi is 53+ days (6-89+ days). One pt has proceeded to allogeneic stem cell transplant. No pts died during induction. One pt died on study on day 47 from sepsis and acute myocardial infarction. The regimen is well tolerated with the main grade ≥ 3 toxicity being mucositis in 3 (25%) pts. Conclusion: Combination of vosaroxin and decitabine is effective and well tolerated in older patients with AML and high-risk MDS. Enrollment is ongoing. Citation Format: Naval Daver, Hagop M. Kantarjian, Guillermo Garcia - Manero, Naveen Pemmaraju, Tapan Kadia, Courtney DiNardo, Nitin Jain, Gautum Borthakur, Jorge Cortes, Craig Adam, Farhad Ravandi. Phase I/II study of vosaroxin and decitabine in older patients (pts) with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT307. doi:10.1158/1538-7445.AM2014-CT307